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    Clinical Trial Results:
    A Phase 2a Randomized Double-blind Placebo Controlled Study to Evaluate the Efficacy and Safety of AMG 301 in Migraine Prevention

    Summary
    EudraCT number
    		 2017-000630-57
    Trial protocol
    		 CZ   DK   SE   FI   DE   AT   NL  
    Global end of trial date
    04 Feb 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Feb 2020
    First version publication date
    15 Feb 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    20150308
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03238781
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen, Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, 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
    04 Feb 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Feb 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of AMG 301 compared to placebo on the change from the baseline period in monthly migraine days in subjects with migraine.
    Protection of trial subjects
    The protocol, protocol amendments, informed consent form, Investigator’s Brochure, and other relevant documents (eg, subject recruitment advertisements) were submitted to an Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs) by the investigator and reviewed and approved by the IRB/IEC. A copy of the written approval of the protocol and informed consent form were received by Amgen before recruitment of subjects into the study and shipment of Amgen investigational product. The investigator or his/her delegated representative (a physician) explained to the subject the aims, methods, anticipated benefits, and potential hazards of the study before any protocol-specific screening procedures or any investigational product(s) were administered, and answered all questions regarding the study. Subjects must be informed that their participation is voluntary.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Sep 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 24
    Country: Number of subjects enrolled
    United States: 129
    Country: Number of subjects enrolled
    Austria: 15
    Country: Number of subjects enrolled
    Czech Republic: 61
    Country: Number of subjects enrolled
    Denmark: 33
    Country: Number of subjects enrolled
    Finland: 32
    Country: Number of subjects enrolled
    Germany: 33
    Country: Number of subjects enrolled
    Sweden: 16
    Worldwide total number of subjects
    343
    EEA total number of subjects
    190
    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)
    343
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 510 subjects were screened.

    Pre-assignment
    Screening details
    		 Participants were randomized 4:3:3 to placebo, AMG 301 210 mg Q4W, or AMG 301 420 mg Q2W, respectively. The randomization was stratified by • chronic migraine versus episodic migraine and • North America versus Rest of World.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject
    Blinding implementation details
    Individual subject treatment assignments were maintained by the IVR/IWR System. Any unplanned unblinding occurring during the study period were documented and reported in the final clinical study report.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants randomized to Placebo were administered 6 subcutaneous (SC) injections on day 1 and weeks 2, 4, 6, 8 and 10 during the 12 week double-blind treatment period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo was presented in identical containers, stored/packaged the same as AMG 301. All injections were administered within 30 minutes on treatment days.

    Arm title
    		 AMG 301 210 mg Q4W
    Arm description
    		 Participants randomized to AMG 301 210 mg every fourth week (Q4W) received a total of 3 AMG 301 subcutaneous (SC) injections (70 mg/mL in each injection) plus 3 matching placebo injections on day 1 and weeks 4 and 8. Participants also received 6 SC placebo injections on weeks 2, 6, and 10 during the 12 week double-blind treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AMG 301
    Investigational medicinal product code
    Other name
    human monoclonal immunoglobulin G1 antagonist
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    AMG 301 was packaged in 5 mL clear glass vials containing 1 mL of 70 mg/mL of AMG 301. All injections were administered within 30 minutes on treatment days.

    Arm title
    		 AMG 301 420 mg Q2W
    Arm description
    		 Participants randomized to AMG 301 420 mg every second week (Q2W) received a total of 6 AMG 301 subcutaneous (SC) injections (70 mg/mL in each injection) on day 1 and weeks 2, 4, 6, 8, and 10 during the 12 week double-blind treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AMG 301
    Investigational medicinal product code
    Other name
    human monoclonal immunoglobulin G1 antagonist
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    AMG 301 was packaged in 5 mL clear glass vials containing 1 mL of 70 mg/mL of AMG 301. All injections were administered within 30 minutes on treatment days.

    Number of subjects in period 1
    		Placebo AMG 301 210 mg Q4W AMG 301 420 mg Q2W
    Started
    137
    104
    102
    Completed
    111
    87
    82
    Not completed
    26
    17
    20
         Consent withdrawn by subject
    23
    14
    16
         Adverse event, non-fatal
    1
    1
    2
         Lost to follow-up
    2
    1
    2
         Decision by sponsor
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants randomized to Placebo were administered 6 subcutaneous (SC) injections on day 1 and weeks 2, 4, 6, 8 and 10 during the 12 week double-blind treatment period.

    Reporting group title
    AMG 301 210 mg Q4W
    Reporting group description
    		 Participants randomized to AMG 301 210 mg every fourth week (Q4W) received a total of 3 AMG 301 subcutaneous (SC) injections (70 mg/mL in each injection) plus 3 matching placebo injections on day 1 and weeks 4 and 8. Participants also received 6 SC placebo injections on weeks 2, 6, and 10 during the 12 week double-blind treatment period.

    Reporting group title
    AMG 301 420 mg Q2W
    Reporting group description
    		 Participants randomized to AMG 301 420 mg every second week (Q2W) received a total of 6 AMG 301 subcutaneous (SC) injections (70 mg/mL in each injection) on day 1 and weeks 2, 4, 6, 8, and 10 during the 12 week double-blind treatment period.

    Reporting group values
    		 Placebo AMG 301 210 mg Q4W AMG 301 420 mg Q2W Total
    Number of subjects
    		 137 104 102 343
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 137 104 102 343
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 41.8 ( 9.9 ) 42.3 ( 9.7 ) 42.5 ( 9.4 ) -
    Sex: Female, Male
    Units:
        Female
    		 117 94 90 301
        Male
    		 20 10 12 42
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 6 6 3 15
        Not Hispanic or Latino
    		 131 98 99 328
        Unknown or Not Reported
    		 0 0 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 0 1
        Asian
    		 0 0 2 2
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 6 2 4 12
        White
    		 129 100 96 325
        More than one race
    		 1 0 0 1
        Unknown or Not Reported
    		 1 1 0 2
    Baseline Migraine Type
    Chronic migraine (CM) was defined as: >= 15 headache days of which >= 8 headache days meet criteria as migraine days during the baseline period based on the electronic diary (eDiary) calculations. Episodic migraine was defined as: <15 headache days of which >=4 headache days meet criteria as migraine days during the baseline period based on the eDiary calculations.
    Units: Subjects
        Chronic migraine
    		 44 39 36 119
        Episodic migraine
    		 93 65 66 224
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 71.8 ( 15.0 ) 73.8 ( 17.2 ) 72.1 ( 14.9 ) -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 168.27 ( 7.82 ) 167.05 ( 8.56 ) 167.55 ( 7.72 ) -
    Body Mass Index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 25.29 ( 4.66 ) 26.37 ( 5.45 ) 25.64 ( 4.78 ) -
    Monthly Migraine Days
    A migraine day is any calendar day from the eDiary in which the participant experienced a migraine headache. A migraine headache is a headache with or without aura, lasting for >= 4 hours, and meeting >=1 of the criteria: a) >= 2 pain features (unilateral, throbbing, moderate to severe, exacerbated with exercise/physical activity) b) >= 1 symptoms (nausea and/or vomiting, photophobia and phonophobia) If the participant took a migraine-specific medication during aura or to treat headache, it was counted as a migraine day. Baseline timeframe was the 28-day period prior to study treatment.
    Units: days
        arithmetic mean (standard deviation)
    		 12.18 ( 5.14 ) 12.47 ( 4.78 ) 12.14 ( 5.32 ) -
    Monthly Headache Days
    A headache day is any calendar day from the eDiary in which the participant experiences a headache (initial onset, continuation or recurrence of the headache). A qualified headache is defined as: - a migraine headache (including an aura-only event that is treated with acute migraine-specific medication), or - a non-migraine headache, which is a headache that lasts >= 4 hours and is not a migraine headache, or - a headache of any duration for which acute headache treatment is administered. Baseline timeframe was the 28-day period prior to study treatment.
    Units: days
        arithmetic mean (standard deviation)
    		 13.45 ( 5.27 ) 13.85 ( 4.90 ) 13.09 ( 5.24 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants randomized to Placebo were administered 6 subcutaneous (SC) injections on day 1 and weeks 2, 4, 6, 8 and 10 during the 12 week double-blind treatment period.

    Reporting group title
    AMG 301 210 mg Q4W
    Reporting group description
    		 Participants randomized to AMG 301 210 mg every fourth week (Q4W) received a total of 3 AMG 301 subcutaneous (SC) injections (70 mg/mL in each injection) plus 3 matching placebo injections on day 1 and weeks 4 and 8. Participants also received 6 SC placebo injections on weeks 2, 6, and 10 during the 12 week double-blind treatment period.

    Reporting group title
    AMG 301 420 mg Q2W
    Reporting group description
    		 Participants randomized to AMG 301 420 mg every second week (Q2W) received a total of 6 AMG 301 subcutaneous (SC) injections (70 mg/mL in each injection) on day 1 and weeks 2, 4, 6, 8, and 10 during the 12 week double-blind treatment period.

    Primary: Change from Baseline in Monthly Migraine Days to the Last 4 Weeks of the 12 Week Double-Blind Treatment Period

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    End point title
    		 Change from Baseline in Monthly Migraine Days to the Last 4 Weeks of the 12 Week Double-Blind Treatment Period
    End point description
    A migraine day is any calendar day from the eDiary in which the participant experienced a migraine headache. A migraine headache is a headache with or without aura, lasting for >= 4 hours, and meeting >=1 of the criteria: a) >= 2 pain features (unilateral, throbbing, moderate to severe, exacerbated with exercise/physical activity) b) >= 1 symptoms (nausea and/or vomiting, photophobia and phonophobia) If the participant took a migraine-specific medication during aura or to treat headache, it was counted as a migraine day. Days without eDiary data in each monthly interval are handled by proration. Negative change from baseline values indicated improvement (i.e. fewer migraine days after treatment as compared to baseline).
    End point type
    Primary
    End point timeframe
    Baseline Day -28 to Day -1; Weeks 9-12
    End point values
    		 Placebo AMG 301 210 mg Q4W AMG 301 420 mg Q2W
    Number of subjects analysed
    119
    93
    85
    Units: days
        least squares mean (standard error)
    -2.45 ( 0.40 )
    -2.20 ( 0.45 )
    -2.19 ( 0.46 )
    Statistical analysis title
    		 Monthly Migraine Days: AMG301 210mg Q4W - Placebo
    Statistical analysis description
    An adjusted analysis is presented that utilized a generalized linear mixed model which included treatment, visit, treatment-by-visit interaction, stratification factors of region and baseline migraine frequency (chronic migraine vs episodic migraine), and baseline value as covariates and assuming a first-order autoregressive covariance structure. The p-values for pairwise comparisons versus placebo are nominal p-values without multiplicity adjustment.
    Comparison groups
    Placebo v AMG 301 210 mg Q4W
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.66 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 difference in least square mean
    Point estimate
    0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.88
         upper limit
    		 1.4
    Notes
    [1] - 2-sided significance level of 0.05
    Statistical analysis title
    		 Monthly Migraine Days: AMG301 420mg Q2W - Placebo
    Statistical analysis description
    An adjusted analysis is presented that utilized a generalized linear mixed model which included treatment, visit, treatment-by-visit interaction, stratification factors of region and baseline migraine frequency (chronic migraine vs episodic migraine), and baseline value as covariates and assuming a first-order autoregressive covariance structure. The p-values for pairwise comparisons versus placebo are nominal p-values without multiplicity adjustment.
    Comparison groups
    Placebo v AMG 301 420 mg Q2W
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.65 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 difference in least square mean
    Point estimate
    0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.89
         upper limit
    		 1.43
    Notes
    [2] - 2-sided significance level of 0.05

    Secondary: Percentage of Participants Who Responded, Defined as At Least a 50% Reduction from the Baseline Period in Monthly Migraine Days in the Last 4 Weeks of the 12-Week Double-Blind Treatment Period

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    End point title
    		 Percentage of Participants Who Responded, Defined as At Least a 50% Reduction from the Baseline Period in Monthly Migraine Days in the Last 4 Weeks of the 12-Week Double-Blind Treatment Period
    End point description
    Responders are participants who had at least a 50% reduction from baseline in monthly migraine days during the last 4 weeks of treatment in the 12-week double blind period.
    End point type
    Secondary
    End point timeframe
    Baseline Day -28 to Day -1; Weeks 9-12
    End point values
    		 Placebo AMG 301 210 mg Q4W AMG 301 420 mg Q2W
    Number of subjects analysed
    119
    93
    85
    Units: percentage of participants
        number (not applicable)
    22.7
    19.4
    18.8
    Statistical analysis title
    		 50% Migraine Days: AMG301 210mg Q4W - Placebo
    Statistical analysis description
    The common odds ratios and p-values are obtained from a Cochran-Mantel-Haenszel test, stratified by stratification factors of region and baseline migraine frequency (chronic migraine vs episodic migraine).
    Comparison groups
    Placebo v AMG 301 210 mg Q4W
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.57 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 1.62
    Notes
    [3] - 2-sided significance level of 0.05
    Statistical analysis title
    		 50% Migraine Days: AMG301 420mg Q2W - Placebo
    Statistical analysis description
    The common odds ratios and p-values are obtained from a Cochran-Mantel-Haenszel test, stratified by stratification factors of region and baseline migraine frequency (chronic migraine vs episodic migraine).
    Comparison groups
    Placebo v AMG 301 420 mg Q2W
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.45 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 1.54
    Notes
    [4] - 2-sided significance level of 0.05

    Secondary: Change from Baseline Period in Monthly Acute Migraine-Specific Medication Days in the Last 4 Weeks of the 12-Week Double-Blind Treatment Period

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    End point title
    		 Change from Baseline Period in Monthly Acute Migraine-Specific Medication Days in the Last 4 Weeks of the 12-Week Double-Blind Treatment Period
    End point description
    Number of days on which acute headache medications (triptans and ergotamine-derivatives, alone or in combination) are used as recorded in eDiary. Monthly acute headache medication treatment days at baseline are the number of acute headache medication treatment days in the baseline period. Days without eDiary data are handled by proration. Negative change from baseline values indicate improvement (i.e. fewer days requiring acute migraine-specific medications after treatment as compared to baseline).
    End point type
    Secondary
    End point timeframe
    Baseline Day -28 to Day -1; Weeks 9-12
    End point values
    		 Placebo AMG 301 210 mg Q4W AMG 301 420 mg Q2W
    Number of subjects analysed
    103
    84
    76
    Units: days
        least squares mean (standard error)
    -1.25 ( 0.29 )
    -1.28 ( 0.33 )
    -1.34 ( 0.34 )
    Statistical analysis title
    		 Migraine Meds: AMG301 210mg Q4W - Placebo
    Statistical analysis description
    Adjusted analysis utilizes a generalized linear mixed model which includes treatment, visit, treatment-by-visit interaction, stratification factors of region and baseline migraine frequency (CM versus EM), and baseline value as covariates and assuming a first-order autoregressive covariance structure. The p-values for pairwise comparisons versus placebo are nominal p-values without multiplicity adjustment.
    Comparison groups
    Placebo v AMG 301 210 mg Q4W
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.94 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 difference in least square mean
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.87
         upper limit
    		 0.81
    Notes
    [5] - 2-sided significance level of 0.05
    Statistical analysis title
    		 Migraine Meds: AMG301 420mg Q2W - Placebo
    Comparison groups
    Placebo v AMG 301 420 mg Q2W
    Number of subjects included in analysis
    179
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.84 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 difference in least square mean
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.94
         upper limit
    		 0.77
    Notes
    [6] - 2-sided significance level of 0.05

    Secondary: Change from Baseline in Mean Physical Impairment Domain Scores as Measured by the Migraine Physical Function Impact Diary (MPFID) Over the Last 4 Weeks of the 12-Week Double-Blind Treatment Period

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    End point title
    		 Change from Baseline in Mean Physical Impairment Domain Scores as Measured by the Migraine Physical Function Impact Diary (MPFID) Over the Last 4 Weeks of the 12-Week Double-Blind Treatment Period
    End point description
    Participants complete the MPFID every day during baseline (Days -28 to Day -1) and the 12-week Double Blind Treatment Period. The MPFID has 2 domains, Impact on Everyday Activities (7 items) and Physical Impairment (5 items), and 1 stand-alone global question that provides an assessment of the overall impact of migraine on participants’ everyday activities. The recall period for each item is the past 24 hours. The Physical Impairment Domain Score is reported here. A participant's response to the difficulty of the 5 physical impairment items is measured using a 5-point scale, with difficulty measurements ranging from 1 to 5. The sum was rescaled to a 0 to 100 scale, with 0=no difficulty and 100=unable to do (maximum burden). Negative change from baseline values indicate improvement in migraine impact.
    End point type
    Secondary
    End point timeframe
    Baseline Day -28 to Day -1; Weeks 9-12
    End point values
    		 Placebo AMG 301 210 mg Q4W AMG 301 420 mg Q2W
    Number of subjects analysed
    119
    93
    86
    Units: units on a scale
        least squares mean (standard error)
    -2.44 ( 0.78 )
    -2.72 ( 0.89 )
    -2.13 ( 0.91 )
    Statistical analysis title
    		 Phys Impair: AMG301 210mg Q4W - Placebo
    Statistical analysis description
    An adjusted analysis is presented that utilized a generalized linear mixed model which included treatment, visit, treatment-by-visit interaction, stratification factors of region and baseline migraine frequency (chronic migraine vs episodic migraine), and baseline value as covariates and assuming a first-order autoregressive covariance structure. The p-values for pairwise comparisons versus placebo are nominal p-values without multiplicity adjustment.
    Comparison groups
    Placebo v AMG 301 210 mg Q4W
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.81 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 difference in least square mean
    Point estimate
    -0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.56
         upper limit
    		 2.01
    Notes
    [7] - 2-sided significance level of 0.05
    Statistical analysis title
    		 Phys Impair: AMG301 420mg Q2W - Placebo
    Statistical analysis description
    An adjusted analysis is presented that utilized a generalized linear mixed model which included treatment, visit, treatment-by-visit interaction, stratification factors of region and baseline migraine frequency (chronic migraine vs episodic migraine), and baseline value as covariates and assuming a first-order autoregressive covariance structure. The p-values for pairwise comparisons versus placebo are nominal p-values without multiplicity adjustment.
    Comparison groups
    Placebo v AMG 301 420 mg Q2W
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.79 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 difference in least square mean
    Point estimate
    0.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.01
         upper limit
    		 2.63
    Notes
    [8] - 2-sided significance level of 0.05

    Secondary: Change from Baseline in Mean Impact on Everyday Activity Domain Scores as Measured by the Migraine Physical Function Impact Diary (MPFID) Over the Last 4 Weeks of the 12-Week Double-Blind Treatment Period

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    End point title
    		 Change from Baseline in Mean Impact on Everyday Activity Domain Scores as Measured by the Migraine Physical Function Impact Diary (MPFID) Over the Last 4 Weeks of the 12-Week Double-Blind Treatment Period
    End point description
    Participants complete the MPFID every day during baseline (Days -28 to Day -1) and the 12-week Double Blind Treatment Period. The MPFID has 2 domains, Impact on Everyday Activities (7 items) and Physical Impairment (5 items), and 1 stand-alone global question that provides an assessment of the overall impact of migraine on participants’ everyday activities. The recall period for each item is the past 24 hours. The Impact on Everyday Activities Domain Score is reported here. A participant's response to the Impact on Everyday Activities 7 items is measured using a 5-point scale, with difficulty measurements ranging from 1 to 5. The sum was rescaled to a 0 to 100 scale, with 0=no difficulty and 100=unable to do (maximum burden). Negative change from baseline values indicate improvement in migraine impact.
    End point type
    Secondary
    End point timeframe
    Baseline Day -28 to Day -1; Weeks 9-12
    End point values
    		 Placebo AMG 301 210 mg Q4W AMG 301 420 mg Q2W
    Number of subjects analysed
    119
    93
    86
    Units: units on a scale
        least squares mean (standard error)
    -3.42 ( 0.79 )
    -4.28 ( 0.89 )
    -2.86 ( 0.92 )
    Statistical analysis title
    		 Everyday Act: AMG301 210mg Q4W - Placebo
    Statistical analysis description
    An adjusted analysis is presented that utilized a generalized linear mixed model which included treatment, visit, treatment-by-visit interaction, stratification factors of region and baseline migraine frequency (chronic migraine vs episodic migraine), and baseline value as covariates and assuming a first-order autoregressive covariance structure. The p-values for pairwise comparisons versus placebo are nominal p-values without multiplicity adjustment.
    Comparison groups
    Placebo v AMG 301 210 mg Q4W
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.46 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 difference in least square mean
    Point estimate
    -0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.15
         upper limit
    		 1.44
    Notes
    [9] - 2-sided significance level of 0.05
    Statistical analysis title
    		 Everyday Act: AMG301 420mg Q2W - Placebo
    Statistical analysis description
    An adjusted analysis is presented that utilized a generalized linear mixed model which included treatment, visit, treatment-by-visit interaction, stratification factors of region and baseline migraine frequency (chronic migraine vs episodic migraine), and baseline value as covariates and assuming a first-order autoregressive covariance structure. The p-values for pairwise comparisons versus placebo are nominal p-values without multiplicity adjustment.
    Comparison groups
    Placebo v AMG 301 420 mg Q2W
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.64 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 difference in least square mean
    Point estimate
    0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.77
         upper limit
    		 2.89
    Notes
    [10] - 2-sided significance level of 0.05

    Secondary: Participants with Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Participants with Treatment-Emergent Adverse Events (TEAEs)
    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.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Week 28 (12 weeks of double-blind treatment plus 16 weeks follow-up after last dose of investigational product)
    End point values
    		 Placebo AMG 301 210 mg Q4W AMG 301 420 mg Q2W
    Number of subjects analysed
    137
    104
    102
    Units: participants
        >= 1 TEAE
    90
    71
    65
        Severity grade >= 2
    41
    43
    39
        Severity grade >= 3
    9
    5
    8
        Severity grade >= 4
    0
    1
    0
        Serious TEAE
    3
    1
    2
        TEAE leading to discontinuation of IP
    3
    2
    5
        Fatal TEAE
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Met Hy’s Law Criteria at Baseline and On Study

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    End point title
    		 Percentage of Participants Who Met Hy’s Law Criteria at Baseline and On Study
    End point description
    Hy's law predicts potential for drug-related hepatotoxicity. Hy's Law cases have three components: - The drug causes hepatocellular injury, generally defined as an elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) by 3-fold or greater above the upper limit of normal (ULN). - Among participants showing such aminotransferase elevations, they also have elevation of their serum total bilirubin of greater than 2 times the ULN, without findings of cholestasis (defined as serum alkaline phosphatase activity less than 2 times the upper limit of normal). - No other reason can be found to explain the combination of increased aminotransferase and serum total bilirubin, such as viral hepatitis, alcohol abuse, ischemia, preexisting liver disease, or another drug capable of causing the observed injury.
    End point type
    Secondary
    End point timeframe
    Baseline: Day 1 On study: Weeks 4, 6, 12, 20, 28
    End point values
    		 Placebo AMG 301 210 mg Q4W AMG 301 420 mg Q2W
    Number of subjects analysed
    137
    104
    102
    Units: percentage of participants
        Baseline
    0
    0
    0
        On study (n=136, 104, 100)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Aminotransferase Test Abnormalities > 3 Times the Upper Limit of Normal (ULN) at Baseline and On Study

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    End point title
    		 Percentage of Participants With Aminotransferase Test Abnormalities > 3 Times the Upper Limit of Normal (ULN) at Baseline and On Study
    End point description
    Aminotransferase tests included alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Percentage of participants with results that were greater than 3 * ULN for either test are reported.
    End point type
    Secondary
    End point timeframe
    Baseline: Day 1 On study: Weeks 4, 6, 12, 20, 28
    End point values
    		 Placebo AMG 301 210 mg Q4W AMG 301 420 mg Q2W
    Number of subjects analysed
    137
    104
    102
    Units: percentage of participants
    number (not applicable)
        Baseline
    0
    1.9
    0
        On study (n=136, 104, 100)
    0.7
    1.9
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Total Bilirubin Test Abnormalities > 2 Times the Upper Limit of Normal (ULN) at Baseline and On Study

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    End point title
    		 Percentage of Participants With Total Bilirubin Test Abnormalities > 2 Times the Upper Limit of Normal (ULN) at Baseline and On Study
    End point description
    Percentage of participants with total bilirubin results that were greater than 2 * ULN are reported.
    End point type
    Secondary
    End point timeframe
    Baseline: Day 1 On study: Weeks 4, 6, 12, 20, 28
    End point values
    		 Placebo AMG 301 210 mg Q4W AMG 301 420 mg Q2W
    Number of subjects analysed
    137
    104
    102
    Units: percentage of participants
        Baseline
    0
    0
    0
        On study (n=136, 104, 100)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Systolic Blood Pressure (SBP) in Categories by Visit

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    End point title
    		 Percentage of Participants with Systolic Blood Pressure (SBP) in Categories by Visit
    End point description
    Participant was expected to be in a supine position (or the most recumbent position possible) in a rested and calm state for at least 5 minutes before blood pressure assessments were conducted. Blood pressure units are millimeters of mercury (mmHg).
    End point type
    Secondary
    End point timeframe
    Day 1, Weeks 2, 4, 6, 8, 10, 12,16, 20, 24, 28
    End point values
    		 Placebo AMG 301 210 mg Q4W AMG 301 420 mg Q2W
    Number of subjects analysed
    137
    104
    102
    Units: percentage of participants
    number (not applicable)
        Day 1 SBP <90 mmHg
    0.9
    0.0
    0.0
        Day 1 SBP > 140 mmHg
    5.5
    7.9
    4.9
        Day 1 SBP > 160 mmHg
    0.9
    0.0
    0.0
        Week 2 SBP < 90 mmHg
    1.5
    0.0
    0.0
        Week 2 SBP > 140 mmHg
    5.2
    2.9
    8.0
        Week 2 SBP > 160 mmHg
    0.0
    0.0
    1.0
        Week 4 SBP < 90 mmHg
    0.0
    0.0
    0.0
        Week 4 SBP > 140 mmHg
    3.0
    3.0
    6.2
        Week 4 SBP > 160 mmHg
    0.7
    0.0
    1.0
        Week 6 SBP < 90 mmHg
    0.8
    0.0
    0.0
        Week 6 SBP > 140 mmHg
    3.1
    3.1
    3.2
        Week 6 SBP > 160 mmHg
    0.0
    0.0
    0.0
        Week 8 SBP < 90 mmHg
    0.0
    0.0
    0.0
        Week 8 SBP > 140 mmHg
    2.3
    5.4
    8.5
        Week 8 SBP > 160 mmHg
    0.0
    0.0
    1.1
        Week 10 SBP < 90 mmHg
    0.0
    0.0
    0.0
        Week 10 SBP > 140 mmHg
    4.1
    1.1
    2.2
        Week 10 SBP > 160 mmHg
    0.0
    0.0
    2.2
        Week 12 SBP < 90 mmHg
    0.8
    0.0
    0.0
        Week 12 SBP > 140 mmHg
    6.4
    2.2
    5.7
        Week 12 SBP > 160 mmHg
    0.0
    0.0
    0.0
        Week 16 SBP < 90 mmHg
    0.9
    0.0
    0.0
        Week 16 SBP > 140 mmHg
    4.4
    4.4
    5.7
        Week 16 SBP > 160 mmHg
    0.0
    0.0
    3.4
        Week 20 SBP < 90 mmHg
    0.9
    0.0
    0.0
        Week 20 SBP > 140 mmHg
    4.4
    8.1
    7.3
        Week 20 SBP > 160 mmHg
    0.9
    0.0
    0.0
        Week 24 SBP < 90 mmHg
    0.0
    1.2
    0.0
        Week 24 SBP > 140 mmHg
    4.7
    6.1
    8.9
        Week 24 SBP > 160 mmHg
    0.0
    0.0
    0.0
        Week 28 SBP < 90 mmHg
    0.9
    1.2
    0.0
        Week 28 SBP > 140 mmHg
    8.3
    4.7
    6.3
        Week 28 SBP > 160 mmHg
    0.9
    1.2
    0.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Diastolic Blood Pressure (DBP) in Categories by Visit

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    End point title
    		 Percentage of Participants with Diastolic Blood Pressure (DBP) in Categories by Visit
    End point description
    Participant was expected to be in a supine position (or the most recumbent position possible) in a rested and calm state for at least 5 minutes before blood pressure assessments were conducted. Blood pressure units are millimeters of mercury (mmHg).
    End point type
    Secondary
    End point timeframe
    Day 1, Weeks 2, 4, 6, 8, 10, 12,16, 20, 24, 28
    End point values
    		 Placebo AMG 301 210 mg Q4W AMG 301 420 mg Q2W
    Number of subjects analysed
    137
    104
    102
    Units: percentage of participants
    number (not applicable)
        Day 1 DBP <50 mmHg
    0.0
    0.0
    0.0
        Day 1 DBP > 90 mmHg
    4.5
    6.7
    7.4
        Day 1 DBP > 100 mmHg
    0.0
    1.1
    0.0
        Week 2 DBP <50 mmHg
    0.7
    0.0
    0.0
        Week 2 DBP > 90 mmHg
    3.7
    4.9
    11.0
        Week 2 DBP > 100 mmHg
    0.7
    1.0
    0.0
        Week 4 DBP <50 mmHg
    0.7
    0.0
    0.0
        Week 4 DBP > 90 mmHg
    5.2
    7.0
    9.3
        Week 4 DBP > 100 mmHg
    0.7
    2.0
    1.0
        Week 6 DBP <50 mmHg
    0.0
    0.0
    0.0
        Week 6 DBP > 90 mmHg
    9.2
    3.1
    7.4
        Week 6 DBP > 100 mmHg
    0.0
    0.0
    1.1
        Week 8 DBP <50 mmHg
    0.0
    0.0
    0.0
        Week 8 DBP > 90 mmHg
    4.6
    6.5
    9.6
        Week 8 DBP > 100 mmHg
    0.0
    1.1
    0.0
        Week 10 DBP <50 mmHg
    0.0
    0.0
    0.0
        Week 10 DBP > 90 mmHg
    6.6
    4.3
    9.9
        Week 10 DBP > 100 mmHg
    0.0
    0.0
    1.1
        Week 12 DBP <50 mmHg
    0.0
    0.0
    0.0
        Week 12 DBP > 90 mmHg
    7.2
    3.3
    8.0
        Week 12 DBP > 100 mmHg
    0.0
    0.0
    1.1
        Week 16 DBP <50 mmHg
    0.0
    0.0
    0.0
        Week 16 DBP > 90 mmHg
    5.3
    5.6
    12.5
        Week 16 DBP > 100 mmHg
    0.0
    0.0
    2.3
        Week 20 DBP <50 mmHg
    0.0
    0.0
    0.0
        Week 20 DBP > 90 mmHg
    8.0
    8.1
    7.3
        Week 20 DBP > 100 mmHg
    0.0
    1.2
    1.2
        Week 24 DBP <50 mmHg
    0.0
    0.0
    0.0
        Week 24 DBP > 90 mmHg
    4.7
    7.3
    11.4
        Week 24 DBP > 100 mmHg
    0.0
    2.4
    1.3
        Week 28 DBP <50 mmHg
    0.0
    0.0
    0.0
        Week 28 DBP > 90 mmHg
    4.6
    10.6
    10.0
        Week 28 DBP > 100 mmHg
    0.0
    1.2
    1.3
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Pulse Rate in Categories by Visit

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    End point title
    		 Percentage of Participants with Pulse Rate in Categories by Visit
    End point description
    Participant was expected to be in a supine position (or the most recumbent position possible) in a rested and calm state for at least 5 minutes before pulse assessments were conducted. Pulse rate units are beats per minute (BPM)
    End point type
    Secondary
    End point timeframe
    Day 1, Weeks 2, 4, 6, 8, 10, 12,16, 20, 24, 28
    End point values
    		 Placebo AMG 301 210 mg Q4W AMG 301 420 mg Q2W
    Number of subjects analysed
    137
    104
    102
    Units: percentage of participants
    number (not applicable)
        Day 1 Pulse rate <60 bpm
    15.5
    13.5
    6.2
        Day 1 Pulse rate >100 bpm
    0.0
    0.0
    0.0
        Week 2 Pulse rate <60 bpm
    11.2
    4.9
    6.0
        Week 2 Pulse rate >100 bpm
    0.7
    1.0
    0.0
        Week 4 Pulse rate <60 bpm
    10.4
    8.0
    6.2
        Week 4 Pulse rate >100 bpm
    0.7
    0.0
    0.0
        Week 6 Pulse rate <60 bpm
    6.9
    8.2
    9.6
        Week 6 Pulse rate >100 bpm
    0.8
    0.0
    1.1
        Week 8 Pulse rate <60 bpm
    9.2
    7.6
    12.8
        Week 8 Pulse rate >100 bpm
    1.5
    0.0
    0.0
        Week 10 Pulse rate <60 bpm
    11.5
    8.6
    6.6
        Week 10 Pulse rate >100 bpm
    0.0
    0.0
    0.0
        Week 12 Pulse rate <60 bpm
    13.6
    13.0
    8.0
        Week 12 Pulse rate >100 bpm
    0.0
    1.1
    1.1
        Week 16 Pulse rate <60 bpm
    10.6
    8.9
    8.0
        Week 16 Pulse rate >100 bpm
    0.0
    0.0
    0.0
        Week 20 Pulse rate <60 bpm
    10.6
    9.3
    9.8
        Week 20 Pulse rate >100 bpm
    0.9
    1.2
    1.2
        Week 24 Pulse rate <60 bpm
    10.4
    8.5
    7.6
        Week 24 Pulse rate >100 bpm
    0.0
    1.2
    1.3
        Week 28 Pulse rate <60 bpm
    8.3
    11.8
    10.0
        Week 28 Pulse rate >100 bpm
    0.9
    1.2
    0.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Temperature in Categories by Visit

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    End point title
    		 Percentage of Participants with Temperature in Categories by Visit
    End point description
    Participant was expected to be in a supine position (or the most recumbent position possible) in a rested and calm state for at least 5 minutes before vital sign assessments were conducted. Temperature units are reported in degrees Celsius (C).
    End point type
    Secondary
    End point timeframe
    Day 1, Weeks 2, 4, 6, 8, 10, 12,16, 20, 24, 28
    End point values
    		 Placebo AMG 301 210 mg Q4W AMG 301 420 mg Q2W
    Number of subjects analysed
    137
    104
    102
    Units: percentage of participants
    number (not applicable)
        Day 1 Temperature < 36 C
    5.5
    10.1
    7.4
        Day 1 Temperature > 38 C
    0.0
    0.0
    0.0
        Week 2 Temperature < 36 C
    11.2
    9.8
    8.0
        Week 2 Temperature > 38 C
    0.0
    0.0
    0.0
        Week 4 Temperature < 36 C
    8.9
    12.0
    10.3
        Week 4 Temperature > 38 C
    0.0
    0.0
    0.0
        Week 6 Temperature < 36 C
    6.1
    12.4
    8.5
        Week 6 Temperature > 38 C
    0.0
    0.0
    0.0
        Week 8 Temperature < 36 C
    7.7
    7.6
    8.5
        Week 8 Temperature > 38 C
    0.0
    0.0
    0.0
        Week 10 Temperature < 36 C
    9.0
    14.0
    7.7
        Week 10 Temperature > 38 C
    0.0
    0.0
    0.0
        Week 12 Temperature < 36 C
    8.0
    13.0
    12.5
        Week 12 Temperature > 38 C
    0.8
    0.0
    0.0
        Week 16 Temperature < 36 C
    6.2
    7.8
    13.6
        Week 16 Temperature > 38 C
    0.0
    0.0
    0.0
        Week 20 Temperature < 36 C
    10.6
    7.0
    9.8
        Week 20 Temperature > 38 C
    0.0
    0.0
    0.0
        Week 24 Temperature < 36 C
    5.7
    8.5
    11.4
        Week 24 Temperature > 38 C
    0.0
    0.0
    0.0
        Week 28 Temperature < 36 C
    6.5
    9.4
    11.3
        Week 28 Temperature > 38 C
    0.0
    0.0
    0.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Respiratory Rates in Categories by Visit

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    End point title
    		 Percentage of Participants with Respiratory Rates in Categories by Visit
    End point description
    Participant was expected to be in a supine position (or the most recumbent position possible) in a rested and calm state for at least 5 minutes before vital sign assessments were conducted. Respiratory rate (RR) is reported in breaths/minute.
    End point type
    Secondary
    End point timeframe
    Day 1, Weeks 2, 4, 6, 8, 10, 12,16, 20, 24, 28
    End point values
    		 Placebo AMG 301 210 mg Q4W AMG 301 420 mg Q2W
    Number of subjects analysed
    137
    104
    102
    Units: percentage of participants
    number (not applicable)
        Day 1 RR < 12 breaths/min
    4.6
    2.2
    3.8
        Day 1 RR > 20 breaths/min
    0.0
    2.2
    1.3
        Week 2 RR < 12 breaths/min
    5.2
    2.9
    5.0
        Week 2 RR > 20 breaths/min
    0.0
    0.0
    0.0
        Week 4 RR < 12 breaths/min
    2.2
    3.0
    5.2
        Week 4 RR > 20 breaths/min
    0.0
    0.0
    2.1
        Week 6 RR < 12 breaths/min
    6.1
    1.0
    4.3
        Week 6 RR > 20 breaths/min
    0.8
    0.0
    0.0
        Week 8 RR < 12 breaths/min
    3.1
    2.2
    1.1
        Week 8 RR > 20 breaths/min
    0.0
    2.2
    0.0
        Week 10 RR < 12 breaths/min
    5.7
    1.1
    4.4
        Week 10 RR > 20 breaths/min
    0.0
    2.2
    0.0
        Week 12 RR < 12 breaths/min
    4.0
    1.1
    0.0
        Week 12 RR > 20 breaths/min
    0.0
    0.0
    0.0
        Week 16 RR < 12 breaths/min
    4.4
    2.2
    4.5
        Week 16 RR > 20 breaths/min
    0.0
    1.1
    0.0
        Week 20 RR < 12 breaths/min
    5.3
    0.0
    1.2
        Week 20 RR > 20 breaths/min
    0.0
    1.2
    0.0
        Week 24 RR < 12 breaths/min
    1.9
    0.0
    0.0
        Week 24 RR > 20 breaths/min
    0.0
    4.9
    0.0
        Week 28 RR < 12 breaths/min
    3.7
    1.2
    2.5
        Week 28 RR > 20 breaths/min
    0.9
    2.4
    1.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 up to Week 28 (12 weeks of double-blind treatment plus 16 weeks follow-up after last dose of investigational product)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants randomized to Placebo were administered 6 subcutaneous (SC) injections on day 1 and weeks 2, 4, 6, 8 and 10 during the 12 week double-blind treatment period.

    Reporting group title
    AMG 301 210 mg Q4W
    Reporting group description
    		 Participants randomized to AMG 301 210 mg every fourth week (Q4W) received a total of 3 AMG 301 subcutaneous (SC) injections (70 mg/mL in each injection) plus 3 matching placebo injections on day 1 and weeks 4 and 8. Participants also received 6 SC placebo injections on weeks 2, 6, and 10 during the 12 week double-blind treatment period.

    Reporting group title
    AMG 301 420 mg Q2W
    Reporting group description
    		 Participants randomized to AMG 301 420 mg every second week (Q2W) received a total of 6 AMG 301 subcutaneous (SC) injections (70 mg/mL in each injection) on day 1 and weeks 2, 4, 6, 8, and 10 during the 12 week double-blind treatment period.

    Serious adverse events
    		 Placebo AMG 301 210 mg Q4W AMG 301 420 mg Q2W
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 137 (2.19%)
    1 / 104 (0.96%)
    2 / 102 (1.96%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Nervous system disorders
    Migraine with aura
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    0 / 102 (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
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Polycystic ovaries
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 102 (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
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    0 / 102 (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
    Erythema nodosum
         subjects affected / exposed
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    0 / 102 (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
    		 Placebo AMG 301 210 mg Q4W AMG 301 420 mg Q2W
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 137 (23.36%)
    27 / 104 (25.96%)
    31 / 102 (30.39%)
    Nervous system disorders
    Migraine
         subjects affected / exposed
    3 / 137 (2.19%)
    2 / 104 (1.92%)
    6 / 102 (5.88%)
         occurrences all number
    3
    3
    7
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    8 / 137 (5.84%)
    5 / 104 (4.81%)
    9 / 102 (8.82%)
         occurrences all number
    8
    5
    12
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 137 (0.00%)
    4 / 104 (3.85%)
    6 / 102 (5.88%)
         occurrences all number
    0
    4
    6
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    8 / 137 (5.84%)
    3 / 104 (2.88%)
    1 / 102 (0.98%)
         occurrences all number
    8
    3
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    5 / 137 (3.65%)
    5 / 104 (4.81%)
    6 / 102 (5.88%)
         occurrences all number
    5
    5
    6
    Nasopharyngitis
         subjects affected / exposed
    13 / 137 (9.49%)
    10 / 104 (9.62%)
    7 / 102 (6.86%)
         occurrences all number
    16
    13
    10

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 May 2017
    - Clarified the number of subjects that were to be screened and enter baseline in order to achieve the target randomization - Clarified when vital signs, PK sampling, and Headache Impact Test were to be collected during the study - Clarified the risks and benefits of the study - Removal of legally acceptable representative from the study - Clarified that upon early discontinuation, a safety follow-up visit was to be performed approximately 30 (+-5) days after the last dosing interval of investigation product - Added additional information for sample size calculation for each AMG 301 group versus placebo - Clarified that the primary analysis set was also known as the efficacy analysis set - Clarified which primary and secondary endpoints were to be included in the interim analysis - Added the responsibilities of the Data Review Team during the double-blind treatment period - Clarified Amgen's regulatory responsibilities when an amendment was determined to be substantial
    17 Oct 2017
    - Updated schedule of activities and footnotes to maintain consistency with the protocol - Updated the exclusion screening criterion to maintain accordance with the World Health Organization's guidelines of assessing impaired glucose regulation/prediabetes with glycosylated hemoglobin (HbA1c) values

    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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