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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study With an Open-Label Period to Evaluate the Efficacy and Safety of Fremanezumab for the Prophylactic Treatment of Migraine in Patients With Inadequate Response to Prior Preventive Treatments

    Summary
    EudraCT number
    2017-002441-30
    Trial protocol
    DK   GB   SE   BE   DE   CZ   FI   NL   ES   IT  
    Global end of trial date
    29 May 2019

    Results information
    Results version number
    v2(current)
    This version publication date
    19 Mar 2020
    First version publication date
    19 Oct 2019
    Other versions
    v1
    Version creation reason

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    TV48125-CNS-30068
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03308968
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Teva Branded Pharmaceutical Products, R&D Inc.
    Sponsor organisation address
    41 Moores Road, Frazer, United States, 19355
    Public contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 8884838279, info.eraclinical@teva.de
    Scientific contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 8884838279, info.eraclinical@teva.de
    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
    26 Jun 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Oct 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    29 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to demonstrate the efficacy of fremanezumab administered as monthly and quarterly subcutaneous injections to adult participants with migraine with documented inadequate response to 2 to 4 classes of prior preventive treatments as compared with placebo.
    Protection of trial subjects
    This study was conducted in full accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations (for example; Code of Federal Regulations Title 21, Parts 50, 54, 56, 312, and 314; European Union Directive 2001/20/EC on the approximation of the laws, regulations, and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    10 Nov 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
    Spain: 78
    Country: Number of subjects enrolled
    Sweden: 37
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    United Kingdom: 36
    Country: Number of subjects enrolled
    United States: 120
    Country: Number of subjects enrolled
    Belgium: 50
    Country: Number of subjects enrolled
    Czech Republic: 188
    Country: Number of subjects enrolled
    Denmark: 34
    Country: Number of subjects enrolled
    Finland: 85
    Country: Number of subjects enrolled
    France: 35
    Country: Number of subjects enrolled
    Germany: 74
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    Netherlands: 23
    Country: Number of subjects enrolled
    Poland: 66
    Worldwide total number of subjects
    838
    EEA total number of subjects
    716
    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)
    807
    From 65 to 84 years
    31
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 838 participants were randomized in a 1:1:1 ratio to placebo, fremanezumab quarterly, or fremanezumab monthly treatment groups.

    Period 1
    Period 1 title
    Double-Blind Period (12 Weeks)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Double-blind (DB) period: Participants with chronic migraine (CM) or episodic migraine (EM) received 3 injections of placebo 1.5 milliliters (mL) subcutaneously (SC) on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56. Open-label (OL) period: Participants with CM or EM received fremanezumab (TEV-48125) 225 milligrams (mg) SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matched to fremanezumab was administered per schedule specified in the arm.

    Arm title
    Fremanezumab Quarterly
    Arm description
    DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56). OL period: Participants with CM or EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matched to fremanezumab was administered per schedule specified in the arm.

    Investigational medicinal product name
    Fremanezumab
    Investigational medicinal product code
    TEV-48125
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Fremanezumab was administered per dose and schedule specified in the arm.

    Arm title
    Fremanezumab Monthly
    Arm description
    DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).OL period: Participants with CM or EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.
    Arm type
    Experimental

    Investigational medicinal product name
    Fremanezumab
    Investigational medicinal product code
    TEV-48125
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Fremanezumab was administered per dose and schedule specified in the arm.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matched to fremanezumab was administered per schedule specified in the arm.

    Number of subjects in period 1
    Placebo Fremanezumab Quarterly Fremanezumab Monthly
    Started
    279
    276
    283
    DB Modified ITT (mITT) analysis set
    278
    276
    283
    Completed
    264
    271
    272
    Not completed
    15
    5
    11
         Protocol deviation
    6
    -
    2
         Other than specified
    1
    -
    2
         Lack of efficacy
    1
    1
    -
         Adverse event, non-fatal
    3
    1
    4
         Non-compliance to study procedures
    1
    1
    -
         Consent withdrawn by subject
    2
    2
    3
         Lost to follow-up
    1
    -
    -
    Period 2
    Period 2 title
    Open-Label Period (12 Weeks)
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Double-blind (DB) period: Participants with chronic migraine (CM) or episodic migraine (EM) received 3 injections of placebo 1.5 milliliters (mL) subcutaneously (SC) on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56. Open-label (OL) period: Participants with CM or EM received fremanezumab (TEV-48125) 225 milligrams (mg) SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.
    Arm type
    Placebo

    Investigational medicinal product name
    Fremanezumab
    Investigational medicinal product code
    TEV-48125
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Fremanezumab was administered per dose and schedule specified in the arm.

    Arm title
    Fremanezumab Quarterly
    Arm description
    DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56). OL period: Participants with CM or EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.
    Arm type
    Experimental

    Investigational medicinal product name
    Fremanezumab
    Investigational medicinal product code
    TEV-48125
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Fremanezumab was administered per dose and schedule specified in the arm.

    Arm title
    Fremanezumab Monthly
    Arm description
    DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).OL period: Participants with CM or EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.
    Arm type
    Experimental

    Investigational medicinal product name
    Fremanezumab
    Investigational medicinal product code
    TEV-48125
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Fremanezumab was administered per dose and schedule specified in the arm.

    Number of subjects in period 2
    Placebo Fremanezumab Quarterly Fremanezumab Monthly
    Started
    264
    271
    272
    OL mITT analysis set
    263
    271
    272
    Completed
    253
    259
    260
    Not completed
    11
    12
    12
         Protocol deviation
    -
    1
    1
         Other than specified
    1
    2
    1
         Lack of efficacy
    1
    2
    -
         Adverse event, non-fatal
    4
    1
    1
         Non-compliance to study procedures
    -
    -
    1
         Consent withdrawn by subject
    5
    5
    7
         Lost to follow-up
    -
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Double-blind (DB) period: Participants with chronic migraine (CM) or episodic migraine (EM) received 3 injections of placebo 1.5 milliliters (mL) subcutaneously (SC) on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56. Open-label (OL) period: Participants with CM or EM received fremanezumab (TEV-48125) 225 milligrams (mg) SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.

    Reporting group title
    Fremanezumab Quarterly
    Reporting group description
    DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56). OL period: Participants with CM or EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.

    Reporting group title
    Fremanezumab Monthly
    Reporting group description
    DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).OL period: Participants with CM or EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.

    Reporting group values
    Placebo Fremanezumab Quarterly Fremanezumab Monthly Total
    Number of subjects
    279 276 283 838
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    46.8 ± 11.10 45.8 ± 10.97 45.9 ± 11.05 -
    Sex: Female, Male
    Units: Subjects
        Female
    233 229 238 700
        Male
    46 47 45 138
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    11 6 7 24
        Not Hispanic or Latino
    255 260 264 779
        Unknown or Not Reported
    13 10 12 35
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    0 0 1 1
        Asian
    1 0 3 4
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        Black or African American
    2 2 4 8
        White
    262 262 262 786
        Other
    1 2 1 4
        Unknown or Not Reported
    13 10 12 35
    Number of Migraine Days During the 28 Day Baseline Period
    A migraine day was defined as when at least 1 of the following situations occurred: A calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache meeting criteria for migraine with or without aura; a calendar day demonstrating at least 4 consecutive hours of a headache meeting criteria for probable migraine; a calendar day demonstrating a headache of any duration that was treated with migraine-specific medications. ‘Number of participants analyzed’ for this measure were 279, 275, and 283 for Placebo, Fremanezumab Quarterly, and Fremanezumab Monthly arms respectively.
    Units: days
        arithmetic mean (standard deviation)
    14.3 ± 6.12 14.1 ± 5.61 14.1 ± 5.58 -
    Number of Headache Days of at Least Moderate Severity During the 28 Day Baseline Period
    Headaches were subjectively rated by participants as mild, moderate or severe. A headache day of at least moderate severity was defined as a calendar day (00:00 to 23:59) demonstrating at least 4 consecutive hours of headache of at least moderate severity or; a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was treated with migraine-specific acute medications (triptans and ergot compounds). ‘Number of participants analyzed’ for this measure were 279, 275, and 283 for Placebo, Fremanezumab Quarterly, and Fremanezumab Monthly arms respectively.
    Units: days
        arithmetic mean (standard deviation)
    12.8 ± 5.92 12.4 ± 5.84 12.7 ± 5.82 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Double-blind (DB) period: Participants with chronic migraine (CM) or episodic migraine (EM) received 3 injections of placebo 1.5 milliliters (mL) subcutaneously (SC) on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56. Open-label (OL) period: Participants with CM or EM received fremanezumab (TEV-48125) 225 milligrams (mg) SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.

    Reporting group title
    Fremanezumab Quarterly
    Reporting group description
    DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56). OL period: Participants with CM or EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.

    Reporting group title
    Fremanezumab Monthly
    Reporting group description
    DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).OL period: Participants with CM or EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.
    Reporting group title
    Placebo
    Reporting group description
    Double-blind (DB) period: Participants with chronic migraine (CM) or episodic migraine (EM) received 3 injections of placebo 1.5 milliliters (mL) subcutaneously (SC) on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56. Open-label (OL) period: Participants with CM or EM received fremanezumab (TEV-48125) 225 milligrams (mg) SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.

    Reporting group title
    Fremanezumab Quarterly
    Reporting group description
    DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56). OL period: Participants with CM or EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.

    Reporting group title
    Fremanezumab Monthly
    Reporting group description
    DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).OL period: Participants with CM or EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56.

    Subject analysis set title
    Fremanezumab Quarterly
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56).

    Subject analysis set title
    Fremanezumab Monthly
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).

    Primary: DB Period: Change From Baseline in Monthly Average Number of Migraine Days During the 12-Week Period After the First Dose of Fremanezumab

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    End point title
    DB Period: Change From Baseline in Monthly Average Number of Migraine Days During the 12-Week Period After the First Dose of Fremanezumab
    End point description
    A migraine day was defined as when at least 1 of the following occurred: A calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache meeting criteria for migraine with or without aura; a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache meeting criteria for probable migraine, a migraine subtype where only 1 migraine criterion was missing; a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was treated with migraine-specific medications (triptans and ergot compounds). Monthly averages were derived and normalized to 28 days equivalent by formula: (number of days of efficacy variable over relevant period/number of days with assessments recorded in e-diary over relevant period)*28. Change was calculated as post-baseline value – baseline value. DB mITT analysis set: participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessment on primary endpoint.
    End point type
    Primary
    End point timeframe
    Baseline (Day -28 to Day -1), up to Week 12
    End point values
    Placebo Fremanezumab Quarterly Fremanezumab Monthly
    Number of subjects analysed
    278
    276
    283
    Units: days/month
        least squares mean (standard error)
    -0.6 ± 0.34
    -3.7 ± 0.34
    -4.1 ± 0.34
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using analysis of covariance (ANCOVA) method with treatment, sex, region, special group of treatment failure (yes or no), migraine classification (that is; CM or EM), and treatment-by-migraine classification interaction as fixed effects, and baseline number of migraine days and years since onset of migraines as covariates. The stratification factors (as randomized) were used in the model.
    Comparison groups
    Placebo v Fremanezumab Quarterly
    Number of subjects included in analysis
    554
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Least square (LS) mean difference
    Point estimate
    -3.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.84
         upper limit
    -2.42
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.36
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Analysis was performed using ANCOVA method with treatment, sex, region, special group of treatment failure (yes or no), migraine classification (that is; CM or EM), and treatment-by-migraine classification interaction as fixed effects, and baseline number of migraine days and years since onset of migraines as covariates. The stratification factors (as randomized) were used in the model.
    Comparison groups
    Placebo v Fremanezumab Monthly
    Number of subjects included in analysis
    561
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -3.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.19
         upper limit
    -2.78
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.36

    Secondary: DB Period: Percentage of Participants Reaching at Least 50 Percent (%) Reduction From Baseline in Monthly Average Number of Migraine Days During the 12-Week Period After the First Dose of Fremanezumab

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    End point title
    DB Period: Percentage of Participants Reaching at Least 50 Percent (%) Reduction From Baseline in Monthly Average Number of Migraine Days During the 12-Week Period After the First Dose of Fremanezumab
    End point description
    A migraine day was defined as when at least 1 of the following situations occurred: A calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache meeting criteria for migraine with or without aura; a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache meeting criteria for probable migraine, a migraine subtype where only 1 migraine criterion was missing; a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was treated with migraine-specific medications (triptans and ergot compounds). Monthly averages were derived and normalized to 28 days equivalent by formula: (number of days of efficacy variable over relevant period/number of days with assessments recorded in e-diary over relevant period)*28. DB mITT analysis set included participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessment on the primary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -28 to Day-1), up to Week 12
    End point values
    Placebo Fremanezumab Quarterly Fremanezumab Monthly
    Number of subjects analysed
    278
    276
    283
    Units: percentage of participants
        number (not applicable)
    9
    34
    34
    No statistical analyses for this end point

    Secondary: DB Period: Change From Baseline in Monthly Average Number of Headache Days of at Least Moderate Severity During the 12-Week Period After the First Dose of Fremanezumab

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    End point title
    DB Period: Change From Baseline in Monthly Average Number of Headache Days of at Least Moderate Severity During the 12-Week Period After the First Dose of Fremanezumab
    End point description
    A headache day of at least moderate severity: a calendar day (00:00 to 23:59) demonstrating at least 4 consecutive hours of headache of at least moderate severity or; a calendar day demonstrating a headache of any duration that was treated with migraine-specific acute medications. Monthly averages were derived and normalized to 28 days equivalent by the following formula: (number of days of efficacy variable over relevant period/number of days with assessments recorded in the e-diary over the relevant period) * 28. LS mean calculated using ANCOVA model with treatment, gender, region, special group of treatment failure(yes/no), migraine classification (EM/CM), and treatment*migraine classification as fixed effects and baseline number of headache days of at least moderate severity and years since onset of migraine as covariates. DB mITT analysis set: participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessment on primary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -28 to Day -1), up to Week 12
    End point values
    Placebo Fremanezumab Quarterly Fremanezumab Monthly
    Number of subjects analysed
    278
    276
    283
    Units: days/month
        least squares mean (standard error)
    -0.6 ± 0.33
    -3.9 ± 0.34
    -4.2 ± 0.34
    No statistical analyses for this end point

    Secondary: DB Period: Change From Baseline in Monthly Average Number of Migraine Days During the 4-Week Period After the First Dose of Fremanezumab

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    End point title
    DB Period: Change From Baseline in Monthly Average Number of Migraine Days During the 4-Week Period After the First Dose of Fremanezumab
    End point description
    A migraine day was defined as when at least 1 of following occurred: A calendar day demonstrating at least 4 consecutive hours of a headache meeting criteria for migraine with/without aura; at least 4 consecutive hours of a headache meeting criteria for probable migraine; a headache of any duration that was treated with migraine-specific drugs. Monthly averages were derived and normalized to 28 days equivalent by:(number of days of efficacy variable over relevant period/number of days with assessments recorded in e-diary over relevant period)*28. LS mean calculated using ANCOVA model with treatment, gender, region, special group of treatment failure(yes/no), migraine classification(EM/CM), and treatment*migraine classification as fixed effects, and baseline number of migraine days, years since onset of migraines as covariates. DB mITT analysis set: participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessment on primary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -28 to Day -1), up to Week 4
    End point values
    Placebo Fremanezumab Quarterly Fremanezumab Monthly
    Number of subjects analysed
    278
    276
    283
    Units: days/month
        least squares mean (standard error)
    -0.6 ± 0.35
    -4.1 ± 0.35
    -4.1 ± 0.35
    No statistical analyses for this end point

    Secondary: DB Period: Percentage of Participants Reaching at Least 50% Reduction From Baseline in Monthly Average Number of Migraine Days During the 4-Week Period After the First Dose of Fremanezumab

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    End point title
    DB Period: Percentage of Participants Reaching at Least 50% Reduction From Baseline in Monthly Average Number of Migraine Days During the 4-Week Period After the First Dose of Fremanezumab
    End point description
    A migraine day was defined as when at least 1 of the following situations occurred: A calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache meeting criteria for migraine with or without aura; a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache meeting criteria for probable migraine, a migraine subtype where only 1 migraine criterion was missing; a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was treated with migraine-specific medications (triptans and ergot compounds). Monthly averages were derived and normalized to 28 days equivalent by formula: (number of days of efficacy variable over relevant period/number of days with assessments recorded in e-diary over relevant period)*28. DB mITT analysis set included participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessment on the primary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -28 to Day-1), up to Week 4
    End point values
    Placebo Fremanezumab Quarterly Fremanezumab Monthly
    Number of subjects analysed
    278
    276
    283
    Units: percentage of participants
        number (not applicable)
    10
    38
    36
    No statistical analyses for this end point

    Secondary: DB Period: Change From Baseline in Monthly Average Number of Days of Use of Any Acute Headache Medications During the 12-Week Period After the First Dose of Fremanezumab

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    End point title
    DB Period: Change From Baseline in Monthly Average Number of Days of Use of Any Acute Headache Medications During the 12-Week Period After the First Dose of Fremanezumab
    End point description
    Baseline data and the mean change from baseline in the monthly average number of days of use of any acute headache medications during the 12-week period after administration of the first dose of study drug (based on Week 0 to 12 data) is reported. Least Squares (LS) mean calculated using analysis of covariance (ANCOVA) model with treatment, gender, region, special group of treatment failure (yes/no), migraine classification (EM/CM), and treatment*migraine classification as fixed effects, and baseline number of migraine days and years since onset of migraines as covariates. DB mITT analysis set included participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessment on the primary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -28 to Day -1), up to Week 12
    End point values
    Placebo Fremanezumab Quarterly Fremanezumab Monthly
    Number of subjects analysed
    278
    276
    283
    Units: days/month
        least squares mean (standard error)
    -0.6 ± 0.32
    -3.7 ± 0.32
    -3.9 ± 0.32
    No statistical analyses for this end point

    Secondary: DB Period: Change From Baseline in Monthly Average Number of Headache Days of at Least Moderate Severity During the 4-Week Period After the First Dose of Fremanezumab

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    End point title
    DB Period: Change From Baseline in Monthly Average Number of Headache Days of at Least Moderate Severity During the 4-Week Period After the First Dose of Fremanezumab
    End point description
    A headache day of at least moderate severity: a calendar day (00:00 to 23:59) demonstrating at least 4 consecutive hours of headache of at least moderate severity or; a calendar day demonstrating a headache of any duration that was treated with migraine-specific acute medications. Monthly averages were derived and normalized to 28 days equivalent by following formula: (number of days of efficacy variable over relevant period/number of days with assessments recorded in the e-diary over the relevant period) * 28. LS mean calculated using ANCOVA model with treatment, gender, region, special group of treatment failure (yes/no), migraine classification (EM/CM), and treatment*migraine classification as fixed effects, and baseline number of headache days of at least moderate severity and years since onset of migraines as covariates. DB mITT analysis set: participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessment on primary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -28 to Day -1), up to Week 4
    End point values
    Placebo Fremanezumab Quarterly Fremanezumab Monthly
    Number of subjects analysed
    278
    276
    283
    Units: days/month
        least squares mean (standard error)
    -0.5 ± 0.34
    -4.2 ± 0.35
    -4.5 ± 0.34
    No statistical analyses for this end point

    Secondary: DB Period: Number of Participants With Adverse Events (AEs) and Who Did Not Complete the Study Due to AEs

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    End point title
    DB Period: Number of Participants With Adverse Events (AEs) and Who Did Not Complete the Study Due to AEs
    End point description
    An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Severe AE was defined as inability to carry out usual activities. Treatment-related AEs were defined as AEs with possible, probable, definite, or missing relationship to study drug. Serious AEs were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. DB safety analysis set included all randomized participants who received at least 1 dose of study drug during the DB treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) up to Week 12
    End point values
    Placebo Fremanezumab Quarterly Fremanezumab Monthly
    Number of subjects analysed
    277
    276
    285
    Units: participants
        Any AEs
    134
    151
    129
        AEs leading to withdrawal from study
    3
    1
    4
    No statistical analyses for this end point

    Secondary: OL Period: Number of Participants With AEs and Who Did Not Complete the Study Due to AEs

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    End point title
    OL Period: Number of Participants With AEs and Who Did Not Complete the Study Due to AEs
    End point description
    An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Severe AE was defined as inability to carry out usual activities. Treatment-related AEs were defined as AEs with possible, probable, definite, or missing relationship to study drug. Serious AEs were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. OL safety analysis set included all participants who received at least 1 dose of study drug during the OL treatment period.
    End point type
    Secondary
    End point timeframe
    Week 12 up to Week 24
    End point values
    Placebo Fremanezumab Quarterly Fremanezumab Monthly
    Number of subjects analysed
    262
    271
    274
    Units: participants
        Any AEs
    137
    149
    155
        AEs leading to withdrawal from study
    4
    1
    2
    No statistical analyses for this end point

    Secondary: DB Period: Number of Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results

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    End point title
    DB Period: Number of Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results
    End point description
    Criteria for potentially clinically significant abnormal serum chemistry values included: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), and lactate dehydrogenase (LDH) (units/liter [U/L]): greater than or equal to (≥) 3*upper limit of normal (ULN); Blood Urea Nitrogen (BUN): ≥10.71 millimoles/liter (mmol/L); creatinine: ≥177 micromoles/liter (µmol/L); bilirubin (total): ≥34.2 µmol/L; and uric acid: ≥625 µmol/L (men), and ≥506 µmol/L (women). A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. DB safety analysis set included all randomized participants who received at least 1 dose of study drug during the DB treatment period. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    Placebo Fremanezumab Quarterly Fremanezumab Monthly
    Number of subjects analysed
    272
    268
    280
    Units: participants
    1
    3
    4
    No statistical analyses for this end point

    Secondary: OL Period: Number of Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results

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    End point title
    OL Period: Number of Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results
    End point description
    Criteria for potentially clinically significant abnormal serum chemistry values included: ALT, AST, ALP, GGT, and LDH (U/L): ≥3*ULN; BUN: ≥10.71 mmol/L; creatinine: ≥177 µmol/L; bilirubin (total): ≥34.2 µmol/L; and uric acid: ≥625 µmol/L (men), and ≥506 µmol/L (women). A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. OL safety analysis set included all participants who received at least 1 dose of study drug during the OL treatment period. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Week 12 up to Week 24
    End point values
    Placebo Fremanezumab Quarterly Fremanezumab Monthly
    Number of subjects analysed
    259
    268
    273
    Units: participants
    2
    3
    2
    No statistical analyses for this end point

    Secondary: DB Period: Number of Participants With Potentially Clinically Significant Abnormal Hematology Results

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    End point title
    DB Period: Number of Participants With Potentially Clinically Significant Abnormal Hematology Results
    End point description
    Criteria for potentially clinically significant abnormal hematology values included: hemoglobin: less than (<) 115 grams/liter (g/L) (in men) or less than or equal to (≤) 95 g/L (in women), hematocrit: <0.37 L/L (in men) or <0.32 L/L (in women), leukocytes: ≥20*10^9/L or ≤3*10^9/L, eosinophils: >=10%, platelets: ≥700*10^9/L or ≤75*10^9/L, and absolute neutrophil count (ANC): ≤1*10^9/L. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. DB safety analysis set included all randomized participants who received at least 1 dose of study drug during the DB treatment period. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    Placebo Fremanezumab Quarterly Fremanezumab Monthly
    Number of subjects analysed
    271
    268
    278
    Units: participants
    11
    12
    3
    No statistical analyses for this end point

    Secondary: OL Period: Number of Participants With Potentially Clinically Significant Abnormal Hematology Results

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    End point title
    OL Period: Number of Participants With Potentially Clinically Significant Abnormal Hematology Results
    End point description
    Criteria for potentially clinically significant abnormal hematology values included: hemoglobin: <115 g/L (in men) or ≤95 g/L (in women), hematocrit: <0.37 L/L (in men) or <0.32 L/L (in women), leukocytes: ≥20*10^9/L or ≤3*10^9/L, eosinophils: >=10%, platelets: ≥700*10^9/L or ≤75*10^9/L, and ANC: ≤1*10^9/L. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. OL safety analysis set included all participants who received at least 1 dose of study drug during the OL treatment period. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Week 12 up to Week 24
    End point values
    Placebo Fremanezumab Quarterly Fremanezumab Monthly
    Number of subjects analysed
    258
    268
    273
    Units: participants
    7
    10
    4
    No statistical analyses for this end point

    Secondary: DB Period: Number of Participants With Potentially Clinically Significant Abnormal Coagulation Laboratory Test Results

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    End point title
    DB Period: Number of Participants With Potentially Clinically Significant Abnormal Coagulation Laboratory Test Results
    End point description
    Criteria for potentially clinically significant abnormal coagulation values included: prothrombin international normalized ratio (INR): greater than (>) 1.5. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. DB safety analysis set included all randomized participants who received at least 1 dose of study drug during the DB treatment period. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    Placebo Fremanezumab Quarterly Fremanezumab Monthly
    Number of subjects analysed
    269
    267
    277
    Units: participants
    2
    4
    4
    No statistical analyses for this end point

    Secondary: OL Period: Number of Participants With Potentially Clinically Significant Abnormal Coagulation Laboratory Test Results

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    End point title
    OL Period: Number of Participants With Potentially Clinically Significant Abnormal Coagulation Laboratory Test Results
    End point description
    Criteria for potentially clinically significant abnormal coagulation values included: prothrombin INR: >1.5. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. OL safety analysis set included all participants who received at least 1 dose of study drug during the OL treatment period. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Week 12 up to Week 24
    End point values
    Placebo Fremanezumab Quarterly Fremanezumab Monthly
    Number of subjects analysed
    257
    270
    272
    Units: participants
    3
    1
    3
    No statistical analyses for this end point

    Secondary: DB Period: Number of Participants With Potentially Clinically Significant Abnormal Urinalysis Laboratory Tests Results

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    End point title
    DB Period: Number of Participants With Potentially Clinically Significant Abnormal Urinalysis Laboratory Tests Results
    End point description
    Criteria for potentially clinically significant abnormal urinalysis values included: urine glucose (milligrams/deciliter [mg/dL]): ≥2 unit increase from baseline, ketones (mg/dL): ≥2 unit increase from baseline, urine total protein (mg/dL): ≥2 unit increase from baseline, and haemoglobin ≥2 unit increase from baseline. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. DB safety analysis set included all randomized participants who received at least 1 dose of study drug during the DB treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    Placebo Fremanezumab Quarterly Fremanezumab Monthly
    Number of subjects analysed
    277
    276
    285
    Units: participants
    0
    0
    0
    No statistical analyses for this end point

    Secondary: OL Period: Number of Participants With Potentially Clinically Significant Abnormal Urinalysis Laboratory Tests Results

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    End point title
    OL Period: Number of Participants With Potentially Clinically Significant Abnormal Urinalysis Laboratory Tests Results
    End point description
    Criteria for potentially clinically significant abnormal urinalysis values included: urine glucose (mg/dL): ≥2 unit increase from baseline, ketones (mg/dL): ≥2 unit increase from baseline, urine total protein (mg/dL): ≥2 unit increase from baseline, and haemoglobin ≥2 unit increase from baseline. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. OL safety analysis set included all participants who received at least 1 dose of study drug during the OL treatment period.
    End point type
    Secondary
    End point timeframe
    Week 12 up to Week 24
    End point values
    Placebo Fremanezumab Quarterly Fremanezumab Monthly
    Number of subjects analysed
    262
    271
    274
    Units: participants
    0
    0
    0
    No statistical analyses for this end point

    Secondary: DB Period: Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Values

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    End point title
    DB Period: Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Values
    End point description
    Criteria for potentially clinically significant abnormal vital signs values included: pulse rate: ≤50 beats/minute (bpm) and decrease of ≥15 bpm, or ≥120 bpm and increase of ≥15 bpm; systolic blood pressure: ≤90 millimeters of mercury (mmHg) and decrease of ≥20 mmHg, or ≥180 mmHg and increase of ≥20 mmHg; diastolic blood pressure: ≤50 mmHg and decrease of ≥15 mmHg or ≥105 mmHg and increase of ≥15 mmHg; respiratory rate: <10 breaths/minute; and body temperature ≥38.3 degrees celsius and change of ≥1.1 degrees celsius. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. B safety analysis set included all randomized participants who received at least 1 dose of study drug during the DB treatment period. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    Placebo Fremanezumab Quarterly Fremanezumab Monthly
    Number of subjects analysed
    277
    276
    283
    Units: participants
    9
    8
    8
    No statistical analyses for this end point

    Secondary: OL Period: Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Values

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    End point title
    OL Period: Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Values
    End point description
    Criteria for potentially clinically significant abnormal vital signs values included: pulse rate: ≤50 bpm and decrease of ≥15 bpm, or ≥120 bpm and increase of ≥15 bpm; systolic blood pressure: ≤90 mmHg and decrease of ≥20 mmHg, or ≥180 mmHg and increase of ≥20 mmHg; diastolic blood pressure: ≤50 mmHg and decrease of ≥15 mmHg or ≥105 mmHg and increase of ≥15 mmHg; respiratory rate: <10 breaths/minute; and body temperature ≥38.3 degrees celsius and change of ≥1.1 degrees celsius. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. OL safety analysis set included all participants who received at least 1 dose of study drug during the OL treatment period. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Week 12 up to Week 24
    End point values
    Placebo Fremanezumab Quarterly Fremanezumab Monthly
    Number of subjects analysed
    261
    270
    273
    Units: participants
    10
    14
    8
    No statistical analyses for this end point

    Secondary: DB Period: Number of Participants With Shift From Baseline to Week 12 in Electrocardiogram (ECG) Parameters

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    End point title
    DB Period: Number of Participants With Shift From Baseline to Week 12 in Electrocardiogram (ECG) Parameters
    End point description
    ECG parameters included: heart rate, PR interval, QRS interval, QT interval corrected using the Fridericia formula (QTcF), QT interval corrected using the Bazett's formula (QTcB) and RR interval. Shifts represented as Baseline - Week 12 value. Abnormal NCS indicated an abnormal but not clinically significant finding. Abnormal CS indicated an abnormal and clinically significant finding. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. DB safety analysis set included all randomized participants who received at least 1 dose of study drug during the DB treatment period. Here, 'Overall number of participants analyzed' = participants with both baseline and Week 12 ECG findings.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo Fremanezumab Quarterly Fremanezumab Monthly
    Number of subjects analysed
    258
    271
    270
    Units: participants
        Normal - Normal
    199
    218
    212
        Normal - Abnormal NCS
    21
    14
    15
        Normal - Abnormal CS
    0
    0
    0
        Abnormal NCS - Normal
    10
    19
    12
        Abnormal NCS - Abnormal NCS
    28
    20
    31
        Abnormal NCS - Abnormal CS
    0
    0
    0
        Abnormal CS - Normal
    0
    0
    0
        Abnormal CS - Abnormal NCS
    0
    0
    0
        Abnormal CS - Abnormal CS
    0
    0
    0
    No statistical analyses for this end point

    Secondary: OL Period: Number of Participants With Shift From Baseline to Week 24 in ECG Parameters

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    End point title
    OL Period: Number of Participants With Shift From Baseline to Week 24 in ECG Parameters
    End point description
    ECG parameters included: heart rate, PR interval, QRS interval, QT interval corrected using the Fridericia formula (QTcF), QT interval corrected using the Bazett's formula (QTcB) and RR interval. Shifts represented as Baseline - Week 24 value. Abnormal NCS indicated an abnormal but not clinically significant finding. Abnormal CS indicated an abnormal and clinically significant finding. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. OL safety analysis set included all participants who received at least 1 dose of study drug during the OL treatment period. Here, 'Overall number of participants analyzed' = participants with both baseline and Week 24 ECG findings.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Fremanezumab Quarterly Fremanezumab Monthly
    Number of subjects analysed
    245
    256
    260
    Units: participants
        Normal - Normal
    193
    214
    203
        Normal - Abnormal NCS
    15
    5
    15
        Normal - Abnormal CS
    0
    0
    1
        Abnormal NCS - Normal
    13
    20
    16
        Abnormal NCS - Abnormal NCS
    24
    17
    25
        Abnormal NCS - Abnormal CS
    0
    0
    0
        Abnormal CS - Normal
    0
    0
    0
        Abnormal CS - Abnormal NCS
    0
    0
    0
        Abnormal CS - Abnormal CS
    0
    0
    0
    No statistical analyses for this end point

    Secondary: DB Period: Number of Participants Who Received Concomitant Medications for Adverse Events

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    End point title
    DB Period: Number of Participants Who Received Concomitant Medications for Adverse Events
    End point description
    Concomitant medications included: agents acting on the renin-angiotensin system, all other therapeutic products (for example: homeopathic preparation), allergens, analgesics, anesthetics, anti-parkinson drugs, antianemic preparations, antibacterials for systemic use, antibiotics and chemotherapeutics for dermatological use, antidiarrheals, intestinal antiinflammatory/antiinfective agents, antifungals for dermatologiocal use, antigout preparations, antihemorrhagics, antihistamines for systemic use, antihypertensives, antiinflammatory and antirheumatic products, antipruritics, antipsoriatics, antivirals for systemic use, blood substitutes and perfusion solutions, cardiac therapy, corticosteroids, cough and cold preparations, diagnostic radiopharmaceuticals, diuretics, vaccines, ophthalmologicals, muscle relaxants, drugs used in diabetes etc. DB safety analysis set included all randomized participants who received at least 1 dose of study drug during the DB treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    Placebo Fremanezumab Quarterly Fremanezumab Monthly
    Number of subjects analysed
    277
    276
    285
    Units: participants
    274
    269
    280
    No statistical analyses for this end point

    Secondary: OL Period: Number of Participants Who Received Concomitant Medications for Adverse Events

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    End point title
    OL Period: Number of Participants Who Received Concomitant Medications for Adverse Events
    End point description
    Concomitant medications included: agents acting on the renin-angiotensin system, all other therapeutic products (for example: homeopathic preparation), allergens, analgesics, anesthetics, anti-parkinson drugs, antianemic preparations, antibacterials for systemic use, antibiotics and chemotherapeutics for dermatological use, antidiarrheals, intestinal antiinflammatory/antiinfective agents, antifungals for dermatologiocal use, antigout preparations, antihemorrhagics, antihistamines for systemic use, antihypertensives, antiinflammatory and antirheumatic products, antipruritics, antipsoriatics, antivirals for systemic use, blood substitutes and perfusion solutions, cardiac therapy, corticosteroids, cough and cold preparations, diagnostic radiopharmaceuticals, diuretics, vaccines, ophthalmologicals, muscle relaxants, drugs used in diabetes etc. OL safety analysis set included all participants who received at least 1 dose of study drug during the OL treatment period.
    End point type
    Secondary
    End point timeframe
    Week 12 up to Week 24
    End point values
    Placebo Fremanezumab Quarterly Fremanezumab Monthly
    Number of subjects analysed
    262
    271
    274
    Units: participants
    262
    266
    270
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline (Day 0) up to follow-up visit (Week 46)
    Adverse event reporting additional description
    Safety analysis set: all participants who received at least 1 dose of study drug. AE data were summarized collectively for both periods. 2 participants (1 with CM and 1 with EM) randomized to placebo but received Fremanezumab monthly dosing during double-blind treatment period. They were analyzed in the treatment arm per actual treatment received.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56. OL period: Participants with CM or EM received fremanezumab (TEV-48125) 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.

    Reporting group title
    Fremanezumab Monthly
    Reporting group description
    DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).OL period: Participants with CM or EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.

    Reporting group title
    Fremanezumab Quarterly
    Reporting group description
    DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56). OL period: Participants with CM or EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.

    Serious adverse events
    Placebo Fremanezumab Monthly Fremanezumab Quarterly
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 277 (4.69%)
    11 / 285 (3.86%)
    10 / 276 (3.62%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Angiomyxoma
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 285 (0.35%)
    0 / 276 (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
    Breast cancer
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 285 (0.00%)
    0 / 276 (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
    Thyroid adenoma
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 285 (0.00%)
    0 / 276 (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
    Uterine leiomyoma
    Additional description: This is a gender-specific AE. Only female participants were at risk.
         subjects affected / exposed [1]
    1 / 231 (0.43%)
    0 / 240 (0.00%)
    0 / 229 (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
    Vulval cancer
    Additional description: This is a gender-specific AE. Only female participants were at risk.
         subjects affected / exposed [2]
    1 / 231 (0.43%)
    0 / 240 (0.00%)
    0 / 229 (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
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 285 (0.35%)
    0 / 276 (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
    Reproductive system and breast disorders
    Dysmenorrhoea
    Additional description: This is a gender-specific AE. Only female participants were at risk.
         subjects affected / exposed [3]
    0 / 231 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometriosis
    Additional description: This is a gender-specific AE. Only female participants were at risk.
         subjects affected / exposed [4]
    0 / 231 (0.00%)
    1 / 240 (0.42%)
    0 / 229 (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
    Menometrorrhagia
    Additional description: This is a gender-specific AE. Only female participants were at risk.
         subjects affected / exposed [5]
    0 / 231 (0.00%)
    1 / 240 (0.42%)
    0 / 229 (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
    Menorrhagia
    Additional description: This is a gender-specific AE. Only female participants were at risk.
         subjects affected / exposed [6]
    0 / 231 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metrorrhagia
    Additional description: This is a gender-specific AE. Only female participants were at risk.
         subjects affected / exposed [7]
    1 / 231 (0.43%)
    0 / 240 (0.00%)
    0 / 229 (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
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 285 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 285 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory fume inhalation disorder
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 285 (0.35%)
    0 / 276 (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
    Rib fracture
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 285 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 285 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 285 (0.00%)
    0 / 276 (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
    Investigations
    Blood pressure increased
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 285 (0.00%)
    0 / 276 (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
    International normalised ratio abnormal
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 285 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 285 (0.35%)
    0 / 276 (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
    Palpitations
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 285 (0.00%)
    0 / 276 (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
    Congenital, familial and genetic disorders
    Congenital diaphragmatic hernia
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 285 (0.00%)
    0 / 276 (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
    Respiratory, thoracic and mediastinal disorders
    Vocal cord thickening
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 285 (0.35%)
    0 / 276 (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
    Nervous system disorders
    Hypoaesthesia
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 285 (0.00%)
    0 / 276 (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
    Intracranial aneurysm
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 285 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 285 (0.00%)
    0 / 276 (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
    Multiple sclerosis
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 285 (0.35%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 285 (0.35%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal tear
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 285 (0.35%)
    0 / 276 (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
    Gastrointestinal disorders
    Anal polyp
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 285 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 285 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 285 (0.00%)
    0 / 276 (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
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 285 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 285 (0.35%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 277 (0.00%)
    2 / 285 (0.70%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 285 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 285 (0.00%)
    1 / 276 (0.36%)
         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
    Dengue fever
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 285 (0.00%)
    0 / 276 (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
    Diverticulitis
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 285 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonsillitis
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 285 (0.00%)
    0 / 276 (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
    Sinusitis
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 285 (0.00%)
    0 / 276 (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
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This is a gender-specific AE. Only female participants were at risk.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This is a gender-specific AE. Only female participants were at risk.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This is a gender-specific AE. Only female participants were at risk.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This is a gender-specific AE. Only female participants were at risk.
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This is a gender-specific AE. Only female participants were at risk.
    [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This is a gender-specific AE. Only female participants were at risk.
    [7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This is a gender-specific AE. Only female participants were at risk.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Fremanezumab Monthly Fremanezumab Quarterly
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    88 / 277 (31.77%)
    81 / 285 (28.42%)
    90 / 276 (32.61%)
    Nervous system disorders
    Migraine
         subjects affected / exposed
    21 / 277 (7.58%)
    12 / 285 (4.21%)
    14 / 276 (5.07%)
         occurrences all number
    26
    14
    15
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    24 / 277 (8.66%)
    32 / 285 (11.23%)
    31 / 276 (11.23%)
         occurrences all number
    53
    80
    66
    Injection site induration
         subjects affected / exposed
    16 / 277 (5.78%)
    18 / 285 (6.32%)
    19 / 276 (6.88%)
         occurrences all number
    52
    65
    41
    Injection site pain
         subjects affected / exposed
    10 / 277 (3.61%)
    14 / 285 (4.91%)
    15 / 276 (5.43%)
         occurrences all number
    20
    42
    42
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    32 / 277 (11.55%)
    25 / 285 (8.77%)
    30 / 276 (10.87%)
         occurrences all number
    37
    30
    41
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 277 (3.61%)
    16 / 285 (5.61%)
    8 / 276 (2.90%)
         occurrences all number
    10
    17
    11

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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