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    Clinical Trial Results:
    A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention

    Summary
    EudraCT number
    		 2014-004464-38
    Trial protocol
    		 FI   SE   CZ   DE   SK   AT   PL   HU   BE   NL  
    Global end of trial date
    19 Jun 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Jul 2018
    First version publication date
    05 Jul 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    20120296
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02456740
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.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
    19 Jun 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of erenumab (AMG 334) compared to placebo on the change from baseline in mean monthly migraine days, in subjects with episodic migraine.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines, the GCPs applicable to all regions where the study was conducted and in accordance with the ethical principles set forth in the Declaration of Helsinki. All centers complied with local regulations. The study protocol and all amendments, the informed consent form, and any accompanying materials provided to subjects were reviewed and approved by an Independent Ethics Committee (IEC) or Institutional Review Board (IRB), as appropriate, at each center/country. The investigator or his/her designee informed the subject of all aspects pertaining to the subject’s participation in the study before any screening procedures were performed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Jul 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 28
    Country: Number of subjects enrolled
    United States: 449
    Country: Number of subjects enrolled
    Austria: 34
    Country: Number of subjects enrolled
    Belgium: 22
    Country: Number of subjects enrolled
    Czech Republic: 74
    Country: Number of subjects enrolled
    Finland: 45
    Country: Number of subjects enrolled
    Germany: 148
    Country: Number of subjects enrolled
    Netherlands: 9
    Country: Number of subjects enrolled
    Poland: 28
    Country: Number of subjects enrolled
    Slovakia: 10
    Country: Number of subjects enrolled
    Sweden: 57
    Country: Number of subjects enrolled
    Turkey: 22
    Country: Number of subjects enrolled
    United Kingdom: 29
    Worldwide total number of subjects
    955
    EEA total number of subjects
    456
    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)
    951
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This study was conducted at 121 centers in Canada, Austria, Belgium, Czech Republic, Finland, Germany, Poland, Slovakia, Sweden, the United Kingdom, Turkey, the Netherlands and USA. The study consisted of a 24-week double-blind treatment phase (DBTP) and a 28-week active treatment phase (ATP).

    Pre-assignment
    Screening details
    		 At the end of the baseline phase, participants were randomized 1:1:1 to receive placebo, erenumab 70 mg, or erenumab 140 mg monthly for 24 weeks. Randomization was stratified by region and treatment status with migraine prophylactic medication. Participants were re-randomized at week 24 to erenumab 70 mg or 140 mg for 28 weeks.

    Period 1
    Period 1 title
    Double-blind Treatment Phase (24 weeks)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo once a month (QM) by subcutaneous injection on day 1 and weeks 4, 8, 12, 16, and 20 in the 24-week double-blind treatment phase.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection once a month

    Arm title
    		 Erenumab 70 mg QM
    Arm description
    		 Participants received erenumab 70 mg QM by subcutaneous injection on day 1 and weeks 4, 8, 12, 16, and 20 in the 24-week double-blind treatment phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Erenumab
    Investigational medicinal product code
    AMG 334
    Other name
    Aimovig™
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection once a month

    Arm title
    		 Erenumab 140 mg QM
    Arm description
    		 Participants received erenumab 140 mg QM by subcutaneous injection on day 1 and weeks 4, 8, 12, 16, and 20 in the 24-week double-blind treatment phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Erenumab
    Investigational medicinal product code
    AMG 334
    Other name
    Aimovig™
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection once a month

    Number of subjects in period 1
    		Placebo Erenumab 70 mg QM Erenumab 140 mg QM
    Started
    319
    317
    319
    Received Study Drug
    319
    314
    319
    Completed
    282
    284
    292
    Not completed
    37
    33
    27
         Consent withdrawn by subject
    27
    28
    21
         Decision by Sponsor
    1
    1
    1
         Lost to follow-up
    9
    4
    5
    Period 2
    Period 2 title
    Active Treatment Phase (Weeks 24 - 52)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo / Erenumab 70 mg
    Arm description
    		 Participants originally randomized to receive placebo in the 24-week double-blind treatment phase were re-randomized at week 24 to receive erenumab 70 mg subcutaneously at weeks 24, 28, 32, 36, 40, 44, and 48 in the active treatment phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Erenumab
    Investigational medicinal product code
    AMG 334
    Other name
    Aimovig™
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection once a month

    Arm title
    		 Erenumab 70 mg / Erenumab 70 mg
    Arm description
    		 Participants originally randomized to receive erenumab 70 mg QM in the 24-week double-blind treatment phase were re-randomized at week 24 to receive erenumab 70 mg subcutaneously at weeks 24, 28, 32, 36, 40, 44, and 48 in the active treatment phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Erenumab
    Investigational medicinal product code
    AMG 334
    Other name
    Aimovig™
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection once a month

    Arm title
    		 Erenumab 140 mg / Erenumab 70 mg
    Arm description
    		 Participants originally randomized to receive erenumab 140 mg QM in the 24-week double-blind treatment phase were re-randomized at week 24 to receive erenumab 70 mg subcutaneously at weeks 24, 28, 32, 36, 40, 44, and 48 in the active treatment phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Erenumab
    Investigational medicinal product code
    AMG 334
    Other name
    Aimovig™
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection once a month

    Arm title
    		 Placebo / Erenumab 140 mg
    Arm description
    		 Participants originally randomized to receive placebo QM in the 24-week double-blind treatment phase were re-randomized at week 24 to receive erenumab 140 mg subcutaneously at weeks 24, 28, 32, 36, 40, 44, and 48 in the active treatment phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Erenumab
    Investigational medicinal product code
    AMG 334
    Other name
    Aimovig™
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection once a month

    Arm title
    		 Erenumab 70 mg / Erenumab 140 mg
    Arm description
    		 Participants originally randomized to receive erenumab 70 mg QM in the 24-week double-blind treatment phase were re-randomized at week 24 to receive erenumab 140 mg subcutaneously at weeks 24, 28, 32, 36, 40, 44, and 48 in the active treatment phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Erenumab
    Investigational medicinal product code
    AMG 334
    Other name
    Aimovig™
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection once a month

    Arm title
    		 Erenumab 140 mg / Erenumab 140 mg
    Arm description
    		 Participants originally randomized to receive erenumab 140 mg QM in the 24-week double-blind treatment phase were re-randomized at week 24 to receive erenumab 140 mg subcutaneously at weeks 24, 28, 32, 36, 40, 44, and 48 in the active treatment phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Erenumab
    Investigational medicinal product code
    AMG 334
    Other name
    Aimovig™
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection once a month

    Number of subjects in period 2 [1]
    		Placebo / Erenumab 70 mg Erenumab 70 mg / Erenumab 70 mg Erenumab 140 mg / Erenumab 70 mg Placebo / Erenumab 140 mg Erenumab 70 mg / Erenumab 140 mg Erenumab 140 mg / Erenumab 140 mg
    Started
    138
    140
    143
    140
    140
    144
    Completed
    124
    123
    130
    131
    128
    126
    Not completed
    14
    17
    13
    9
    12
    18
         Consent withdrawn by subject
    10
    11
    9
    8
    8
    9
         Protocol specified criteria
    1
    4
    -
    -
    -
    5
         Death
    -
    -
    -
    -
    1
    -
         Lost to follow-up
    3
    2
    4
    1
    3
    4
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Fourteen subjects who completed the double-blind treatment phase did not continue onto the active treatment phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo once a month (QM) by subcutaneous injection on day 1 and weeks 4, 8, 12, 16, and 20 in the 24-week double-blind treatment phase.

    Reporting group title
    Erenumab 70 mg QM
    Reporting group description
    		 Participants received erenumab 70 mg QM by subcutaneous injection on day 1 and weeks 4, 8, 12, 16, and 20 in the 24-week double-blind treatment phase.

    Reporting group title
    Erenumab 140 mg QM
    Reporting group description
    		 Participants received erenumab 140 mg QM by subcutaneous injection on day 1 and weeks 4, 8, 12, 16, and 20 in the 24-week double-blind treatment phase.

    Reporting group values
    		 Placebo Erenumab 70 mg QM Erenumab 140 mg QM Total
    Number of subjects
    		 319 317 319 955
    Age Categorical
    Units: Subjects
        18 - 64 years
    		 317 317 317 951
        65 - 74 years
    		 2 0 2 4
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 41.3 ( 11.2 ) 41.1 ( 11.3 ) 40.4 ( 11.1 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 274 268 272 814
        Male
    		 45 49 47 141
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 2 0 1 3
        Asian
    		 8 5 4 17
        Black or African American
    		 24 24 18 66
        Multiple
    		 2 1 0 3
        Native Hawaiian or Other Pacific Islander
    		 0 0 1 1
        White
    		 277 281 293 851
        Other
    		 6 6 2 14
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 32 26 22 80
        Not Hispanic or Latino
    		 287 291 297 875
    Region
    Units: Subjects
        North America
    		 158 159 160 477
        Other
    		 161 158 159 478
    Treatment Status with Migraine Prophylactic Medication
    Units: Subjects
        Current migraine prophylactic treatment
    		 8 6 7 21
        Prior migraine prophylactic treatment only
    		 119 119 120 358
        No prior / current migraine prophylactic treatment
    		 192 192 192 576
    Monthly Migraine Days
    A migraine day was any calendar day in which the participant experienced a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). A qualified migraine headache was defined either as a migraine without aura or a migraine with aura. Monthly migraine days were calculated as the number of migraine days in the 4-week baseline phase. Data are reported for participants with non-missing data (318, 316, and 319 subjects in each treatment group respectively).
    Units: migraine days / month
        arithmetic mean (standard deviation)
    		 8.23 ( 2.51 ) 8.29 ( 2.47 ) 8.34 ( 2.48 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo once a month (QM) by subcutaneous injection on day 1 and weeks 4, 8, 12, 16, and 20 in the 24-week double-blind treatment phase.

    Reporting group title
    Erenumab 70 mg QM
    Reporting group description
    		 Participants received erenumab 70 mg QM by subcutaneous injection on day 1 and weeks 4, 8, 12, 16, and 20 in the 24-week double-blind treatment phase.

    Reporting group title
    Erenumab 140 mg QM
    Reporting group description
    		 Participants received erenumab 140 mg QM by subcutaneous injection on day 1 and weeks 4, 8, 12, 16, and 20 in the 24-week double-blind treatment phase.
    Reporting group title
    Placebo / Erenumab 70 mg
    Reporting group description
    		 Participants originally randomized to receive placebo in the 24-week double-blind treatment phase were re-randomized at week 24 to receive erenumab 70 mg subcutaneously at weeks 24, 28, 32, 36, 40, 44, and 48 in the active treatment phase.

    Reporting group title
    Erenumab 70 mg / Erenumab 70 mg
    Reporting group description
    		 Participants originally randomized to receive erenumab 70 mg QM in the 24-week double-blind treatment phase were re-randomized at week 24 to receive erenumab 70 mg subcutaneously at weeks 24, 28, 32, 36, 40, 44, and 48 in the active treatment phase.

    Reporting group title
    Erenumab 140 mg / Erenumab 70 mg
    Reporting group description
    		 Participants originally randomized to receive erenumab 140 mg QM in the 24-week double-blind treatment phase were re-randomized at week 24 to receive erenumab 70 mg subcutaneously at weeks 24, 28, 32, 36, 40, 44, and 48 in the active treatment phase.

    Reporting group title
    Placebo / Erenumab 140 mg
    Reporting group description
    		 Participants originally randomized to receive placebo QM in the 24-week double-blind treatment phase were re-randomized at week 24 to receive erenumab 140 mg subcutaneously at weeks 24, 28, 32, 36, 40, 44, and 48 in the active treatment phase.

    Reporting group title
    Erenumab 70 mg / Erenumab 140 mg
    Reporting group description
    		 Participants originally randomized to receive erenumab 70 mg QM in the 24-week double-blind treatment phase were re-randomized at week 24 to receive erenumab 140 mg subcutaneously at weeks 24, 28, 32, 36, 40, 44, and 48 in the active treatment phase.

    Reporting group title
    Erenumab 140 mg / Erenumab 140 mg
    Reporting group description
    		 Participants originally randomized to receive erenumab 140 mg QM in the 24-week double-blind treatment phase were re-randomized at week 24 to receive erenumab 140 mg subcutaneously at weeks 24, 28, 32, 36, 40, 44, and 48 in the active treatment phase.

    Primary: Change From Baseline in Mean Monthly Migraine Days to the Last 3 Months of the Double-blind Treatment Period

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    End point title
    		 Change From Baseline in Mean Monthly Migraine Days to the Last 3 Months of the Double-blind Treatment Period
    End point description
    A migraine day was any calendar day in which the participant experienced a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). A qualified migraine headache was defined either as a migraine with or without aura. The change from baseline in monthly migraine days was calculated as the average number of migraine days per month during the last 3 months (months 4, 5, and 6) of the 24-week double-blind treatment phase – the number of migraine days during the 4-week baseline phase. The analysis was conducted in the efficacy analysis set which includes participants who received at least 1 dose of study drug and had at least 1 change from baseline measurement in monthly migraine days in the double-blind treatment phase.
    End point type
    Primary
    End point timeframe
    4-week baseline phase and the last 3 months (months 4, 5, and 6) of the 24-week double-blind treatment phase
    End point values
    		 Placebo Erenumab 70 mg QM Erenumab 140 mg QM
    Number of subjects analysed
    316
    312
    318
    Units: migraine days / month
        least squares mean (standard error)
    -1.83 ( 0.18 )
    -3.23 ( 0.18 )
    -3.67 ( 0.18 )
    Statistical analysis title
    		 Analysis of Monthly Migraine Days
    Statistical analysis description
    The primary endpoint was analyzed using a generalized linear mixed model which includes treatment, visit, treatment by visit interaction, stratification factors (region and prior/current treatment with migraine prophylactic medication), and baseline value as covariates.
    Comparison groups
    Placebo v Erenumab 70 mg QM
    Number of subjects included in analysis
    628
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.001
    Method
    		 Generalized Linear Mixed Model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.88
         upper limit
    		 -0.92
    Notes
    [1] - The primary endpoint was tested independently for each erenumab dose at an alpha level of 0.04 for 70 mg and of 0.01 for 140 mg to maintain the type 1 error rate at an alpha level of 0.05.
    Statistical analysis title
    		 Analysis of Monthly Migraine Days
    Statistical analysis description
    The primary endpoint was analyzed using a generalized linear mixed model which includes treatment, visit, treatment by visit interaction, stratification factors (region and prior/current treatment with migraine prophylactic medication), and baseline value as covariates.
    Comparison groups
    Placebo v Erenumab 140 mg QM
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.001
    Method
    		 Generalized Linear Mixed Model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.33
         upper limit
    		 -1.37
    Notes
    [2] - The primary endpoint was tested independently for each erenumab dose at an alpha level of 0.04 for 70 mg and of 0.01 for 140 mg to maintain the type 1 error rate at an alpha level of 0.05.

    Secondary: Percentage of Participants with at Least a 50% Reduction From Baseline in Monthly Migraine Days in the Last 3 Months of the Double-blind Treatment Phase

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    End point title
    		 Percentage of Participants with at Least a 50% Reduction From Baseline in Monthly Migraine Days in the Last 3 Months of the Double-blind Treatment Phase
    End point description
    A migraine day was any calendar day in which the participant experienced a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). A qualified migraine headache was defined either as a migraine without aura or a migraine with aura. At least a 50% reduction from baseline in monthly migraine days was determined if the change in monthly migraine days from the 4-week baseline phase to the last 3 months (mean of months 4, 5 and 6) of the 24-week double-blind treatment phase * 100 / baseline monthly migraine days was less than or equal to -50%. The analysis was conducted in the efficacy analysis set which includes participants who received at least 1 dose of study drug and had at least 1 change from baseline measurement in monthly migraine days in the double-blind treatment phase. Participants with missing data at months 4, 5, and 6 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    4-week baseline phase and the last 3 months (months 4, 5, and 6) of the 24-week double-blind treatment phase
    End point values
    		 Placebo Erenumab 70 mg QM Erenumab 140 mg QM
    Number of subjects analysed
    316
    312
    318
    Units: percentage of participants
        number (not applicable)
    26.6
    43.3
    50.0
    Statistical analysis title
    		 Analysis of Migraine Response
    Statistical analysis description
    Analyzed using a Cochran-Mantel-Haenszel test, stratified by the randomization stratification factors (region and prior/current treatment with migraine prophylactic medication).
    Comparison groups
    Placebo v Erenumab 70 mg QM
    Number of subjects included in analysis
    628
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.52
         upper limit
    		 2.98
    Notes
    [3] - If the primary endpoint was statistically significant for the erenumab 70 mg group, using a gate-keeping strategy, the first two (first tier) secondary endpoints were tested using the Hochberg method at an alpha level of 0.04.
    Statistical analysis title
    		 Analysis of Migraine Response
    Statistical analysis description
    Analyzed using a Cochran-Mantel-Haenszel test, stratified by the randomization stratification factors (region and prior/current treatment with migraine prophylactic medication).
    Comparison groups
    Placebo v Erenumab 140 mg QM
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.01
         upper limit
    		 3.94
    Notes
    [4] - If the primary endpoint was statistically significant for the erenumab 140 mg group, using a gate-keeping strategy, the first two (first tier) secondary endpoints were tested using the Hochberg method at an alpha level of 0.01.

    Secondary: Change From Baseline in Mean Monthly Acute Migraine-specific Medication Treatment Days to the Last 3 Months of the Double-blind Treatment Period

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    End point title
    		 Change From Baseline in Mean Monthly Acute Migraine-specific Medication Treatment Days to the Last 3 Months of the Double-blind Treatment Period
    End point description
    Monthly acute migraine-specific medication treatment days is the number of days on which migraine specific medications were used between monthly doses of study drug. Migraine-specific medications includes two categories of medications: triptan-based migraine medications and ergotamine-based migraine medications. The change from baseline in monthly acute migraine-specific treatment days was calculated as the average number of migraine-specific treatment days per month during the last 3 months of the 24-week double-blind treatment phase – the number of migraine-specific treatment days during the 4-week baseline phase. The analysis was conducted in the efficacy analysis set which includes participants who received at least 1 dose of study drug and had at least 1 change from baseline measurement in monthly acute migraine-specific treatment days in the double-blind treatment phase.
    End point type
    Secondary
    End point timeframe
    4-week baseline phase and the last 3 months (months 4, 5, and 6) of the 24-week double-blind treatment phase
    End point values
    		 Placebo Erenumab 70 mg QM Erenumab 140 mg QM
    Number of subjects analysed
    316
    312
    318
    Units: Acute migraine-specific med days/mo
        least squares mean (standard error)
    -0.20 ( 0.11 )
    -1.13 ( 0.11 )
    -1.61 ( 0.11 )
    Statistical analysis title
    		 Analysis of Migraine Treatment Days
    Statistical analysis description
    Analyzed using a generalized linear mixed model which includes treatment, visit, treatment by visit interaction, stratification factors (region and prior/current treatment with migraine prophylactic medication), and baseline value as covariates.
    Comparison groups
    Placebo v Erenumab 70 mg QM
    Number of subjects included in analysis
    628
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.001
    Method
    		 Generalized Linear Mixed Model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.23
         upper limit
    		 -0.64
    Notes
    [5] - If the primary endpoint was statistically significant for the erenumab 70 mg group, using a gate-keeping strategy, the first two (first tier) secondary endpoints were tested using the Hochberg method at an alpha level of 0.04.
    Statistical analysis title
    		 Analysis of Migraine Treatment Days
    Statistical analysis description
    Analyzed using a generalized linear mixed model which includes treatment, visit, treatment by visit interaction, (stratification factors region and prior/current treatment with migraine prophylactic medication), and baseline value as covariates.
    Comparison groups
    Placebo v Erenumab 140 mg QM
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 < 0.001
    Method
    		 Generalized Linear Mixed Model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.71
         upper limit
    		 -1.12
    Notes
    [6] - If the primary endpoint was statistically significant for the erenumab 140 mg group, using a gate-keeping strategy, the first two (first tier) secondary endpoints were tested using the Hochberg method at an alpha level of 0.01.

    Secondary: Change From Baseline in Mean Monthly Average Physical Impairment Domain Score Measured by MPFID in the Last 3 Months of the Double-blind Treatment Phase

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    End point title
    		 Change From Baseline in Mean Monthly Average Physical Impairment Domain Score Measured by MPFID in the Last 3 Months of the Double-blind Treatment Phase
    End point description
    The Migraine Physical Function Impact Diary (MPFID) is a self-administered 13-item instrument measuring physical functioning. It has two domains, Impact on Everyday Activities (7 items) and Physical Impairment (5 items), and a stand-alone global question. Participants completed the MPFID daily based on the past 24 hours. Difficulty items ranged from “Without any difficulty” (1) to “Unable to do” (5) and frequency items ranged from “None of the time” (1) to “All of the time” (5). For each domain, response scores were summed and rescaled to 0 – 100, where higher scores represent greater impact of migraine. Change from baseline was calculated as mean monthly average physical impairment score over the last 3 months of the DBTP - baseline monthly average physical impairment score. The analysis was conducted in the efficacy analysis set including participants who received ≥ 1 dose of study drug and had ≥ 1 change from baseline in MPFID average physical impairment domain score in the DBTP.
    End point type
    Secondary
    End point timeframe
    4-week baseline phase and the last 3 months (months 4, 5, and 6) of the 24-week double-blind treatment phase
    End point values
    		 Placebo Erenumab 70 mg QM Erenumab 140 mg QM
    Number of subjects analysed
    316
    312
    318
    Units: units on a scale
        least squares mean (standard error)
    -2.38 ( 0.40 )
    -4.24 ( 0.40 )
    -4.81 ( 0.40 )
    Statistical analysis title
    		 Analysis of Average Physical Impairment Score
    Statistical analysis description
    Analyzed using a generalized linear mixed model which includes treatment, visit, treatment by visit interaction, stratification factors (region and prior/current treatment with migraine prophylactic medication), and baseline value as covariates.
    Comparison groups
    Placebo v Erenumab 140 mg QM
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.001
    Method
    		 Generalized Linear Mixed Model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.51
         upper limit
    		 -1.35
    Notes
    [7] - If the first tier secondary endpoints were statistically significant for both erenumab doses the erenumab 140 mg group for the 2 remaining MPFID secondary endpoints was tested using the Hochberg method at a level of 0.05; If only the erenumab 70 mg group or 140 mg group showed statistical significance for the first tier secondary endpoints then the erenumab 140 group for the 2 remaining MPFID secondary endpoints was tested for significance at a level of either 0.04 or 0.01 respectively.
    Statistical analysis title
    		 Analysis of Average Physical Impairment Score
    Statistical analysis description
    Analyzed using a generalized linear mixed model which includes treatment, visit, treatment by visit interaction, stratification factors (region and prior/current treatment with migraine prophylactic medication), and baseline value as covariates.
    Comparison groups
    Placebo v Erenumab 70 mg QM
    Number of subjects included in analysis
    628
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 < 0.001
    Method
    		 Generalized Linear Mixed Model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.95
         upper limit
    		 -0.77
    Notes
    [8] - If the erenumab 140 mg group for both remaining MPFID secondary endpoints was statistically significant, then the erenumab 70 mg group for the two remaining MPFID secondary endpoints was tested for significance using the Hochberg method with the same alpha level carried over from 140 mg group.

    Secondary: Change From Baseline in Mean Monthly Average Impact on Everyday Activities Score Measured by MPFID in the Last 3 Months of the Double-blind Treatment Phase

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    End point title
    		 Change From Baseline in Mean Monthly Average Impact on Everyday Activities Score Measured by MPFID in the Last 3 Months of the Double-blind Treatment Phase
    End point description
    The MPFID is a self-administered 13-item instrument measuring physical functioning. It has two domains, Impact on Everyday Activities (7 items) and Physical Impairment (5 items), and a stand-alone global question. Participants completed the MPFID daily based on the past 24 hours. Difficulty items ranged from “Without any difficulty” (1) to “Unable to do” (5) and frequency items ranged from “None of the time” (1) to “All of the time” (5). For each domain, response scores were summed and rescaled to 0 – 100, where higher scores represent greater impact of migraine. Change from baseline was calculated as mean monthly impact on everyday activities score over the last 3 months of the DBTP – baseline monthly impact on everyday activities score. The analysis was conducted in the efficacy analysis set including participants who received ≥ 1 dose of study drug and had ≥ 1 change from baseline measurement in MPFID average impact on everyday activities domain score in the DBTP.
    End point type
    Secondary
    End point timeframe
    4-week baseline phase and the last 3 months (months 4, 5, and 6) of the 24-week double-blind treatment phase
    End point values
    		 Placebo Erenumab 70 mg QM Erenumab 140 mg QM
    Number of subjects analysed
    316
    312
    318
    Units: units on a scale
        least squares mean (standard error)
    -3.30 ( 0.39 )
    -5.52 ( 0.39 )
    -5.86 ( 0.39 )
    Statistical analysis title
    		 Analysis of Impact on Everyday Activities Score
    Statistical analysis description
    Analyzed using a generalized linear mixed model which includes treatment, visit, treatment by visit interaction, stratification factors (region and prior/current treatment with migraine prophylactic medication), and baseline value as covariates.
    Comparison groups
    Placebo v Erenumab 140 mg QM
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 < 0.001
    Method
    		 Generalized Linear Mixed Model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.62
         upper limit
    		 -1.51
    Notes
    [9] - If the first tier secondary endpoints were statistically significant for both erenumab doses the erenumab 140 mg group for the 2 remaining MPFID secondary endpoints was tested using the Hochberg method at a level of 0.05; If only the erenumab 70 mg group or 140 mg group showed statistical significance for the first tier secondary endpoints then the erenumab 140 group for the 2 remaining MPFID secondary endpoints was tested for significance at a level of either 0.04 or 0.01 respectively.
    Statistical analysis title
    		 Analysis of Impact on Everyday Activities Score
    Statistical analysis description
    Analyzed using a generalized linear mixed model which includes treatment, visit, treatment by visit interaction, stratification factors (region and prior/current treatment with migraine prophylactic medication), and baseline value as covariates.
    Comparison groups
    Placebo v Erenumab 70 mg QM
    Number of subjects included in analysis
    628
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 < 0.001
    Method
    		 Generalized Linear Mixed Model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.28
         upper limit
    		 -1.16
    Notes
    [10] - If the erenumab 140 mg group for both remaining MPFID secondary endpoints was statistically significant, then the erenumab 70 mg group for the two remaining MPFID secondary endpoints was tested for significance using the Hochberg method with the same alpha level carried over from 140 mg group.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to 16 weeks after the last dose. The double-blind treatment phase was 24 weeks and the open-label treatment phase was 28 weeks.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Double-blind Treatment Phase: Placebo
    Reporting group description
    		 Participants received placebo once a month (QM) by subcutaneous injection on day 1 and weeks 4, 8, 12, 16, and 20 in the 24-week double-blind treatment phase.

    Reporting group title
    Double-blind Treatment Phase: Erenumab 70 mg
    Reporting group description
    		 Participants received erenumab 70 mg QM by subcutaneous injection on day 1 and weeks 4, 8, 12, 16, and 20 in the 24-week double-blind treatment phase.

    Reporting group title
    Double-blind Treatment Phase: Erenumab 140 mg
    Reporting group description
    		 Participants received erenumab 140 mg QM by subcutaneous injection on day 1 and weeks 4, 8, 12, 16, and 20 in the 24-week double-blind treatment phase.

    Reporting group title
    Active Treatment Phase: Erenumab 70 mg
    Reporting group description
    		 Participants received erenumab 70 mg subcutaneously at weeks 24, 28, 32, 36, 40, 44, and 48 in the active treatment phase.

    Reporting group title
    Active Treatment Phase: Erenumab 140 mg
    Reporting group description
    		 Participants received erenumab 140 mg subcutaneously at weeks 24, 28, 32, 36, 40, 44, and 48 in the active treatment phase.

    Serious adverse events
    		 Double-blind Treatment Phase: Placebo Double-blind Treatment Phase: Erenumab 70 mg Double-blind Treatment Phase: Erenumab 140 mg Active Treatment Phase: Erenumab 70 mg Active Treatment Phase: Erenumab 140 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 319 (2.19%)
    8 / 314 (2.55%)
    8 / 319 (2.51%)
    14 / 421 (3.33%)
    14 / 424 (3.30%)
         number of deaths (all causes)
    0
    0
    0
    0
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    0 / 421 (0.00%)
    1 / 424 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast fibroma
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    0 / 421 (0.00%)
    1 / 424 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prolactin-producing pituitary tumour
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    0 / 421 (0.00%)
    1 / 424 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    1 / 319 (0.31%)
    0 / 421 (0.00%)
    1 / 424 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    1 / 421 (0.24%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 319 (0.31%)
    1 / 314 (0.32%)
    1 / 319 (0.31%)
    0 / 421 (0.00%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    0 / 421 (0.00%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast cyst
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    0 / 421 (0.00%)
    1 / 424 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    0 / 421 (0.00%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 314 (0.32%)
    0 / 319 (0.00%)
    0 / 421 (0.00%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Nasal septum deviation
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    1 / 421 (0.24%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    1 / 421 (0.24%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    1 / 319 (0.31%)
    0 / 421 (0.00%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    0 / 421 (0.00%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    1 / 421 (0.24%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    0 / 421 (0.00%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post-traumatic neck syndrome
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 314 (0.32%)
    0 / 319 (0.00%)
    0 / 421 (0.00%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    0 / 421 (0.00%)
    1 / 424 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    0 / 421 (0.00%)
    1 / 424 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    1 / 421 (0.24%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Arrhythmogenic right ventricular dysplasia
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    0 / 421 (0.00%)
    1 / 424 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardiac disorders
    Pericarditis
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    0 / 421 (0.00%)
    1 / 424 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral venous thrombosis
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    1 / 319 (0.31%)
    0 / 421 (0.00%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Idiopathic intracranial hypertension
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    1 / 421 (0.24%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 314 (0.32%)
    0 / 319 (0.00%)
    0 / 421 (0.00%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Migraine with aura
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    1 / 421 (0.24%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    1 / 319 (0.31%)
    1 / 421 (0.24%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    1 / 421 (0.24%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Idiopathic orbital inflammation
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    1 / 421 (0.24%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    1 / 421 (0.24%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    1 / 421 (0.24%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    1 / 421 (0.24%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 319 (0.00%)
    2 / 314 (0.64%)
    0 / 319 (0.00%)
    0 / 421 (0.00%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    0 / 421 (0.00%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 314 (0.32%)
    0 / 319 (0.00%)
    0 / 421 (0.00%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    0 / 421 (0.00%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    1 / 319 (0.31%)
    0 / 421 (0.00%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    0 / 421 (0.00%)
    1 / 424 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    1 / 319 (0.31%)
    0 / 421 (0.00%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    0 / 421 (0.00%)
    2 / 424 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    0 / 421 (0.00%)
    1 / 424 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    1 / 319 (0.31%)
    0 / 421 (0.00%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    1 / 319 (0.31%)
    0 / 421 (0.00%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative abscess
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    1 / 421 (0.24%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    1 / 319 (0.31%)
    0 / 421 (0.00%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 314 (0.32%)
    0 / 319 (0.00%)
    0 / 421 (0.00%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    1 / 319 (0.31%)
    0 / 421 (0.00%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    1 / 319 (0.31%)
    0 / 421 (0.00%)
    0 / 424 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 314 (0.00%)
    0 / 319 (0.00%)
    0 / 421 (0.00%)
    1 / 424 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Double-blind Treatment Phase: Placebo Double-blind Treatment Phase: Erenumab 70 mg Double-blind Treatment Phase: Erenumab 140 mg Active Treatment Phase: Erenumab 70 mg Active Treatment Phase: Erenumab 140 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    53 / 319 (16.61%)
    53 / 314 (16.88%)
    54 / 319 (16.93%)
    83 / 421 (19.71%)
    63 / 424 (14.86%)
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    19 / 319 (5.96%)
    21 / 314 (6.69%)
    15 / 319 (4.70%)
    25 / 421 (5.94%)
    19 / 424 (4.48%)
         occurrences all number
    26
    26
    18
    27
    21
    Viral upper respiratory tract infection
         subjects affected / exposed
    34 / 319 (10.66%)
    32 / 314 (10.19%)
    39 / 319 (12.23%)
    58 / 421 (13.78%)
    44 / 424 (10.38%)
         occurrences all number
    44
    40
    46
    73
    56

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Oct 2015
    • Allowed patients to be on 1 stable migraine prophylactic treatment while on-study to evaluate the effect of AMG 334 in a broader patient population. • Updated C-SSRS language to provide guidance to physician or study center staff in case of any suicidal ideation or behavior. • Removed several exploratory endpoints from inclusion in supplemental statistical analysis. • Updated pregnancy and lactation reporting. • Added collection of menses start date each month to allow for subgroup analysis of the effect of AMG 334 on menstrual-related migraine
    03 Jun 2016
    • Revised and reordered 2 MPFID-related secondary objectives/endpoints to include a definition of treatment response. - On the basis of the results of the observational validation study 20140136, a within-subject reduction in MPFID score of ≥ 5 points from month 1 to month 4 was determined to represent a clinically meaningful change for each MPFID domain. This a priori responder definition was therefore incorporated into the 2 MPFID-related secondary endpoints of this study protocol. • Included an unblinded, interim analysis (safety data only) of the active treatment period that would only be implemented in the event that 140 mg SC QM is selected as the dose for commercialization. This analysis would provide long-term safety data on subjects exposed to 140 mg AMG 334 SC QM. • Revised 2 MPFID-related exploratory objectives/endpoints. • Allowed for the collection of data on: - use of triptans or ergotamine-derivatives before the study - employment status - migraine triggers • Updated AMG 334 safety and tolerability data. • Made minor text clarifications, additions, and edits throughout the protocol.
    18 Oct 2016
    • Reverted the 2 MPFID-related secondary objectives/endpoints to those in in the original protocol. • On the basis of the primary analysis of phase 3 study 20120297 in episodic migraine, it was found that the responder definition in the 2 MPFID-related secondary dichotomous endpoints (ie, ≥ 5 point reduction in the physical impairment domain and impact on everyday activities domain as measured by the MPFID) derived from a previous observational study may not be as appropriate as the continuous measure of MPFID scores, as implemented in the MPFID-related exploratory endpoints. Therefore, the 2 MPFID-related secondary endpoints were switched with corresponding exploratory endpoints.

    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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