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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
    		 2014-004463-20
    Trial protocol
    		 PT   GR   DK   ES  
    Global end of trial date
    20 Mar 2017

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    20120297
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02483585
    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
    20 Mar 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the effect of erenumab (AMG 334) compared to placebo on the change from baseline in 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
    20 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
    United States: 338
    Country: Number of subjects enrolled
    Denmark: 99
    Country: Number of subjects enrolled
    France: 19
    Country: Number of subjects enrolled
    Greece: 25
    Country: Number of subjects enrolled
    Portugal: 14
    Country: Number of subjects enrolled
    Russian Federation: 33
    Country: Number of subjects enrolled
    Spain: 34
    Country: Number of subjects enrolled
    Switzerland: 15
    Worldwide total number of subjects
    577
    EEA total number of subjects
    191
    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)
    573
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 69 centers in Denmark, France, Greece, Portugal, Russia, Spain, Switzerland, and the USA. Participants were enrolled from 20 July 2015 to 19 April 2016.

    Pre-assignment
    Screening details
    		 Participants were randomized 1:1 to placebo or erenumab 70 mg once a month (QM). Randomization was stratified by region (North America vs Other) and treatment status with migraine prophylactic medication (current, prior, or no prior or current migraine prophylactic medication treatment).

    Period 1
    Period 1 title
    Double-blind Treatment Phase
    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 on day 1 and at weeks 4 and 8 by subcutaneous injection in the 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 once a month by subcutaneous injection

    Arm title
    		 Erenumab 70 mg QM
    Arm description
    		 Participants received erenumab 70 mg on day 1 and at weeks 4 and 8 by subcutaneous injection in the 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 once a month by subcutaneous injection

    Number of subjects in period 1
    		Placebo Erenumab 70 mg QM
    Started
    291
    286
    Received Treatment
    289
    283
    Completed
    275
    271
    Not completed
    16
    15
         Consent withdrawn by subject
    12
    12
         Decision by Sponsor
    1
    1
         Lost to follow-up
    3
    2
    Period 2
    Period 2 title
    Open-label Treatment Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo/Erenumab
    Arm description
    		 Participants who received placebo in the double-blind treatment phase received erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 in the open-label 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 once a month by subcutaneous injection

    Arm title
    		 Erenumab/Erenumab
    Arm description
    		 Participants who received erenumab in the double-blind treatment phase received erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 in the open-label 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 once a month by subcutaneous injection

    Number of subjects in period 2 [1]
    		Placebo/Erenumab Erenumab/Erenumab
    Started
    270
    268
    Completed
    243
    243
    Not completed
    27
    25
         Consent withdrawn by subject
    18
    14
         Protocol specified criteria
    6
    5
         Decision by Sponsor
    -
    1
         Lost to follow-up
    3
    5
    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: Eight subjects who completed the double-blind treatment phase did not continue onto the open-label treatment phase: 4 subjects withdrew consent and 4 subjects did not continue in the study due to ‘protocol specified criteria’.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase.

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

    Reporting group values
    		 Placebo Erenumab 70 mg QM Total
    Number of subjects
    		 291 286 577
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 290 283 573
        From 65-84 years
    		 1 3 4
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.2 ± 11.5 42.3 ± 11.4 -
    Gender Categorical
    Units: Subjects
        Female
    		 247 245 492
        Male
    		 44 41 85
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 2 2
        Black or African American
    		 27 24 51
        Multiple
    		 2 1 3
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        White
    		 259 259 518
        Other
    		 2 0 2
    Ethnicity
    Units: Subjects
        Hispanic/Latino
    		 34 23 57
        Not Hispanic/Latino
    		 257 263 520
    Region
    Units: Subjects
        North America
    		 170 168 338
        Other
    		 121 118 239
    Treatment Status with Migraine Prophylactic Medication
    Units: Subjects
        Current migraine prophylactic medication treatment
    		 18 17 35
        Prior migraine prophylactic treatment only
    		 120 119 239
        No prior / current migraine prophylactic treatment
    		 153 150 303
    Disease Duration of Migraine With or Without Aura
    Units: years
        arithmetic mean (standard deviation)
    		 20.03 ± 12.08 21.70 ± 12.62 -
    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.
    Units: days
        arithmetic mean (standard deviation)
    		 8.38 ± 2.60 8.14 ± 2.65 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase.

    Reporting group title
    Erenumab 70 mg QM
    Reporting group description
    		 Participants received erenumab 70 mg on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase.
    Reporting group title
    Placebo/Erenumab
    Reporting group description
    		 Participants who received placebo in the double-blind treatment phase received erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 in the open-label treatment phase.

    Reporting group title
    Erenumab/Erenumab
    Reporting group description
    		 Participants who received erenumab in the double-blind treatment phase received erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 in the open-label treatment phase.

    Subject analysis set title
    Double-blind Treatment Phase: Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants who received at least 1 dose of placebo by subcutaneous injection in the double-blind treatment period.

    Subject analysis set title
    Double-blind Treatment Phase: Erenumab 70 mg QM
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants who received at least 1 dose of erenumab 70 mg by subcutaneous injection in the double-blind treatment period.

    Subject analysis set title
    Open-label Treatment Phase: Erenumab 70 mg QM
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants who received at least 1 dose of erenumab 70 mg by subcutaneous injection in the open-label treatment period.

    Primary: Change from Baseline in Monthly Migraine Days at Week 12

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    End point title
    		 Change from Baseline in Monthly Migraine Days at Week 12
    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 number of migraine days during the last 4 weeks of the 12-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 day in the double-blind treatment phase.
    End point type
    Primary
    End point timeframe
    4-week baseline phase and the last 4 weeks of the 12-week double-blind treatment phase
    End point values
    		 Placebo Erenumab 70 mg QM
    Number of subjects analysed
    288 [1]
    282 [2]
    Units: migraine days / month
        least squares mean (standard error)
    -1.84 ± 0.21
    -2.88 ± 0.21
    Notes
    [1] - Participants in the efficacy analysis set
    [2] - Participants in the efficacy analysis set
    Statistical analysis title
    		 Primary Analysis
    Statistical analysis description
    The primary endpoint was analyzed using a linear mixed effects model including treatment group, baseline value, stratification factors (region and prior/current treatment with migraine prophylactic medication), scheduled visit, and the interaction of treatment group with scheduled visit.
    Comparison groups
    Placebo v Erenumab 70 mg QM
    Number of subjects included in analysis
    570
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.001
    Method
    		 Generalized linear mixed model
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.61
         upper limit
    		 -0.47
    Notes
    [3] - A sequential testing procedure, specifically, the hierarchical gate-keeping procedures and Hochberg method, was used to maintain the 2-sided study-wise type I error at 0.05 between the primary and efficacy secondary endpoints.

    Secondary: Percentage of Participants with at Least a 50% Reduction From Baseline in Monthly Migraine Days at Week 12

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    End point title
    		 Percentage of Participants with at Least a 50% Reduction From Baseline in Monthly Migraine Days at Week 12
    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. Monthly migraine days were calculated as the number of migraine days in the 4-week baseline phase and during the last 4 weeks of treatment. 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 4 weeks of the 12-week double-blind treatment phase * 100 / baseline monthly migraine days was less than or equal to -50%. This analysis was performed using the efficacy analysis set; participants with missing post-baseline data were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    4-week baseline phase and the last 4 weeks of the 12-week double-blind treatment phase
    End point values
    		 Placebo Erenumab 70 mg QM
    Number of subjects analysed
    288
    282
    Units: percentage of participants
        number (not applicable)
    29.5
    39.7
    Statistical analysis title
    		 Analysis of Reduction in Monthly Migraine Days
    Statistical analysis description
    Analyzed using a Cochran-Mantel-Haenszel (CMH) test after the missing data were imputed as non-response, stratified by 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
    570
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.12
         upper limit
    		 2.27

    Secondary: Change From Baseline in Monthly Acute Migraine-specific Medication Treatment Days at Week 12

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    End point title
    		 Change From Baseline in Monthly Acute Migraine-specific Medication Treatment Days at Week 12
    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. This analysis was performed using the efficacy analysis set.
    End point type
    Secondary
    End point timeframe
    4-week baseline phase and the last 4 weeks of the 12-week double-blind treatment phase
    End point values
    		 Placebo Erenumab 70 mg QM
    Number of subjects analysed
    288 [4]
    282 [5]
    Units: acute migraine treatment days / month
        least squares mean (standard error)
    -0.62 ± 0.14
    -1.21 ± 0.14
    Notes
    [4] - Efficacy analysis set
    [5] - Efficacy analysis set
    Statistical analysis title
    		 Analysis of Acute Migraine-specific Treatment
    Statistical analysis description
    Analyzed using a linear mixed effects model including treatment group, baseline value, stratification factors (region and prior/current treatment with migraine prophylactic medication), scheduled visit, and the interaction of treatment group with scheduled visit.
    Comparison groups
    Placebo v Erenumab 70 mg QM
    Number of subjects included in analysis
    570
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Generalized linear mixed model
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.96
         upper limit
    		 -0.21

    Secondary: Percentage of Participants with at Least a 5-point Reduction from Baseline in Average Impact on Everyday Activities Domain Score Measured by MPFID at Week 12

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    End point title
    		 Percentage of Participants with at Least a 5-point Reduction from Baseline in Average Impact on Everyday Activities Domain Score Measured by MPFID at Week 12
    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 one stand-alone global question. Participants respond to items on a 5-point scale, with difficulty items ranging from “Without any difficulty” (0) to “Unable to do” (5) and frequency items ranging from “None of the time” (0) to “All of the time” (5). For each domain, the scores were calculated as the sum of the responses and rescaled to a 0 – 100 scale, with higher scores representing greater impact of migraine. Monthly average MPFID score is the sum of observed MPFID scores divided by the total number of observed MPFID scores between monthly doses of study drug. The analysis was conducted in the efficacy analysis set; participants with missing post-baseline data were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    4-week baseline phase and the last 4 weeks of the 12-week double-blind treatment phase
    End point values
    		 Placebo Erenumab 70 mg QM
    Number of subjects analysed
    288
    282
    Units: percentage of participants
        number (not applicable)
    35.8
    40.4
    Statistical analysis title
    		 Analysis of Impact on Everyday Activities
    Statistical analysis description
    Analyzed using a Cochran-Mantel-Haenszel (CMH) test after the missing data were imputed as non-response, stratified by 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
    570
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.26
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.71

    Secondary: Percentage of Participants with at Least a 5 Point Reduction from Baseline in Average Impact on Physical Impairment Domain Score Measured by MPFID at Week 12

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    End point title
    		 Percentage of Participants with at Least a 5 Point Reduction from Baseline in Average Impact on Physical Impairment Domain Score Measured by MPFID at Week 12
    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 one stand-alone global question. Participants respond to items on a 5-point scale, with difficulty items ranging from “Without any difficulty” (0) to “Unable to do” (5) and frequency items ranging from “None of the time” (0) to “All of the time” (5). For each domain, the scores were calculated as the sum of the responses and rescaled to a 0 – 100 scale, with higher scores representing greater impact of migraine. Monthly average MPFID score is the sum of observed MPFID scores divided by the total number of observed MPFID scores between monthly doses of study drug. The analysis was conducted in the efficacy analysis set; participants with missing post-baseline data were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    4-week baseline phase and the last 4 weeks of the 12-week double-blind treatment phase
    End point values
    		 Placebo Erenumab 70 mg QM
    Number of subjects analysed
    288
    282
    Units: percentage of participants
        number (not applicable)
    27.1
    33.0
    Statistical analysis title
    		 Analysis of Reduction in Physical Impairment
    Statistical analysis description
    Analyzed using a Cochran-Mantel-Haenszel (CMH) test after the missing data were imputed as non-response, stratified by 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
    570
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.13
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 1.9

    Secondary: Number of Participants with Adverse Events

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    End point title
    		 Number of Participants with Adverse Events
    End point description
    Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4, where: Grade 1 = Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; Grade 2 = Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL); Grade 3 = Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL; Grade 4 = Life-threatening consequences; urgent intervention indicated Grade 5 = Death related to AE. For the double-blind treatment phase adverse events were analyzed for all randomized participants who received at least one dose of study drug. For the open-label treatment phase adverse events were analyzed for all participants who received at least one dose of study drug in the open-label treatment phase.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to 12 weeks after the last dose. The double-blind treatment phase was 12 weeks and the open-label treatment phase was 28 weeks.
    End point values
    		 Double-blind Treatment Phase: Placebo Double-blind Treatment Phase: Erenumab 70 mg QM Open-label Treatment Phase: Erenumab 70 mg QM
    Number of subjects analysed
    289
    283
    538
    Units: participants
        Any adverse event
    158
    136
    337
        Adverse event Grade ≥ 2
    96
    72
    245
        Adverse event Grade ≥ 3
    8
    6
    34
        Adverse event Grade ≥ 4
    0
    0
    2
        Serious adverse events
    5
    3
    15
        AE leading to discontinuation of study drug
    1
    5
    13
        Fatal adverse events
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants who Developed Antibodies to Erenumab

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    End point title
    		 Number of Participants who Developed Antibodies to Erenumab
    End point description
    Blood samples were first tested in an electrochemiluminescence (ECL)-based bridging immunoassay to detect anti-drug antibodies (ADA) against erenumab. Samples confirmed to be positive for binding antibodies were subsequently tested in a cell-based bioassay to determine neutralizing activity against erenumab (Neutralizing Antibody Assay). Developing antibody incidence indicates participants with a negative or no result at baseline and a positive result at any time post-baseline. If a sample was positive for binding antibodies and demonstrated neutralizing activity at the same time point, the sample was defined as positive for neutralizing antibodies. Transient indicates negative result at the subject's last time point tested, for those subjects with a positive binding/neutralizing result post-baseline. Participants who received at least one dose of erenumab and with post-baseline data are included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (the period prior to the first dose erenumab 70 mg) and post-baseline (the period after the first dose of erenumab 70 mg until 12 weeks after last dose)
    End point values
    		 Placebo Erenumab 70 mg QM
    Number of subjects analysed
    269 [6]
    279 [7]
    Units: participants
        Binding antibody positive
    25
    24
        -Transient binding antibody positive
    10
    11
        Neutralizing antibody positive
    0
    2
        -Transient neutralizing antibody positive
    0
    2
    Notes
    [6] - Participants who received at least one dose of erenumab 70 mg and with a post-baseline result
    [7] - Participants who received at least one dose of erenumab 70 mg and with a post-baseline result
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to 12 weeks after the last dose. The double-blind treatment phase was 12 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 (12 weeks): Placebo
    Reporting group description
    		 Participants received placebo on day 1 and at weeks 4 and 8 by subcutaneous injection during the double-blind treatment phase.

    Reporting group title
    Double-blind Treatment Phase (12 weeks): Erenumab 70 mg QM
    Reporting group description
    		 Participants received erenumab 70 mg on day 1 and at weeks 4 and 8 by subcutaneous injection.

    Reporting group title
    Open-label Treatment Phase (28 weeks): Erenumab 70 mg QM
    Reporting group description
    		 Participants received erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 during the open-label treatment phase.

    Serious adverse events
    		 Double-blind Treatment Phase (12 weeks): Placebo Double-blind Treatment Phase (12 weeks): Erenumab 70 mg QM Open-label Treatment Phase (28 weeks): Erenumab 70 mg QM
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 289 (1.73%)
    3 / 283 (1.06%)
    15 / 538 (2.79%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 289 (0.00%)
    0 / 283 (0.00%)
    2 / 538 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 283 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Nasal septal operation
         subjects affected / exposed
    0 / 289 (0.00%)
    0 / 283 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 283 (0.00%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometriosis
         subjects affected / exposed
    0 / 289 (0.00%)
    0 / 283 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 289 (0.00%)
    0 / 283 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngeal haematoma
         subjects affected / exposed
    0 / 289 (0.00%)
    0 / 283 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 289 (0.00%)
    0 / 283 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ligament rupture
         subjects affected / exposed
    0 / 289 (0.00%)
    0 / 283 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural pulmonary embolism
         subjects affected / exposed
    0 / 289 (0.00%)
    0 / 283 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 289 (0.00%)
    0 / 283 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 289 (0.00%)
    0 / 283 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Migraine
         subjects affected / exposed
    1 / 289 (0.35%)
    1 / 283 (0.35%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 289 (0.00%)
    0 / 283 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Iridocyclitis
         subjects affected / exposed
    0 / 289 (0.00%)
    0 / 283 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Visual acuity reduced
         subjects affected / exposed
    0 / 289 (0.00%)
    0 / 283 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    0 / 289 (0.00%)
    0 / 283 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 283 (0.00%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 289 (0.00%)
    0 / 283 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 283 (0.00%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 283 (0.35%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumococcal bacteraemia
         subjects affected / exposed
    0 / 289 (0.00%)
    0 / 283 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 289 (0.00%)
    0 / 283 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 289 (0.00%)
    0 / 283 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 289 (0.00%)
    0 / 283 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 283 (0.35%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 283 (0.00%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Double-blind Treatment Phase (12 weeks): Placebo Double-blind Treatment Phase (12 weeks): Erenumab 70 mg QM Open-label Treatment Phase (28 weeks): Erenumab 70 mg QM
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 289 (15.92%)
    54 / 283 (19.08%)
    140 / 538 (26.02%)
    Nervous system disorders
    Migraine
         subjects affected / exposed
    7 / 289 (2.42%)
    5 / 283 (1.77%)
    28 / 538 (5.20%)
         occurrences all number
    7
    6
    35
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    12 / 289 (4.15%)
    17 / 283 (6.01%)
    30 / 538 (5.58%)
         occurrences all number
    14
    32
    95
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    14 / 289 (4.84%)
    18 / 283 (6.36%)
    41 / 538 (7.62%)
         occurrences all number
    14
    20
    45
    Viral upper respiratory tract infection
         subjects affected / exposed
    17 / 289 (5.88%)
    17 / 283 (6.01%)
    53 / 538 (9.85%)
         occurrences all number
    18
    18
    61

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Oct 2015
    Major changes included: - Allowed subjects to be on 1 stable migraine prophylactic treatment while on study. This would allow evaluation of the effect of AMG 334 in a broader patient population. - Updated C-SSRS language to provide guidance to physician or site staff in case of any suicidal ideation or behavior. - Removed several exploratory endpoints to be included in the supplemental statistical analysis. - Updated pregnancy and lactation reporting guidance. - Added collection of menses start date each month to allow for subgroup analysis of effect of AMG 334 on menstrual-related migraine. - Added a blinded interim analysis to evaluate the new MPFID PRO instrument.
    26 May 2016
    - Refined and reordered 2 MPFID-related secondary objectives/endpoints to include a definition of treatment response. - On the basis of the results of the PRO 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. - Revised 2 PRO-related exploratory objectives/endpoints. - Allowed for the collection of data on use of triptans or ergotamine-derivatives prior to the study, employment status, and migraine triggers. - Updated AMG 334 safety and tolerability data. - Minor text clarifications, additions, and edits throughout the protocol were also made.

    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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