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    Clinical Trial Results:
    A Randomized, double-blind, cross-over study to assess erenumab effect on brain networks function and structure in comparison to placebo in episodic migraine patients (RESET BRAIN)

    Summary
    EudraCT number
    		 2018-004875-11
    Trial protocol
    		 IT  
    Global end of trial date
    05 Jul 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Jul 2022
    First version publication date
    16 Jul 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CAMG334AIT03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03977649
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG  , 41 613241111, Novartis.email@Novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG  , 41 613241111, Novartis.email@Novartis.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
    05 Jul 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jul 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective was to evaluate whether the prophylactic treatment of a cohort of episodic migraine patients for 3 months with erenumab was able to produce significant changes versus placebo in the functional recruitment and connectivity of multisensory processing areas and, as such, modulate the dysfunctional pain network (chosen as primary area of interest) in the CNS of these patients.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 May 2017
    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: 61
    Worldwide total number of subjects
    61
    EEA total number of subjects
    61
    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)
    61
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 There were 70 participants screened for the trial and 61 randomized.

    Period 1
    Period 1 title
    Overall Study
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Erenumab Sequence 1
    Arm description
    		 Erenumab 140 mg administered subcutaneously every 4 weeks for 12 weeks (2 syringes/70mg/mL)
    Arm type
    		 Experimental

    Investigational medicinal product name
    erenumab
    Investigational medicinal product code
    AMG334
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    140 mg administered monthly as 2 syringes of 70mg/mL

    Arm title
    		 Placebo Sequence 1
    Arm description
    		 Matching placebo every 4 weeks for 12 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    AMG334
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Matching placebo administered monthly as 2 syringes

    Arm title
    		 Erenumab - Sequence 1 and 2
    Arm description
    		 All participants who received erenumab in either sequence
    Arm type
    		 Experimental

    Investigational medicinal product name
    erenumab
    Investigational medicinal product code
    AMG334
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    140 mg administered monthly as 2 syringes of 70mg/mL

    Arm title
    		 Placebo - Sequence 1 and 2
    Arm description
    		 All participants who received placebo in either sequence
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    AMG334
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Matching placebo administered monthly as 2 syringes

    Number of subjects in period 1
    		Erenumab Sequence 1 Placebo Sequence 1 Erenumab - Sequence 1 and 2 Placebo - Sequence 1 and 2
    Started
    30
    31
    59
    57
    Completed
    26
    28
    59
    57
    Not completed
    4
    3
    0
    0
         COVID-19 pandemic
    2
    -
    -
    -
         Adverse event, non-fatal
    1
    1
    -
    -
         Subject/Guardian Decision
    1
    2
    -
    -
    Period 2
    Period 2 title
    Sequence 1
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Erenumab Sequence 1
    Arm description
    		 Erenumab 140 mg administered subcutaneously every 4 weeks for 12 weeks (2 syringes/70mg/mL)
    Arm type
    		 Experimental

    Investigational medicinal product name
    erenumab
    Investigational medicinal product code
    AMG334
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    140 mg administered monthly as 2 syringes of 70mg/mL

    Arm title
    		 Placebo Sequence 1
    Arm description
    		 Matching placebo every 4 weeks for 12 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    AMG334
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Matching placebo administered monthly as 2 syringes

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 is also included in the Overall Period
    Number of subjects in period 2
    		Erenumab Sequence 1 Placebo Sequence 1
    Started
    30
    31
    Completed
    26
    28
    Not completed
    4
    3
         COVID-19 pandemic
    2
    -
         Adverse event, non-fatal
    1
    1
         Subject/Guardian Decision
    1
    2

    Baseline characteristics

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

    Reporting group values
    		 Sequence 1 Total
    Number of subjects
    		 61 61
    Age Categorical
    Units:
        Between 18 and 65 years
    		 61 61
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 45.4 ( 9.94 ) -
    Sex: Female, Male
    Units:
        Female
    		 53 53
        Male
    		 8 8
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 60 60
        Pacific Islander
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    Erenumab Sequence 1
    Reporting group description
    		 Erenumab 140 mg administered subcutaneously every 4 weeks for 12 weeks (2 syringes/70mg/mL)

    Reporting group title
    Placebo Sequence 1
    Reporting group description
    		 Matching placebo every 4 weeks for 12 weeks

    Reporting group title
    Erenumab - Sequence 1 and 2
    Reporting group description
    		 All participants who received erenumab in either sequence

    Reporting group title
    Placebo - Sequence 1 and 2
    Reporting group description
    		 All participants who received placebo in either sequence
    Reporting group title
    Erenumab Sequence 1
    Reporting group description
    		 Erenumab 140 mg administered subcutaneously every 4 weeks for 12 weeks (2 syringes/70mg/mL)

    Reporting group title
    Placebo Sequence 1
    Reporting group description
    		 Matching placebo every 4 weeks for 12 weeks

    Subject analysis set title
    Erenumab – Sequence 1
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Erenumab 140 mg administered subcutaneously every 4 weeks for 12 weeks (2 syringes/70mg/mL)

    Subject analysis set title
    Placebo - Sequence 1
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Matching placebo every 4 weeks for 12 week

    Subject analysis set title
    Placebo - Sequence 1
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Matching placebo to erenumab every 4 weeks for 12 weeks

    Subject analysis set title
    Erenumab - Sequence 1
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Erenumab 140 mg administered subcutaneously every 4 weeks for 12 weeks (2 syringes/70mg/mL)

    Subject analysis set title
    Difference between Responder and Non-Responder - erenumab
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Erenumab 140 mg administered subcutaneously every 4 weeks for 12 weeks (2 syringes/70mg/mL)

    Subject analysis set title
    Difference between Responder and Non-Responder - placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Matching placebo every 4 weeks for 12 weeks

    Subject analysis set title
    All Patients
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Erenumab 140 mg administered subcutaneously every 4 weeks for 12 weeks (2 syringes/70mg/mL) or matching placebo

    Subject analysis set title
    Erenumab – Period 1
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Erenumab 140 mg administered subcutaneously every 4 weeks for 12 weeks (2 syringes/70mg/mL)

    Subject analysis set title
    Placebo - Sequence 1
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Matching placebo every 4 weeks for 12 weeks

    Subject analysis set title
    Erenumab + Placebo Sequence 1 Total
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Erenumab and placebo arms combined to analyze differences in increase of RS FCs

    Subject analysis set title
    Placebo + erenumab Sequence 1 Total
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Erenumab and placebo arms combined to analyze differences in increase of RS FCs

    Subject analysis set title
    Erenumab + Pacebo Sequence 1 Total
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Erenumab and placebo arms combined to analyze differences in increase of RS FC

    Subject analysis set title
    Placebo + erenumab Sequence 1 Total
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Erenumab and placebo arms combined to analyze differences in increase of RS FC

    Subject analysis set title
    Erenumab + Placebo Sequence 1 Total
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Erenumab and placebo arms combined to analyze differences in increase of RS FC

    Subject analysis set title
    Erenumab – Sequence 1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Erenumab 140 mg administered subcutaneously every 4 weeks for 12 weeks (2 syringes/70mg/mL)

    Primary: Significant resting state functional connectivity (RS FC) changes in the functional networks as measured by Magnetic Resonance Imaging (MRI)

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    End point title
    		 Significant resting state functional connectivity (RS FC) changes in the functional networks as measured by Magnetic Resonance Imaging (MRI) [1]
    End point description
    FC is the strength with which every area of the brain is connected with a reference area, constituting the seed region of the functional network. In total, 22 functional networks were constructed for this study. A voxel is the single 3-dimensional unit that embeds the strength of FC for each element of the image (in our case, of the brain). Larger numbers of voxel indicate wider regions of the brain showing differences of FC. Increased or decreased in the category description indicates an increase or decrease from baseline. FC maps were constructed starting from RS fMRI sequences. Structural MRI sequences (FLAIR, T2 and 3D T1 weighted scans) were also acquired. Abbreviations: N=Network, L=left, R=right, Cere=cerebellar(um), MFG=middle frontal gyrus, SMFG=superior medial frontal gyrus, DMN=Default mode network, ACC=anterior cingulate cortex, PCG=precentral gyrus, SMA=supplementary motor area,
    End point type
    Primary
    End point timeframe
    Baseline to Month 3
    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: Resting state (RS) functional Magnetic Resonance Imaging (fMRI) data from each study scan were pre-processed using the CONN toolbox. RS fMRI images were analyzed and reported using classical methodology used for fMR
    End point values
    		 Erenumab – Sequence 1
    Number of subjects analysed
    27
    Units: voxels
        Cerebellar N, Decreased RS FC, R Cere crus II
    73
        DMN, Increased RS FC in R MFG
    53
        DMN, Increased RS FC in L MFG
    95
        ault mode network II, Decreased RS FC in L ACC
    95
        Sec Vis network I, Increased RS FC in L PCG
    73
        L PAG network, Increased RS FC in L SMA
    90
        L pontine network, Increased RS FC in L Cere
    194
        L pontine network, Increased RS FC in R Cere
    72
        R PAG network, Increased RS FC in L Cere (crus I)
    154
        R pontine N, Increased RS FC in L Cere (crus I)
    113
        R thalamic network, Decreased RS FC in R insula
    58
    No statistical analyses for this end point

    Primary: Significant resting state functional connectivity (RS FC) changes in the functional networks for placebo

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    End point title
    		 Significant resting state functional connectivity (RS FC) changes in the functional networks for placebo [2]
    End point description
    FC is the strength with which every area of the brain is connected with a reference area, constituting the seed region of the functional network (FN). In total, 22 FNs were constructed for this study. A voxel is a single 3-dimensional unit that embeds the strength of FC for each element of the image (brain). Larger numbers of voxel indicate wider regions of the brain showing differences of FC. Increased or decreased in the category description indicates increase or decrease from baseline. FC maps were constructed starting from RS fMRI sequences. Structural MRI sequences (FLAIR, T2 and 3D T1 weighted scans) were also acquired. Abbrev: DMN=Default mode network, L=left, R=right, MTG=middle temporal gyrus, SFG=superior frontal gyrus, ECN=Executive control network, IFG=Inferior frontal gyrus, SuMG=supramarginal gyrus, Prim vis=Primary visual network. STG= superior temporal gyrus, PIG= parietal inferior gyrus, LPN= L pontine network, LTN=L thalamic network, RPN=Right pontine network.
    End point type
    Primary
    End point timeframe
    Baseline to Month 3
    Notes
    [2] - 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: Resting state (RS) functional Magnetic Resonance Imaging (fMRI) data from each study scan were pre-processed using the CONN toolbox. RS fMRI images were analyzed and reported using classical methodology used for fMR
    End point values
    		 Placebo - Sequence 1
    Number of subjects analysed
    27
    Units: voxels
        DMN II, decreased RS FC in L MTG BA=21
    95
        DMN II, decreased RS FC in R MTG BA=21
    140
        Default mode N II, decreased RS FC in L MTG BA=21
    56
        Default mode N II, decreased RS FC in R MTG BA=21
    55
        DMN II, decreased RS FC in R Precuneus
    53
        DMN II, decreased RS FC in R SFG
    53
        ECN, decreased RS FC in L precuneus
    129
        ECN, decreased RS FC in R IFG
    50
        Auditory network, increased RS FC in R SuMG
    55
        Auditory network, decreased RS FC in R cere
    53
        Auditory network, decreased RS FC in L cerebellum
    61
        Prim vis network, decreased RS FC in L hippocampus
    114
        Secondary visual network, decreased RS FC in L STG
    187
        Salience N, decreased RS FC in R lingual gyrus
    380
        Salience N, decreased RS FC in L calcarine
    71
        Salience N, decreased RS FC in L PIG
    64
        Left PAG network, decreased RS FC in R cerebellum
    185
        LPN, decreased RS FC in L angular gyrus
    77
        LPN, decreased RS FC in R angular gyrus
    76
        LPN, decreased RS FC in L middle frontal gyrus
    63
        LPN, decreased RS FC in L inferior parietal gyrus
    55
        LTN, decreased RS FC in L angular gyrus
    693
        LTN, decreased RS FC, Left precuneus
    210
        R hypothal network, decreased RS FC in L cuneus
    119
        RPN, decreased RS FC in R cerebellum
    79
        RPN, decreased RS FC in L middle cingulum
    52
        R thalamic N, decreased RS FC in L precuneus
    133
        R thalamic N, decreased RS FC in L calcarine
    214
    No statistical analyses for this end point

    Primary: Significant resting state functional connectivity (RS FC) differences in the functional networks as measured by Magnetic Resonance Imaging (MRI) between erenumab and placebo

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    End point title
    		 Significant resting state functional connectivity (RS FC) differences in the functional networks as measured by Magnetic Resonance Imaging (MRI) between erenumab and placebo [3]
    End point description
    FC is the strength with which every area of the brain is connected with a reference area, constituting the seed region of the functional network (FN). In total, 22 FNs were constructed for this study. A voxel is a single 3-dimensional unit that embeds the strength of FC for each element of the image (brain). Larger numbers of voxel indicate wider regions of the brain showing differences of FC. Increased or decreased in the category description indicates an increase or decrease in the placebo vs the erenumab group. Functional connectivity maps were constructed starting from resting state (RS) functional MRI sequences. Structural MRI sequences (FLAIR, T2 and 3D T1 weighted scans) were also acquired.
    End point type
    Primary
    End point timeframe
    Baseline to Month 3
    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: Resting state (RS) functional Magnetic Resonance Imaging (fMRI) data from each study scan were pre-processed using the CONN toolbox. RS fMRI images were analyzed and reported using classical methodology used for fMR
    End point values
    		 Erenumab - Sequence 1
    Number of subjects analysed
    54
    Units: voxels
        Cere network, increased RS FC in R and L precuneus
    299
        L PAG N, increased RS FC in Cere vermis and R cere
    178
        Left STN N, increased RS FC in L thalamus
    54
        RPN, increased RS FC in L cerebellum (crus I)
    99
        RPN, increased RS FC in R inferior parietal gyrus
    58
        RPN, increased RS FC in R cerebellum
    72
    No statistical analyses for this end point

    Primary: Significant resting state functional connectivity (RS FC) differences between clinical response groups of participants in the functional networks for erenumab

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    End point title
    		 Significant resting state functional connectivity (RS FC) differences between clinical response groups of participants in the functional networks for erenumab [4]
    End point description
    A clinical response is defined as a reduction of 50% in monthly migraine days (MMD) from baseline to month 3. FC is the strength with which every area of the brain is connected with a reference area, constituting the seed region of the functional network (FN). In total, 22 FNs were constructed for this study. A voxel is the single 3-dimensional unit that embeds the strength of FC for each element of the image (the brain). Larger numbers of voxel indicate wider regions of the brain showing differences of FC. Increased or decreased in the category description indicates an increase or decrease from baseline. FC maps were constructed starting from RS fMRI sequences. Structural MRI sequences (FLAIR, T2 and 3D T1 weighted scans) were also acquired.
    End point type
    Primary
    End point timeframe
    Baseline to Month 3
    Notes
    [4] - 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: Resting state (RS) functional Magnetic Resonance Imaging (fMRI) data from each study scan were pre-processed using the CONN toolbox. RS fMRI images were analyzed and reported using classical methodology used for fMR
    End point values
    		 Difference between Responder and Non-Responder - erenumab
    Number of subjects analysed
    27
    Units: voxels
        Default mode network II, Left cerebellum (crus II)
    62
        Primary visual network, Right cuneus
    188
        Secondary visual network II, Right lingual gyrus
    78
        Left thalamic network, Right lingual gyrus BA=17
    153
        Left thalamic network, Left lingual gyrus
    205
        Left thalamic network, Right precuneus
    51
    No statistical analyses for this end point

    Primary: Significant resting state functional connectivity (RS FC) differences between clinical response groups of participants in the functional networks for placebo

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    End point title
    		 Significant resting state functional connectivity (RS FC) differences between clinical response groups of participants in the functional networks for placebo [5]
    End point description
    A clinical response is defined as a reduction of 50% in monthly migraine days (MMD) from baseline to month 3. FC is the strength with which every area of the brain is connected with a reference area, constituting the seed region of the functional network (FN). In total, 22 FNs were constructed for this study. A voxel is the single 3-dimensional unit that embeds the strength of FC for each element of the image (the brain). Larger numbers of voxel indicate wider regions of the brain showing differences of FC. Increased or decreased in the category description indicates an increase or decrease from baseline. FC maps were constructed starting from RS fMRI sequences. Structural MRI sequences (FLAIR, T2 and 3D T1 weighted scans) were also acquired.
    End point type
    Primary
    End point timeframe
    Baseline to Month 3
    Notes
    [5] - 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: Resting state (RS) functional Magnetic Resonance Imaging (fMRI) data from each study scan were pre-processed using the CONN toolbox. RS fMRI images were analyzed and reported using classical methodology used for fMR
    End point values
    		 Difference between Responder and Non-Responder - placebo
    Number of subjects analysed
    27
    Units: voxels
    105
    No statistical analyses for this end point

    Primary: Significant differences in resting state functional connectivity (RS FC) changes over time between erenumab and placebo in the ICA-like networks

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    End point title
    		 Significant differences in resting state functional connectivity (RS FC) changes over time between erenumab and placebo in the ICA-like networks [6]
    End point description
    Functional connectivity is the strength with which every area of the brain is connected with a reference area, constituting the seed region of the functional network. In total, 22 functional networks were constructed for this study. A voxel is the single 3-dimensional unit that embeds the strength of functional connectivity for each element of the image (in our case, of the brain). Larger numbers of voxel indicate wider regions of the brain showing differences of functional connectivity. Increased in the category description indicates an increase or decrease in the placebo vs the erenumab group. Functional connectivity maps were constructed starting from resting state (RS) functional MRI sequences. Structural MRI sequences (FLAIR, T2 and 3D T1 weighted scans) were also acquired. Abbreviations: ECN=Executive control network, R=right, L= left, IFG=inferior frontal gyrus, SFG=superior frontal gyrus.
    End point type
    Primary
    End point timeframe
    Baseline to Month 3
    Notes
    [6] - 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: Resting state (RS) functional Magnetic Resonance Imaging (fMRI) data from each study scan were pre-processed using the CONN toolbox. RS fMRI images were analyzed and reported using classical methodology used for fMR
    End point values
    		 Placebo - Sequence 1
    Number of subjects analysed
    54
    Units: voxels
        ECN, increased RS FC in R IFG
    112
        R thalamic network, increased RS FC in R SFG
    110
    No statistical analyses for this end point

    Secondary: Correlation between changes in the ICA-like and seed-based RS functional connectivity (FC) strength over 3 months and concomitant patients’ clinical response in all patients

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    End point title
    		 Correlation between changes in the ICA-like and seed-based RS functional connectivity (FC) strength over 3 months and concomitant patients’ clinical response in all patients
    End point description
    Clinical outcomes: percentage of change in monthly migraine, reduction in monthly average severity of migraine pain, percentage of reduction in monthly number of days with use of acute treatments, change in HIT-6 score. Abbreviations: MMDs= Monthly migraine days, Prim Vis=Primary visual, N=Network, R=right, SFG=superior frontal gyrus, Calc=Calcarine cortex
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 3
    End point values
    		 All Patients
    Number of subjects analysed
    44
    Units: voxels
        MMDs, Prim Vis N, R calcarine cortex
    5
        MMDs, Prim Vis N, R thalamic network
    5
        HIT-6 score, R thalamic network, R SFG
    13
        Severity of migraine pain, Prim Vis N, R calc
    29
    No statistical analyses for this end point

    Secondary: Correlation between changes in the ICA-like and seed-based RS functional connectivity (FC) strength over 3 months and concomitant patients’ clinical response in erenumab

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    End point title
    		 Correlation between changes in the ICA-like and seed-based RS functional connectivity (FC) strength over 3 months and concomitant patients’ clinical response in erenumab
    End point description
    Clinical outcomes: the percentage of change in monthly migraine days, the change in HIT-6 score, the severity of migraine pain
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 3
    End point values
    		 Erenumab Sequence 1
    Number of subjects analysed
    22
    Units: voxels
    5
    No statistical analyses for this end point

    Secondary: Correlation between the changes of RS FC in brain regions mediating allodynia and changes in the ASC-12 score. Abbreviations: R=right, L= left, SFG=superior frontal gyrus.

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    End point title
    		 Correlation between the changes of RS FC in brain regions mediating allodynia and changes in the ASC-12 score. Abbreviations: R=right, L= left, SFG=superior frontal gyrus.
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 3
    End point values
    		 All Patients
    Number of subjects analysed
    44
    Units: voxels
        ASC-12 score, R thalamic Network, L SFG
    5
    No statistical analyses for this end point

    Secondary: Baseline functional MRI markers predictive of good clinical response to erenumab

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    End point title
    		 Baseline functional MRI markers predictive of good clinical response to erenumab
    End point description
    The predictive value of the baseline RS FC of the regions of interest were investigated for treatment clinical response, defined by the achievement of at least 50% reduction of monthly migraine days at month 3 versus baseline.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 3
    End point values
    		 Erenumab – Sequence 1
    Number of subjects analysed
    22
    Units: Z score
        number (confidence interval 95%)
    .95 (0.92 to 0.99)
    No statistical analyses for this end point

    Secondary: Change from baseline in monthly migraine days (MMD)

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    End point title
    		 Change from baseline in monthly migraine days (MMD)
    End point description
    Monthly migraine days are the number of days with a qualified migraine divided by the number of days of observations, multiplied by 30.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 3
    End point values
    		 Erenumab – Period 1 Placebo - Sequence 1
    Number of subjects analysed
    30
    31
    Units: days
        least squares mean (confidence interval 95%)
    -4.985 (-6.385 to -3.585)
    -1.067 (-2.441 to 0.307)
    Statistical analysis title
    		 MMD
    Comparison groups
    Erenumab – Period 1 v Placebo - Sequence 1
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0002
    Method
    		 ANCOVA
    Parameter type
    		 Difference of Least Square Means
    Point estimate
    -3.918
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.88
         upper limit
    		 -1.956

    Secondary: Change from baseline in migraine pain

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    End point title
    		 Change from baseline in migraine pain
    End point description
    The monthly average severity of migraine pain at each visit is calculated as the mean of the pain scores reported in the diary during the previous month. Scoring was from 1 to 10 with the higher scores indicating greater pain.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 3
    End point values
    		 Erenumab – Period 1 Placebo - Sequence 1
    Number of subjects analysed
    30
    31
    Units: scores on a scale
        least squares mean (confidence interval 95%)
    -0.604 (-1.198 to -0.009)
    -0.014 (-0.608 to 0.580)
    Statistical analysis title
    		 Pain
    Comparison groups
    Erenumab – Period 1 v Placebo - Sequence 1
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1665
    Method
    		 ANCOVA
    Parameter type
    		 Difference of Least Square Means
    Point estimate
    -0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.433
         upper limit
    		 0.254

    Secondary: Change from Baseline in number of days of acute treatments

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    End point title
    		 Change from Baseline in number of days of acute treatments
    End point description
    Acute treatments were recorded in participants diary and included: xxxx
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 3
    End point values
    		 Erenumab – Period 1 Placebo - Sequence 1
    Number of subjects analysed
    30
    31
    Units: days
        least squares mean (confidence interval 95%)
    -4.087 (-5.458 to -2.717)
    0.089 (-1.255 to 1.434)
    Statistical analysis title
    		 Days acute tx
    Comparison groups
    Erenumab – Period 1 v Placebo - Sequence 1
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Difference of Least Square Means
    Point estimate
    -4.177
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.097
         upper limit
    		 -2.257

    Secondary: Change from Baseline in Headache Impact Test (HIT-6) score

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    End point title
    		 Change from Baseline in Headache Impact Test (HIT-6) score
    End point description
    The HIT-6 is a self-administered questionnaire which measures adverse headache impact to assess headache severity in the previous month (frequency of pain severity, headaches limiting daily activity, wanting to lie down during a headache) and change in a patient’s clinical status over a short period of time (feeling too tired to work or do daily activities because of a headache, feeling “fed up” or irritated because of headaches, and headaches limiting ability to concentrate or work on daily activities). Each of the 6 questions had 5 responses: never, rarely, sometimes, very often, or always. Total possible scores ranged from 36 to 78. Scores were categorized into 4 grades: little or no impact (49 or less), some impact (50-55), substantial impact (56-59), and severe impact (60-78). Patients completed the HIT-6 in their diary during their scheduled visit.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 3
    End point values
    		 Erenumab – Period 1 Placebo - Sequence 1
    Number of subjects analysed
    30
    31
    Units: scores on a scale
        least squares mean (confidence interval 95%)
    -11.822 (-14.833 to -8.810)
    -4.764 (-7.719 to -1.809)
    Statistical analysis title
    		 HIT-6
    Comparison groups
    Erenumab – Period 1 v Placebo - Sequence 1
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0016
    Method
    		 ANCOVA
    Parameter type
    		 Difference of Least Square Means
    Point estimate
    -7.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.29
         upper limit
    		 -2.82

    Secondary: Change from Baseline in Allodynia Symptom checklist -12 (ASC-12)

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    End point title
    		 Change from Baseline in Allodynia Symptom checklist -12 (ASC-12)
    End point description
    The ASC-12 measures overall allodynia (sensory hypersensitivity) and subtypes and has 12 questions about the frequency of allodynia symptoms associated with headache attacks. For individuals with more than one type of headache, questions were directed to the “most severe type of headache” based on the prior evidence indicating that the most severe type was likely to be migraine. The response categories were scored as; 0=never, rarely, less than half the time, and half the time or more, does not apply to me; 1=less than half the time; and 2=half the time or more; and total score ranged from 0 to 24. Scores indicated: <=2 allodynia was not present, 3-5=mild allodynia; 6-8=moderate allodynia; and >=9=severe allodynia. Patients completed this questionnaire during their scheduled visits.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 3
    End point values
    		 Erenumab – Period 1 Placebo - Sequence 1
    Number of subjects analysed
    30
    31
    Units: scores on a scale
        least squares mean (confidence interval 95%)
    -11.822 (-14.833 to -8.810)
    -4.764 (-7.719 to -1.809)
    Statistical analysis title
    		 ASC-12
    Comparison groups
    Erenumab – Period 1 v Placebo - Sequence 1
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0016
    Method
    		 ANCOVA
    Parameter type
    		 Difference of Least Square Means
    Point estimate
    -7.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.29
         upper limit
    		 -2.82

    Secondary: Change from Baseline in Number of days of clinical symptoms during migraine attacks

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    End point title
    		 Change from Baseline in Number of days of clinical symptoms during migraine attacks
    End point description
    Clinical outcome symptoms were collected by patients at home using a paper diary. The recall period was the past 24 hours.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 3
    End point values
    		 Erenumab – Period 1 Placebo - Sequence 1
    Number of subjects analysed
    30
    31
    Units: days
    least squares mean (confidence interval 95%)
        Aura during migraine attack
    -0.383 (-0.551 to -0.216)
    -0.578 (-0.745 to -0.410)
        Nausea during migraine attack
    -2.433 (-3.453 to -1.414)
    -1.614 (-2.634 to -0.595)
        Vomiting during migraine attack
    -0.233 (-0.891 to 0.425)
    -0.119 (-0.777 to 0.539)
        Photophobia during migraine attack
    -3.898 (-5.126 to -2.670)
    -0.416 (-1.621 to 0.789)
        Phonophobia during migraine attack
    -3.898 (-5.126 to -2.670)
    -0.416 (-1.621 to 0.789)
        Photophobia and Phonophobia during migraine attack
    -3.336 (-4.558 to -2.115)
    -0.351 (-1.549 to 0.848)
    Statistical analysis title
    		 Aura
    Comparison groups
    Erenumab – Period 1 v Placebo - Sequence 1
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0155
    Method
    		 ANCOVA
    Parameter type
    		 Difference of Least Square Means
    Point estimate
    -5.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.161
         upper limit
    		 -1.119
    Statistical analysis title
    		 Nausea
    Comparison groups
    Erenumab – Period 1 v Placebo - Sequence 1
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1053
    Method
    		 ANCOVA
    Parameter type
    		 Difference of Least Square Means
    Point estimate
    0.195
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.042
         upper limit
    		 0.431
    Statistical analysis title
    		 Vomiting
    Comparison groups
    Erenumab – Period 1 v Placebo - Sequence 1
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0155
    Method
    		 ANCOVA
    Parameter type
    		 Difference of Least Square Means
    Point estimate
    -5.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.161
         upper limit
    		 -1.119
    Statistical analysis title
    		 Photophobia
    Comparison groups
    Erenumab – Period 1 v Placebo - Sequence 1
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0035
    Method
    		 ANCOVA
    Parameter type
    		 Difference of Least Square Means
    Point estimate
    -2.692
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.456
         upper limit
    		 -0.928
    Statistical analysis title
    		 Phonophobia
    Comparison groups
    Erenumab – Period 1 v Placebo - Sequence 1
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0002
    Method
    		 ANCOVA
    Parameter type
    		 Difference of Least Square Means
    Point estimate
    -3.482
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.222
         upper limit
    		 -1.743
    Statistical analysis title
    		 Photophobia and phonophobia
    Comparison groups
    Erenumab – Period 1 v Placebo - Sequence 1
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0011
    Method
    		 ANCOVA
    Parameter type
    		 Difference of Least Square Means
    Point estimate
    -2.986
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.712
         upper limit
    		 -1.26

    Secondary: Change from Baseline in Number of days of clinical symptoms during migraine attacks

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    End point title
    		 Change from Baseline in Number of days of clinical symptoms during migraine attacks
    End point description
    Clinical outcome symptoms were collected by patients at home using a paper diary. The recall period was the past 24 hours.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 3
    End point values
    		 Erenumab – Period 1 Placebo - Sequence 1
    Number of subjects analysed
    30
    31
    Units: days
    least squares mean (confidence interval 95%)
        Aura
    -0.383 (-0.551 to -0.216)
    -0.578 (-0.745 to -0.410)
        Nausea
    -2.433 (-3.453 to -1.414)
    -1.614 (-2.634 to -0.595)
        Vomiting
    -0.233 (-0.891 to 0.425)
    -0.119 (-0.777 to 0.539)
        Photophobia
    -3.898 (-5.126 to -2.670)
    -0.416 (-1.621 to 0.789)
        Phonophobia
    -3.898 (-5.126 to -2.670)
    -0.416 (-1.621 to 0.789)
        Photophobia and Phonophobia
    -3.336 (-4.558 to -2.115)
    -0.351 (-1.549 to 0.848)
    Statistical analysis title
    		 Aura
    Comparison groups
    Erenumab – Period 1 v Placebo - Sequence 1
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0155
    Method
    		 ANCOVA
    Parameter type
    		 Difference of Least Square Means
    Point estimate
    -5.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.161
         upper limit
    		 -1.119
    Statistical analysis title
    		 Nausea
    Comparison groups
    Erenumab – Period 1 v Placebo - Sequence 1
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1053
    Method
    		 ANCOVA
    Parameter type
    		 Difference of Least Square Means
    Point estimate
    0.195
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.042
         upper limit
    		 0.431
    Statistical analysis title
    		 Vomiting
    Comparison groups
    Erenumab – Period 1 v Placebo - Sequence 1
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0155
    Method
    		 ANCOVA
    Parameter type
    		 Difference of Least Square Means
    Point estimate
    -5.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.161
         upper limit
    		 -1.119
    Statistical analysis title
    		 Photophobia
    Comparison groups
    Erenumab – Period 1 v Placebo - Sequence 1
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0035
    Method
    		 ANCOVA
    Parameter type
    		 Difference of Least Square Means
    Point estimate
    -2.692
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.456
         upper limit
    		 -0.928
    Statistical analysis title
    		 Phonophobia
    Comparison groups
    Erenumab – Period 1 v Placebo - Sequence 1
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0002
    Method
    		 ANCOVA
    Parameter type
    		 Difference of Least Square Means
    Point estimate
    -3.482
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.222
         upper limit
    		 -1.743

    Secondary: Change from Baseline in Hospital Anxiety and Depression Scale (HADS) scores

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    End point title
    		 Change from Baseline in Hospital Anxiety and Depression Scale (HADS) scores
    End point description
    The HADS is a fourteen-item scale. Seven of the items relate to anxiety (HSD-A) and seven to depression (HAD-D). Calculations of scores: each of the 14 items is rated on a 4-point scale (0 to 3). All items except 7 and 10 are scored as Yes, definitely=3 to No, not at all=0. Items 7 and 10 are scored as: Yes, definitely=0 to No, not at all=3. The HAD-A and HAD-D sub-scores range from 0 to 21 points; scores ≥11 indicate the presence of anxious or depressive disorders; scores between 8-10 points are borderline abnormal, and scores ≤7 indicate that the disorder is not present. Patients completed this questionnaire during their scheduled visit.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 3
    End point values
    		 Erenumab – Period 1 Placebo - Sequence 1
    Number of subjects analysed
    30
    31
    Units: scores on a scale
    least squares mean (confidence interval 95%)
        HAD-Anxiety
    -2.284 (-3.183 to -1.385)
    -1.060 (-1.942 to -0.178)
        HAD-Depression
    -2.241 (-3.230 to -1.252)
    -1.249 (-2.220 to -0.278)
    Statistical analysis title
    		 HAD-Anxiety
    Comparison groups
    Erenumab – Period 1 v Placebo - Sequence 1
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0572
    Method
    		 ANCOVA
    Parameter type
    		 Difference of Least Square Means
    Point estimate
    -1.224
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.487
         upper limit
    		 0.039
    Statistical analysis title
    		 HAD-Depression
    Comparison groups
    Erenumab – Period 1 v Placebo - Sequence 1
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.157
    Method
    		 ANCOVA
    Parameter type
    		 Difference of Least Square Means
    Point estimate
    -0.992
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.378
         upper limit
    		 0.395

    Secondary: RS FC increase, from baseline to month 3 of treatment, in erenumab patients compared to placebo in brain regions involved in allodynia

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    End point title
    		 RS FC increase, from baseline to month 3 of treatment, in erenumab patients compared to placebo in brain regions involved in allodynia
    End point description
    Functional connectivity is the strength with which every area of the brain is connected with a reference area, constituting the seed region of the functional network. In total, 22 functional networks were constructed for this study. A voxel is the single 3-dimensional unit that embeds the strength of functional connectivity for each element of the image (in our case, of the brain). Larger numbers of voxel indicate wider regions of the brain showing differences of functional connectivity. Increased in the category description indicates an increase of connectivity in erenumab vs placebo patients. Functional connectivity maps were constructed starting from resting state (RS) functional MRI sequences. Structural MRI sequences (FLAIR, T2 and 3D T1 weighted scans) were also acquired. Abbreviations: N=Network, R=right, L=left, DMN=Default mode network
    End point type
    Secondary
    End point timeframe
    Baseline up Month 3
    End point values
    		 Erenumab + Placebo Sequence 1 Total
    Number of subjects analysed
    54
    Units: voxels
        Cerebellar N, increased RS FC, L and R precuneus
    74
        DMN II, increased RS FC, R cerebellum
    62
        L PAG N, increased RS FC, R cerebellum
    72
    No statistical analyses for this end point

    Secondary: RS FC increase, from baseline to month 3 of treatment, in placebo patients compared to erenumab in brain regions involved in allodynia

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    End point title
    		 RS FC increase, from baseline to month 3 of treatment, in placebo patients compared to erenumab in brain regions involved in allodynia
    End point description
    Functional connectivity is the strength with which every area of the brain is connected with a reference area, constituting the seed region of the functional network. In total, 22 functional networks were constructed for this study. A voxel is the single 3-dimensional unit that embeds the strength of functional connectivity for each element of the image (in our case, of the brain). Larger numbers of voxel indicate wider regions of the brain showing differences of functional connectivity. Increased in the category description indicates an increase of connectivity in placebo vs erenumab patients. Functional connectivity maps were constructed starting from resting state (RS) functional MRI sequences. Structural MRI sequences (FLAIR, T2 and 3D T1 weighted scans) were also acquired. Abbreviations: N=Network, R=right, L=left, SFG= superior frontal gyrus, ACC=anterior cingulate cortex.
    End point type
    Secondary
    End point timeframe
    Baseline up Month 3
    End point values
    		 Placebo + erenumab Sequence 1 Total
    Number of subjects analysed
    54
    Units: voxels
        R thalamic N, increased RS FC in R SFG
    327
        R thalamic N, increased RS FS in L SFG
    60
        R thalamic N, increased RS FC in R and L ACC
    56
    No statistical analyses for this end point

    Secondary: RS FC increase, from baseline to month 3 of treatment, in erenumab patients compared to placebo in brain regions involved in photophobia

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    End point title
    		 RS FC increase, from baseline to month 3 of treatment, in erenumab patients compared to placebo in brain regions involved in photophobia
    End point description
    Functional connectivity is the strength with which every area of the brain is connected with a reference area, constituting the seed region of the functional network. In total, 22 functional networks were constructed for this study. A voxel is the single 3-dimensional unit that embeds the strength of functional connectivity for each element of the image (in our case, of the brain). Larger numbers of voxel indicate wider regions of the brain showing differences of functional connectivity. Increased in the category description indicates an increase of connectivity in erenumab vs placebo patients. Functional connectivity maps were constructed starting from resting state (RS) functional MRI sequences. Structural MRI sequences (FLAIR, T2 and 3D T1 weighted scans) were also acquired. Abbreviations: N=Network, R=right, L=left, DMN=Default mode network, Prim Vis=Primary visual, Sec Vis=Secondary visual.
    End point type
    Secondary
    End point timeframe
    Baseline up Month 3
    End point values
    		 Erenumab + Placebo Sequence 1 Total
    Number of subjects analysed
    54
    Units: voxels
        Cerebellar N, increased RS FC, L and R precuneus
    74
        DMN II, increased RS FC, R cerebellum
    62
        Prim Vis N, increased RS FC, R calcarine cortex
    119
        Prim Vis N, increased RS FC, L postcentral gyrus
    92
        Sec Vis N II, increased RS FC, L precentral gyus
    52
        L PAG N, increased RS FC, R cerebellum
    72
    No statistical analyses for this end point

    Secondary: RS FC increase, from baseline to month 3 of treatment, in placebo patients compared to erenumab in brain regions involved in photophobia

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    End point title
    		 RS FC increase, from baseline to month 3 of treatment, in placebo patients compared to erenumab in brain regions involved in photophobia
    End point description
    Functional connectivity is the strength with which every area of the brain is connected with a reference area, constituting the seed region of the functional network. In total, 22 functional networks were constructed for this study. A voxel is the single 3-dimensional unit that embeds the strength of functional connectivity for each element of the image (in our case, of the brain). Larger numbers of voxel indicate wider regions of the brain showing differences of functional connectivity. Increased in the category description indicates an increase of connectivity in placebo vs erenumab patients. Functional connectivity maps were constructed starting from resting state (RS) functional MRI sequences. Structural MRI sequences (FLAIR, T2 and 3D T1 weighted scans) were also acquired. Abbreviations: N=Network, R=right, L=left, SFG= superior frontal gyrus, ACC=anterior cingulate cortex.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 3
    End point values
    		 Placebo + erenumab Sequence 1 Total
    Number of subjects analysed
    54
    Units: voxels
        R thalamic N, increased RS FC in R SFG
    327
        R thalamic N, increased RS FC in L SFG
    60
        R thalamic N,,increased RS FC in R and L ACC
    56
    No statistical analyses for this end point

    Secondary: RS FC increase, from baseline to month 3 of treatment, in erenumab patients compared to placebo in brain regions involved in phonophobia

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    End point title
    		 RS FC increase, from baseline to month 3 of treatment, in erenumab patients compared to placebo in brain regions involved in phonophobia
    End point description
    Functional connectivity is the strength with which every area of the brain is connected with a reference area, constituting the seed region of the functional network. In total, 22 functional networks were constructed for this study. A voxel is the single 3-dimensional unit that embeds the strength of functional connectivity for each element of the image (in our case, of the brain). Larger numbers of voxel indicate wider regions of the brain showing differences of functional connectivity. Increased in the category description indicates an increase of connectivity in erenumab vs placebo patients. Functional connectivity maps were constructed starting from resting state (RS) functional MRI sequences. Structural MRI sequences (FLAIR, T2 and 3D T1 weighted scans) were also acquired. Abbreviations: N=Network, R=right, L=left, DMN=Default mode network.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 3
    End point values
    		 Erenumab + Pacebo Sequence 1 Total
    Number of subjects analysed
    54
    Units: voxels
        Cerebellar N, increased RS FC in L and R precuneus
    74
        DMN II, increased RS FC in R cerebellum
    62
        L PAG N, increased RS FC in R cerebellum
    72
    No statistical analyses for this end point

    Secondary: RS FC increase, from baseline to month 3 of treatment, in placebo patients compared to erenumab in brain regions involved in phonophobia

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    End point title
    		 RS FC increase, from baseline to month 3 of treatment, in placebo patients compared to erenumab in brain regions involved in phonophobia
    End point description
    Functional connectivity is the strength with which every area of the brain is connected with a reference area, constituting the seed region of the functional network. In total, 22 functional networks were constructed for this study. A voxel is the single 3-dimensional unit that embeds the strength of functional connectivity for each element of the image (in our case, of the brain). Larger numbers of voxel indicate wider regions of the brain showing differences of functional connectivity. Increased in the category description indicates an increase of connectivity in placebo vs erenumab patients. Functional connectivity maps were constructed starting from resting state (RS) functional MRI sequences. Structural MRI sequences (FLAIR, T2 and 3D T1 weighted scans) were also acquired. Abbreviations: N=Network, R=right, L=left, SFG= superior frontal gyrus, ACC=anterior cingulate cortex.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 3
    End point values
    		 Placebo + erenumab Sequence 1 Total
    Number of subjects analysed
    54
    Units: voxels
        R thalamic N, increased RS FC in L SFG
    327
        R thalamic N, increased RS FC in R SFG
    60
        R thalamic N, increased RS FC in R and L ACC
    56
    No statistical analyses for this end point

    Secondary: RS FC increase, from baseline to month 3 of treatment, in erenumab patients compared to placebo in brain regions involved in nausea

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    End point title
    		 RS FC increase, from baseline to month 3 of treatment, in erenumab patients compared to placebo in brain regions involved in nausea
    End point description
    Functional connectivity is the strength with which every area of the brain is connected with a reference area, constituting the seed region of the functional network. In total, 22 functional networks were constructed for this study. A voxel is the single 3-dimensional unit that embeds the strength of functional connectivity for each element of the image (in our case, of the brain). Larger numbers of voxel indicate wider regions of the brain showing differences of functional connectivity. Increased in the category description indicates an increase of connectivity in erenumab vs placebo patients. Functional connectivity maps were constructed starting from resting state (RS) functional MRI sequences. Structural MRI sequences (FLAIR, T2 and 3D T1 weighted scans) were also acquired. Abbreviations: N=Network, R=right, L=left
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 3
    End point values
    		 Erenumab + Placebo Sequence 1 Total
    Number of subjects analysed
    54
    Units: voxels
        Cerebellar N, increased RS FC in L and R precuneus
    74
        L PAG N, increased RS FC in R cerebellum
    72
    No statistical analyses for this end point

    Secondary: RS FC increase, from baseline to month 3 of treatment, in erenumab patients compared to placebo in brain regions involved in the emotional control of pain

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    End point title
    		 RS FC increase, from baseline to month 3 of treatment, in erenumab patients compared to placebo in brain regions involved in the emotional control of pain
    End point description
    Functional connectivity is the strength with which every area of the brain is connected with a reference area, constituting the seed region of the functional network. In total, 22 functional networks were constructed for this study. A voxel is the single 3-dimensional unit that embeds the strength of functional connectivity for each element of the image (in our case, of the brain). Larger numbers of voxel indicate wider regions of the brain showing differences of functional connectivity. Increased in the category description indicates an increase of connectivity in erenumab vs placebo patients. Functional connectivity maps were constructed starting from resting state (RS) functional MRI sequences. Structural MRI sequences (FLAIR, T2 and 3D T1 weighted scans) were also acquired. Abbreviations: N=Network, R=right, L=left
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 3
    End point values
    		 Erenumab + Placebo Sequence 1 Total
    Number of subjects analysed
    54
    Units: voxels
        Cerebellar N, increased RS FC in L and R precuneus
    74
        L PAG N, increased RS FC in R cerebellum
    62
    No statistical analyses for this end point

    Secondary: RS FC increase, from baseline to month 3 of treatment, in placebo patients compared to erenumab in brain regions involved in the emotional control of pain

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    End point title
    		 RS FC increase, from baseline to month 3 of treatment, in placebo patients compared to erenumab in brain regions involved in the emotional control of pain
    End point description
    Functional connectivity is the strength with which every area of the brain is connected with a reference area, constituting the seed region of the functional network. In total, 22 functional networks were constructed for this study. A voxel is the single 3-dimensional unit that embeds the strength of functional connectivity for each element of the image (in our case, of the brain). Larger numbers of voxel indicate wider regions of the brain showing differences of functional connectivity. Increased in the category description indicates an increase of connectivity in placebo vs erenumab patients. Functional connectivity maps were constructed starting from resting state (RS) functional MRI sequences. Structural MRI sequences (FLAIR, T2 and 3D T1 weighted scans) were also acquired. Abbreviations: N=Network, R=right, L=left, SFG= superior frontal gyrus, ACC=anterior cingulate cortex
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 3
    End point values
    		 Placebo + erenumab Sequence 1 Total
    Number of subjects analysed
    54
    Units: voxels
        R thalamic N, increased RS FC in R SFG
    327
        R thalamic N, increased RS FC in L SFG
    60
        R thalamic N, increased RS FC in R and L ACC
    56
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from first dose of study treatment until end of study treatment for a maximum of 136 days plus a 30 day post treatment follow-up for a maximum duration of 166 days.
    Adverse event reporting additional description
    All participants received erenumab and also received placebo. All participants are counted in both arms.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group title
    Erenumab
    Reporting group description
    		 Erenumab

    Serious adverse events
    		 Placebo Erenumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Placebo Erenumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 57 (29.82%)
    28 / 59 (47.46%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 59 (1.69%)
         occurrences all number
    1
    1
    Fatigue
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Injection site erythema
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Fibrocystic breast disease
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Genital tract inflammation
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Menopausal symptoms
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Menstruation delayed
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Pelvic fluid collection
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 59 (1.69%)
         occurrences all number
    1
    1
    Oropharyngeal pain
         subjects affected / exposed
    2 / 57 (3.51%)
    1 / 59 (1.69%)
         occurrences all number
    2
    1
    Productive cough
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Rhinitis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Epicondylitis
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Wrist fracture
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Sciatica
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Eye disorders
    Glaucoma
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Abdominal distension
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain lower
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Aphthous ulcer
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    2
    Constipation
         subjects affected / exposed
    0 / 57 (0.00%)
    8 / 59 (13.56%)
         occurrences all number
    0
    8
    Diarrhoea
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Toothache
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Alopecia
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 59 (1.69%)
         occurrences all number
    1
    1
    Hyperhidrosis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 59 (1.69%)
         occurrences all number
    1
    1
    Rash
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Rash pruritic
         subjects affected / exposed
    1 / 57 (1.75%)
    2 / 59 (3.39%)
         occurrences all number
    1
    2
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Glycosuria
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Back pain
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Myalgia
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Tendon disorder
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Infections and infestations
    COVID-19
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 59 (0.00%)
         occurrences all number
    2
    0
    Candida infection
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Cystitis
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 57 (3.51%)
    1 / 59 (1.69%)
         occurrences all number
    2
    1
    Omphalitis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Paronychia
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Suspected COVID-19
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 57 (1.75%)
    4 / 59 (6.78%)
         occurrences all number
    1
    6
    Urinary tract infection
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Hypercalcaemia
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Hyperkalaemia
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0

    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.
    Cross-over without washout between sequences (SEQ). Analysis determined there was a carry-over effect (C-O E); analysis was changed to parallel with SEQ 1 used for efficacy and both SEQs for safety; some AEs in placebo group may be due to C-O E.
    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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