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    Clinical Trial Results:
    A Phase 4, Randomized, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy and Safety of Erenumab in Adults With Chronic Migraine and Medication Overuse Headache

    Summary
    EudraCT number
    		 2018-003342-16
    Trial protocol
    		 CZ   ES   PL   PT   FI   HU   GB   AT   IT  
    Global end of trial date
    23 Jun 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Mar 2024
    First version publication date
    09 Mar 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    20170703
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03971071
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States,
    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
    13 Jun 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jun 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective is to evaluate the effect of erenumab compared with placebo on achieving medication overuse headache (MOH) remission during the double-blind treatment period (DBTP).
    Protection of trial subjects
    The study was conducted in accordance with International Council for Harmonisation Good Clinical Practice regulations/guidelines. All participants provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, and all amendments, the informed consent form and any accompanying materials provided to the participants were reviewed and approved by the Institutional Review Boards or Independent Ethics Committee at each study center.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Oct 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 47
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Austria: 10
    Country: Number of subjects enrolled
    Czechia: 121
    Country: Number of subjects enrolled
    Finland: 33
    Country: Number of subjects enrolled
    France: 105
    Country: Number of subjects enrolled
    Hungary: 60
    Country: Number of subjects enrolled
    Italy: 57
    Country: Number of subjects enrolled
    Poland: 88
    Country: Number of subjects enrolled
    Portugal: 46
    Country: Number of subjects enrolled
    Spain: 46
    Country: Number of subjects enrolled
    United Kingdom: 6
    Worldwide total number of subjects
    620
    EEA total number of subjects
    566
    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)
    598
    From 65 to 84 years
    22
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants were enrolled at 67 study centers in North America, Europe, and Australia, and participated from 07 October 2019 to 13 June 2023.

    Pre-assignment
    Screening details
    		 Adults with chronic migraine and medication overuse headaches according to the International Classification of Headache Disorders 3rd Edition criteria were randomized 1:1:1 to receive erenumab 70 mg or 140 mg or matching placebo. Prior to enrollment and randomization, participants completed a 4-week baseline period to evaluate eligibility.

    Period 1
    Period 1 title
    Double-blind Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo (DBTP)
    Arm description
    		 Participants were randomized to receive matching placebo subcutaneously (SC) every 4 weeks (QM) for 24 weeks in the DBTP. Participants who successfully completed the DBTP could continue to the optional OLTP and were randomized 1:1 to receive erenumab 70 mg or 140 mg SC QM in the OLTP for up to 28 weeks.
    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
    Matching placebo was administered SC QM for 24 weeks in the DBTP.

    Arm title
    		 Erenumab 70 mg (DBTP)
    Arm description
    		 Participants were randomized to receive 1 mL of erenumab 70 mg/mL SC QM for 24 weeks in the DBTP. Participants who successfully completed the DBTP could continue to receive erenumab 70 mg in the optional OLTP for up to 28 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Erenumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Erenumab was administered SC QM for 24 weeks in the DBTP.

    Arm title
    		 Erenumab 140 mg (DBTP)
    Arm description
    		 Participants were randomized to receive 1 mL of erenumab 140 mg/mL SC QM for 24 weeks in the DBTP. Participants who successfully completed the DBTP could continue to receive erenumab 140 mg in the optional OLTP for up to 28 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Erenumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Erenumab was administered SC QM for 24 weeks in the DBTP.

    Number of subjects in period 1
    		Placebo (DBTP) Erenumab 70 mg (DBTP) Erenumab 140 mg (DBTP)
    Started
    206
    207
    207
    Opioid-treated: > 4 days/month
    12 [1]
    12 [2]
    12 [3]
    Nonopioid-treated: ≤ 4 days/month
    194 [4]
    195
    195 [5]
    Completed
    197
    193
    201
    Not completed
    9
    14
    6
         Consent withdrawn by subject
    7
    11
    6
         Not specified
    2
    2
    -
         Sponsor decision
    -
    1
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This milestone represents the opioid-treated cohort and included participants with > 4 days/ month of opioid medication use during the baseline period, and is included for purposes of exploratory analyses only.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This milestone represents the opioid-treated cohort and included participants with > 4 days/ month of opioid medication use during the baseline period, and is included for purposes of exploratory analyses only.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This milestone represents the opioid-treated cohort and included participants with > 4 days/ month of opioid medication use during the baseline period, and is included for purposes of exploratory analyses only.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This milestone represents the nonopioid-treated cohort and included participants with ≤ 4 days/ month of opioid medication use during the baseline period.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This milestone represents the nonopioid-treated cohort and included participants with ≤ 4 days/ month of opioid medication use during the baseline period.
    Period 2
    Period 2 title
    Open-label Treatment Period (OLTP)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Erenumab 70 mg (OLTP)
    Arm description
    		 Eligible participants continued to the Open-label Treatment Period (OLTP) and received erenumab 70 mg SC QM for 28 weeks (up to Week 52). Eligible participants included participants randomized to erenumab 70 mg in the DBTP and participants randomized to placebo in the DBTP, re-randomized to erenumab 70 mg in the OLTP.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Erenumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Erenumab was administered SC QM for 28 weeks in the OLTP.

    Arm title
    		 Erenumab 140 mg (OLTP)
    Arm description
    		 Eligible participants continued to the OLTP and received erenumab 140 mg SC QM for 28 weeks (up to Week 52). Eligible participants included participants randomized to erenumab 140 mg in the DBTP and participants randomized to placebo in the DBTP, re-randomized to erenumab 140 mg in the OLTP.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Erenumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Erenumab was administered SC QM for 28 weeks in the OLTP.

    Number of subjects in period 2 [6]
    		Erenumab 70 mg (OLTP) Erenumab 140 mg (OLTP)
    Started
    291
    296
    Completed
    281
    281
    Not completed
    10
    15
         Consent withdrawn by subject
    10
    13
         Sponsor decision
    -
    1
         Lost to follow-up
    -
    1
    Notes
    [6] - 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: The number of participants starting the OLTP included eligible participants who completed the DBTP, and not all participants proceeded to the optional OLTP.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo (DBTP)
    Reporting group description
    		 Participants were randomized to receive matching placebo subcutaneously (SC) every 4 weeks (QM) for 24 weeks in the DBTP. Participants who successfully completed the DBTP could continue to the optional OLTP and were randomized 1:1 to receive erenumab 70 mg or 140 mg SC QM in the OLTP for up to 28 weeks.

    Reporting group title
    Erenumab 70 mg (DBTP)
    Reporting group description
    		 Participants were randomized to receive 1 mL of erenumab 70 mg/mL SC QM for 24 weeks in the DBTP. Participants who successfully completed the DBTP could continue to receive erenumab 70 mg in the optional OLTP for up to 28 weeks.

    Reporting group title
    Erenumab 140 mg (DBTP)
    Reporting group description
    		 Participants were randomized to receive 1 mL of erenumab 140 mg/mL SC QM for 24 weeks in the DBTP. Participants who successfully completed the DBTP could continue to receive erenumab 140 mg in the optional OLTP for up to 28 weeks.

    Reporting group values
    		 Placebo (DBTP) Erenumab 70 mg (DBTP) Erenumab 140 mg (DBTP) Total
    Number of subjects
    		 206 207 207 620
    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)
    		 200 201 197 598
        From 65-84 years
    		 6 6 10 22
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.3 ( 12.5 ) 43.1 ( 11.6 ) 43.5 ( 12.2 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 166 170 174 510
        Male
    		 40 37 33 110
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 1 0 2
        Asian
    		 1 0 1 2
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 2 4 2 8
        White
    		 196 187 187 570
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 6 15 17 38
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 9 10 13 32
        Not Hispanic or Latino
    		 196 197 194 587
        Unknown or Not Reported
    		 1 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    Placebo (DBTP)
    Reporting group description
    		 Participants were randomized to receive matching placebo subcutaneously (SC) every 4 weeks (QM) for 24 weeks in the DBTP. Participants who successfully completed the DBTP could continue to the optional OLTP and were randomized 1:1 to receive erenumab 70 mg or 140 mg SC QM in the OLTP for up to 28 weeks.

    Reporting group title
    Erenumab 70 mg (DBTP)
    Reporting group description
    		 Participants were randomized to receive 1 mL of erenumab 70 mg/mL SC QM for 24 weeks in the DBTP. Participants who successfully completed the DBTP could continue to receive erenumab 70 mg in the optional OLTP for up to 28 weeks.

    Reporting group title
    Erenumab 140 mg (DBTP)
    Reporting group description
    		 Participants were randomized to receive 1 mL of erenumab 140 mg/mL SC QM for 24 weeks in the DBTP. Participants who successfully completed the DBTP could continue to receive erenumab 140 mg in the optional OLTP for up to 28 weeks.
    Reporting group title
    Erenumab 70 mg (OLTP)
    Reporting group description
    		 Eligible participants continued to the Open-label Treatment Period (OLTP) and received erenumab 70 mg SC QM for 28 weeks (up to Week 52). Eligible participants included participants randomized to erenumab 70 mg in the DBTP and participants randomized to placebo in the DBTP, re-randomized to erenumab 70 mg in the OLTP.

    Reporting group title
    Erenumab 140 mg (OLTP)
    Reporting group description
    		 Eligible participants continued to the OLTP and received erenumab 140 mg SC QM for 28 weeks (up to Week 52). Eligible participants included participants randomized to erenumab 140 mg in the DBTP and participants randomized to placebo in the DBTP, re-randomized to erenumab 140 mg in the OLTP.

    Primary: Number of Participants with Absence of Medication Overuse Headaches at Month 6

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    End point title
    		 Number of Participants with Absence of Medication Overuse Headaches at Month 6
    End point description
    Absence of medication overuse headaches at month 6 was defined as mean monthly acute headache medication days (AHMD) < 10 days over months 4, 5, and 6 (weeks 13 through 24) or mean monthly headache days (MHD) < 14 days over months 4, 5, and 6 (weeks 13 through 24) of the DBTP where an AHMD was defined as a calendar day in which the participant takes at least 1 acute headache medication. Efficacy analysis set (nonopioid-treated cohort): randomized participants with an opioid medication use of ≤ 4 days per month during the baseline period and who received at least 1 dose of IP during DBTP.
    End point type
    Primary
    End point timeframe
    Months 4, 5, and 6 (weeks 13 through 24) of the DBTP
    End point values
    		 Placebo (DBTP) Erenumab 70 mg (DBTP) Erenumab 140 mg (DBTP)
    Number of subjects analysed
    194
    194
    194
    Units: participants
    102
    117
    134
    Statistical analysis title
    		 Erenumab 140 mg versus Placebo
    Statistical analysis description
    Common odds ratio and p-value were obtained from a Cochran-Mantel-Haenszel test, stratified by concomitant oral migraine preventive treatment initiated before screening and taken during baseline (Yes or No).
    Comparison groups
    Placebo (DBTP) v Erenumab 140 mg (DBTP)
    Number of subjects included in analysis
    388
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Common Odds Ratio
    Point estimate
    2.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.33
         upper limit
    		 3.05
    Statistical analysis title
    		 Erenumab 70 mg versus Placebo
    Statistical analysis description
    Common odds ratio and p-value were obtained from a Cochran-Mantel-Haenszel test, stratified by concomitant oral migraine preventive treatment initiated before screening and taken during baseline (Yes or No).
    Comparison groups
    Placebo (DBTP) v Erenumab 70 mg (DBTP)
    Number of subjects included in analysis
    388
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.13
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Common Odds Ratio
    Point estimate
    1.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 2.05

    Secondary: Change from Baseline in Mean Monthly AHMDs Over Months 4, 5, and 6

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    End point title
    		 Change from Baseline in Mean Monthly AHMDs Over Months 4, 5, and 6
    End point description
    An AHMD was defined as a calendar day in which the participant takes at least 1 acute headache medication. Acute headache medications included triptan-based, ergotamine-based and ditan-based migraine medications, non-opioid and opioid-containing acute headache medications, non-opioid butalbital and opioid-containing butalbital containing medications. Efficacy analysis set (nonopioid-treated cohort): randomized participants with an opioid medication use of ≤ 4 days per month during the baseline period and who received at least 1 dose of IP during DBTP. Participants with evaluable data from weeks 13 through 24 are included.
    End point type
    Secondary
    End point timeframe
    Baseline and months 4, 5, and 6 (weeks 13 through 24) of the DBTP
    End point values
    		 Placebo (DBTP) Erenumab 70 mg (DBTP) Erenumab 140 mg (DBTP)
    Number of subjects analysed
    194
    193
    194
    Units: days per month
        least squares mean (standard error)
    -6.61 ( 0.41 )
    -7.83 ( 0.41 )
    -9.35 ( 0.41 )
    Statistical analysis title
    		 Erenumab 70 mg versus Placebo
    Statistical analysis description
    Covariates: treatment, visit, treatment-by-visit, concomitant oral migraine preventive treatment initiated before screening and taken during baseline (Yes or No), and baseline value.
    Comparison groups
    Placebo (DBTP) v Erenumab 70 mg (DBTP)
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.033 [1]
    Method
    		 Linear Mixed Model
    Parameter type
    		 Least squares mean difference
    Point estimate
    -1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.35
         upper limit
    		 -0.1
    Notes
    [1] - Nominal p-value is presented without multiplicity adjustment.
    Statistical analysis title
    		 Erenumab 140 mg versus Placebo
    Statistical analysis description
    Covariates: treatment, visit, treatment-by-visit, concomitant oral migraine preventive treatment initiated before screening and taken during baseline (Yes or No), and baseline value.
    Comparison groups
    Placebo (DBTP) v Erenumab 140 mg (DBTP)
    Number of subjects included in analysis
    388
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [2]
    Method
    		 Linear Mixed Model
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -2.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.87
         upper limit
    		 -1.62
    Notes
    [2] - Nominal p-value is presented without multiplicity adjustment.

    Secondary: Number of Participants with Sustained MOH Remission at Month 6

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    End point title
    		 Number of Participants with Sustained MOH Remission at Month 6
    End point description
    Sustained MOH remission was defined as the absence of MOH at month 3 (week 12) and month 6 (week 24) of the DBTP. Absence of MOH was achieved when mean monthly AHMD < 10 days or mean monthly headache days < 14 days over the 3-month period (weeks 12 to 24). Efficacy analysis set (nonopioid-treated cohort): randomized participants with an opioid medication use of ≤ 4 days per month during the baseline period and who received at least 1 dose of IP during DBTP.
    End point type
    Secondary
    End point timeframe
    Month 3 (week 12) to month 6 (week 24) of the DBTP
    End point values
    		 Placebo (DBTP) Erenumab 70 mg (DBTP) Erenumab 140 mg (DBTP)
    Number of subjects analysed
    194
    194
    194
    Units: participants
    73
    96
    119
    Statistical analysis title
    		 Erenumab 140 mg versus Placebo
    Statistical analysis description
    Common odds ratio and p-value were obtained from a Cochran-Mantel-Haenszel test, stratified by concomitant oral migraine preventive treatment initiated before screening and taken during baseline (Yes or No).
    Comparison groups
    Placebo (DBTP) v Erenumab 140 mg (DBTP)
    Number of subjects included in analysis
    388
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Common odds ratio
    Point estimate
    2.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.75
         upper limit
    		 3.96
    Statistical analysis title
    		 Erenumab 70 mg versus Placebo
    Statistical analysis description
    Common odds ratio and p-value were obtained from a Cochran-Mantel-Haenszel test, stratified by concomitant oral migraine preventive treatment initiated before screening and taken during baseline (Yes or No).
    Comparison groups
    Placebo (DBTP) v Erenumab 70 mg (DBTP)
    Number of subjects included in analysis
    388
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.019
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Common odds ratio
    Point estimate
    1.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.08
         upper limit
    		 2.43

    Secondary: Change from Baseline in Mean Headache Impact Test 6 (HIT-6) Score Over Months 4, 5, and 6

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    End point title
    		 Change from Baseline in Mean Headache Impact Test 6 (HIT-6) Score Over Months 4, 5, and 6
    End point description
    The HIT-6 is a 6-item short-form self-administered questionnaire to assess headache severity in the previous month, with a total score ranging from 36 to 78, with higher scores representing greater impact of headache, i.e., higher burden. Efficacy analysis set (nonopioid-treated cohort): randomized participants with an opioid medication use of ≤ 4 days per month during the baseline period and who received at least 1 dose of IP during DBTP. Participants with evaluable data from weeks 13 through 24 are included.
    End point type
    Secondary
    End point timeframe
    Baseline and months 4, 5, and 6 (weeks 13 through 24) of the DBTP
    End point values
    		 Placebo (DBTP) Erenumab 70 mg (DBTP) Erenumab 140 mg (DBTP)
    Number of subjects analysed
    184
    189
    188
    Units: score on a scale
        least squares mean (standard error)
    -5.02 ( 0.49 )
    -6.18 ( 0.48 )
    -8.82 ( 0.48 )
    Statistical analysis title
    		 Erenumab 140 mg versus Placebo
    Statistical analysis description
    Covariates: treatment, visit, treatment-by-visit, concomitant oral migraine preventive treatment initiated before screening and taken during baseline (Yes or No), and baseline value.
    Comparison groups
    Placebo (DBTP) v Erenumab 140 mg (DBTP)
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [3]
    Method
    		 Linear Mixed Model
    Parameter type
    		 Least squares mean difference
    Point estimate
    -3.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.12
         upper limit
    		 -2.47
    Notes
    [3] - Nominal p-value is presented without multiplicity adjustment.
    Statistical analysis title
    		 Erenumab 70 mg versus Placebo
    Statistical analysis description
    Covariates: treatment, visit, treatment-by-visit, concomitant oral migraine preventive treatment initiated before screening and taken during baseline (Yes or No), and baseline value.
    Comparison groups
    Placebo (DBTP) v Erenumab 70 mg (DBTP)
    Number of subjects included in analysis
    373
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.086 [4]
    Method
    		 Linear Mixed Model
    Parameter type
    		 Least squares mean difference
    Point estimate
    -1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.49
         upper limit
    		 0.17
    Notes
    [4] - Nominal p-value is presented without multiplicity adjustment.

    Secondary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
    End point description
    TEAEs were defined as any adverse event (AE) that started on or after first dose of IP, and up to the end of the study (52 weeks). Any clinically significant changes in vital signs were included as TEAEs. Safety analysis set: randomized participants who received at least 1 dose of IP.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 24 (DBTP) and Week 25 to 52 weeks (OLTP)
    End point values
    		 Placebo (DBTP) Erenumab 70 mg (OLTP) Erenumab 70 mg (DBTP) Erenumab 140 mg (OLTP) Erenumab 140 mg (DBTP)
    Number of subjects analysed
    206
    291
    206
    296
    206
    Units: participants
    130
    178
    139
    182
    142
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 to Week 24 (DBTP) and Week 25 to 52 weeks (OLTP).
    Adverse event reporting additional description
    Deaths, serious AEs and other AEs are reported for all participants who received at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Placebo (DBTP)
    Reporting group description
    		 Participants were randomized to receive matching placebo SC QM for 24 weeks in the DBTP.

    Reporting group title
    Erenumab 70 mg (DBTP)
    Reporting group description
    		 Participants were randomized to receive 1 mL of erenumab 70 mg/mL SC QM for 24 weeks in the DBTP.

    Reporting group title
    Erenumab 140 mg (OLTP)
    Reporting group description
    		 Eligible participants continued to the OLTP and received erenumab 140 mg SC QM for 28 weeks (up to Week 52). Eligible participants included participants randomized to erenumab 140 mg in the DBTP and participants randomized to placebo in the DBTP, re-randomized to erenumab 140 mg in the OLTP.

    Reporting group title
    Erenumab 70 mg (OLTP)
    Reporting group description
    		 Eligible participants continued to the OLTP and received erenumab 70 mg SC QM for 28 weeks (up to Week 52). Eligible participants included participants randomized to erenumab 70 mg in the DBTP and participants randomized to placebo in the DBTP, re-randomized to erenumab 70 mg in the OLTP.

    Reporting group title
    Erenumab 140 mg (DBTP)
    Reporting group description
    		 Participants were randomized to receive 1 mL of erenumab 140 mg/mL SC QM for 24 weeks in the DBTP.

    Serious adverse events
    		 Placebo (DBTP) Erenumab 70 mg (DBTP) Erenumab 140 mg (OLTP) Erenumab 70 mg (OLTP) Erenumab 140 mg (DBTP)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 206 (3.88%)
    3 / 206 (1.46%)
    12 / 296 (4.05%)
    6 / 291 (2.06%)
    3 / 206 (1.46%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neuroendocrine carcinoma metastatic
         subjects affected / exposed
    0 / 206 (0.00%)
    0 / 206 (0.00%)
    0 / 296 (0.00%)
    0 / 291 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 206 (0.00%)
    0 / 206 (0.00%)
    0 / 296 (0.00%)
    0 / 291 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer stage I
         subjects affected / exposed
    0 / 206 (0.00%)
    0 / 206 (0.00%)
    0 / 296 (0.00%)
    1 / 291 (0.34%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 206 (0.00%)
    0 / 206 (0.00%)
    1 / 296 (0.34%)
    0 / 291 (0.00%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometrial hyperplasia
         subjects affected / exposed
    0 / 206 (0.00%)
    0 / 206 (0.00%)
    1 / 296 (0.34%)
    0 / 291 (0.00%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 206 (0.00%)
    0 / 206 (0.00%)
    1 / 296 (0.34%)
    0 / 291 (0.00%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    0 / 206 (0.00%)
    0 / 206 (0.00%)
    1 / 296 (0.34%)
    0 / 291 (0.00%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Multiple fractures
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 206 (0.00%)
    0 / 296 (0.00%)
    0 / 291 (0.00%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 206 (0.00%)
    0 / 296 (0.00%)
    0 / 291 (0.00%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 206 (0.00%)
    0 / 206 (0.00%)
    0 / 296 (0.00%)
    1 / 291 (0.34%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 206 (0.00%)
    0 / 296 (0.00%)
    0 / 291 (0.00%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 206 (0.00%)
    0 / 206 (0.00%)
    1 / 296 (0.34%)
    0 / 291 (0.00%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Presyncope
         subjects affected / exposed
    0 / 206 (0.00%)
    0 / 206 (0.00%)
    0 / 296 (0.00%)
    0 / 291 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 206 (0.49%)
    1 / 296 (0.34%)
    0 / 291 (0.00%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 206 (0.00%)
    0 / 206 (0.00%)
    1 / 296 (0.34%)
    0 / 291 (0.00%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 206 (0.00%)
    0 / 206 (0.00%)
    0 / 296 (0.00%)
    1 / 291 (0.34%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Volvulus
         subjects affected / exposed
    0 / 206 (0.00%)
    0 / 206 (0.00%)
    1 / 296 (0.34%)
    0 / 291 (0.00%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal prolapse
         subjects affected / exposed
    0 / 206 (0.00%)
    0 / 206 (0.00%)
    0 / 296 (0.00%)
    1 / 291 (0.34%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 206 (0.49%)
    0 / 296 (0.00%)
    0 / 291 (0.00%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sphincter of Oddi dysfunction
         subjects affected / exposed
    0 / 206 (0.00%)
    0 / 206 (0.00%)
    0 / 296 (0.00%)
    1 / 291 (0.34%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 206 (0.00%)
    0 / 296 (0.00%)
    0 / 291 (0.00%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Periarthritis
         subjects affected / exposed
    0 / 206 (0.00%)
    0 / 206 (0.00%)
    1 / 296 (0.34%)
    0 / 291 (0.00%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 206 (0.00%)
    0 / 296 (0.00%)
    1 / 291 (0.34%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 206 (0.00%)
    2 / 296 (0.68%)
    0 / 291 (0.00%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 206 (0.49%)
    0 / 296 (0.00%)
    0 / 291 (0.00%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 206 (0.00%)
    0 / 296 (0.00%)
    0 / 291 (0.00%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mastoiditis
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 206 (0.00%)
    0 / 296 (0.00%)
    0 / 291 (0.00%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolic pneumonia
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 206 (0.00%)
    0 / 296 (0.00%)
    0 / 291 (0.00%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 206 (0.00%)
    0 / 206 (0.00%)
    1 / 296 (0.34%)
    0 / 291 (0.00%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 206 (0.00%)
    0 / 206 (0.00%)
    1 / 296 (0.34%)
    0 / 291 (0.00%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 206 (0.00%)
    0 / 206 (0.00%)
    1 / 296 (0.34%)
    0 / 291 (0.00%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo (DBTP) Erenumab 70 mg (DBTP) Erenumab 140 mg (OLTP) Erenumab 70 mg (OLTP) Erenumab 140 mg (DBTP)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    29 / 206 (14.08%)
    67 / 206 (32.52%)
    75 / 296 (25.34%)
    65 / 291 (22.34%)
    72 / 206 (34.95%)
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    9 / 206 (4.37%)
    31 / 206 (15.05%)
    24 / 296 (8.11%)
    22 / 291 (7.56%)
    34 / 206 (16.50%)
         occurrences all number
    14
    36
    26
    22
    35
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 206 (1.94%)
    8 / 206 (3.88%)
    3 / 296 (1.01%)
    1 / 291 (0.34%)
    12 / 206 (5.83%)
         occurrences all number
    4
    8
    3
    1
    15
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 206 (1.94%)
    12 / 206 (5.83%)
    14 / 296 (4.73%)
    15 / 291 (5.15%)
    9 / 206 (4.37%)
         occurrences all number
    6
    14
    16
    17
    12
    COVID-19
         subjects affected / exposed
    14 / 206 (6.80%)
    25 / 206 (12.14%)
    39 / 296 (13.18%)
    31 / 291 (10.65%)
    33 / 206 (16.02%)
         occurrences all number
    14
    26
    41
    32
    34

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Apr 2019
    - Primary, secondary, and exploratory endpoints were modified and estimands added. - Study procedures and eligibility requirements were simplified.
    27 May 2020
    - Updated study duration to approximately 59 weeks. - Updated the Schedule of Activities to clarify the baseline period, information collected and processed by IRT, the clinical outcome assessment or patient reported outcomes to be done post-randomization on day 1 in the clinic, informed consent, and timing of the entry and exit interviews. - Updated key exclusion criteria to update changes in drug regimen of an allowed migraine preventive medication within 2 months from screening, to remove criterion for body mass index > 40 kg/m^2 at screening, to clarify if participant has a known hypersensitivity to any of the components to be administered during dosing to be excluded from the study, and to update the participants taking short-acting opioids or opioid-containing analgesic for any indication as exclusion criteria. - Clarified that the blinding will be continued in both double-blind and open-label treatment periods. - Updated exploratory objectives and endpoints.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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