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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Parallel-Group Study Evaluating the Long-Term Safety, Tolerability, and Efficacy of Subcutaneous Administration of Fremanezumab (TEV-48125) for the Preventive Treatment of Migraine

    Summary
    EudraCT number
    		 2015-004550-18
    Trial protocol
    		 DE   CZ   ES   FI   DK  
    Global end of trial date
    07 Dec 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Aug 2019
    First version publication date
    30 Aug 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    TV48125-CNS-30051
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02638103
    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
    07 Dec 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the long-term safety and tolerability of subcutaneous (SC) fremanezumab (TEV-48125) in the preventive treatment of migraine.
    Protection of trial subjects
    This study was conducted in full accordance with the International Council for 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; EU Directive 2001/20/EC on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of GCP in the conduct of clinical trials on medicinal products for human use).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Mar 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 48
    Country: Number of subjects enrolled
    Czech Republic: 79
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    Finland: 42
    Country: Number of subjects enrolled
    Israel: 33
    Country: Number of subjects enrolled
    Japan: 176
    Country: Number of subjects enrolled
    Poland: 44
    Country: Number of subjects enrolled
    Russian Federation: 59
    Country: Number of subjects enrolled
    United States: 1390
    Worldwide total number of subjects
    1890
    EEA total number of subjects
    184
    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)
    1831
    From 65 to 84 years
    59
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants with chronic or episodic migraine (CM or EM) who completed the pivotal efficacy studies of fremanezumab (TV48125-CNS-30049 [NCT02621931] and TV48125-CNS-30050 [NCT02629861]) and agreed to participate in this study; and new participants meeting eligibility criteria (not rolling over from pivotal studies), were enrolled in this study.

    Pre-assignment
    Screening details
    		 A total of 1890 participants were enrolled, including 917 participants with CM rolled over from Study TV48125-CNS-30049, 661 participants with EM rolled over from Study TV48125-CNS-30050, and 312 newly enrolled participants (193 with CM and 119 with EM).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TEV-48125 225 mg Monthly: New/Placebo Rollover Participants
    Arm description
    		 Participants with CM who were randomized to the placebo treatment group or participants who did not rollover from the pivotal efficacy study, received fremanezumab (TEV-48125) 675 milligrams (mg) subcutaneously (SC) as loading dose (3 injections of fremanezumab 225 mg/1.5 milliliters [mL] on Day 0) followed by 11 monthly SC doses of fremanezumab at 225 mg (1 injection of fremanezumab 225 mg/1.5mL and 2 injections of placebo 1.5 mL on Days 84, 168, and 252; and 1 injection of fremanezumab 225 mg/1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308). Participants with EM who were randomized to the placebo treatment group or participants who did not rollover from the pivotal efficacy study, received 12 monthly SC doses of fremanezumab at 225 mg (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL on Days 0, 84, 168, and 252; and 1 injection of fremanezumab 225 mg/1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).
    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 as per the 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 as per the dose and schedule specified in the arm.

    Arm title
    		 TEV-48125 225 mg Monthly: Active Rollover Participants
    Arm description
    		 Participants with CM who were randomized to the active treatment group (Fremanezumab 675/225 mg) in the pivotal efficacy study, received fremanezumab 675 mg SC as loading dose (3 injections of fremanezumab 225 mg/1.5 mL on Day 0) followed by 11 monthly SC doses of fremanezumab at 225 mg (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL on Days 84, 168, and 252; and 1 injection of fremanezumab 225 mg/1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308). Participants with EM who were randomized to the active treatment group (Fremanezumab 225 mg) in the pivotal efficacy study, received 12 monthly SC doses of fremanezumab at 225 mg (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL on Days 0, 84, 168, and 252; and 1 injection of fremanezumab 225 mg/1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).
    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 as per the 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 as per the dose and schedule specified in the arm.

    Arm title
    		 TEV-48125 675 mg Quarterly: New/Placebo Rollover Participants
    Arm description
    		 Participants with CM or EM who were randomized to the placebo treatment group or participants who did not rollover from the pivotal efficacy study, received fremanezumab 675 mg SC once every 3 months for 12 months for a total of 4 doses (3 injections of fremanezumab 225 mg/1.5 mL on Days 0, 84, 168, and 252; and 1 injection of placebo 1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).
    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 as per the 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 as per the dose and schedule specified in the arm.

    Arm title
    		 TEV-48125 675 mg Quarterly: Active Rollover Participants
    Arm description
    		 Participants with CM or EM who were randomized to the active treatment group (Fremanezumab 675 mg) in the pivotal efficacy study, received fremanezumab 675 mg SC once every 3 months for 12 months for a total of 4 doses (3 injections of fremanezumab 225 mg/1.5 mL on Days 0, 84, 168, and 252; and 1 injection of placebo 1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).
    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 as per the 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 as per the schedule specified in the arm.

    Number of subjects in period 1
    		TEV-48125 225 mg Monthly: New/Placebo Rollover Participants TEV-48125 225 mg Monthly: Active Rollover Participants TEV-48125 675 mg Quarterly: New/Placebo Rollover Participants TEV-48125 675 mg Quarterly: Active Rollover Participants
    Started
    419
    526
    420
    525
    Safety analysis set
    418
    526
    419
    525
    Full analysis set (FAS)
    416
    520
    419
    523
    Completed
    313
    408
    335
    383
    Not completed
    106
    118
    85
    142
         Consent withdrawn by subject
    43
    53
    30
    61
         Adverse event, non-fatal
    13
    12
    19
    12
         Pregnancy
    2
    3
    -
    1
         Other than specified
    5
    4
    2
    4
         Lost to follow-up
    26
    33
    20
    37
         Protocol deviation
    1
    2
    1
    4
         Non-compliance to Study Procedures
    2
    1
    1
    1
         Lack of efficacy
    14
    10
    12
    22

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TEV-48125 225 mg Monthly: New/Placebo Rollover Participants
    Reporting group description
    		 Participants with CM who were randomized to the placebo treatment group or participants who did not rollover from the pivotal efficacy study, received fremanezumab (TEV-48125) 675 milligrams (mg) subcutaneously (SC) as loading dose (3 injections of fremanezumab 225 mg/1.5 milliliters [mL] on Day 0) followed by 11 monthly SC doses of fremanezumab at 225 mg (1 injection of fremanezumab 225 mg/1.5mL and 2 injections of placebo 1.5 mL on Days 84, 168, and 252; and 1 injection of fremanezumab 225 mg/1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308). Participants with EM who were randomized to the placebo treatment group or participants who did not rollover from the pivotal efficacy study, received 12 monthly SC doses of fremanezumab at 225 mg (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL on Days 0, 84, 168, and 252; and 1 injection of fremanezumab 225 mg/1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).

    Reporting group title
    TEV-48125 225 mg Monthly: Active Rollover Participants
    Reporting group description
    		 Participants with CM who were randomized to the active treatment group (Fremanezumab 675/225 mg) in the pivotal efficacy study, received fremanezumab 675 mg SC as loading dose (3 injections of fremanezumab 225 mg/1.5 mL on Day 0) followed by 11 monthly SC doses of fremanezumab at 225 mg (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL on Days 84, 168, and 252; and 1 injection of fremanezumab 225 mg/1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308). Participants with EM who were randomized to the active treatment group (Fremanezumab 225 mg) in the pivotal efficacy study, received 12 monthly SC doses of fremanezumab at 225 mg (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL on Days 0, 84, 168, and 252; and 1 injection of fremanezumab 225 mg/1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).

    Reporting group title
    TEV-48125 675 mg Quarterly: New/Placebo Rollover Participants
    Reporting group description
    		 Participants with CM or EM who were randomized to the placebo treatment group or participants who did not rollover from the pivotal efficacy study, received fremanezumab 675 mg SC once every 3 months for 12 months for a total of 4 doses (3 injections of fremanezumab 225 mg/1.5 mL on Days 0, 84, 168, and 252; and 1 injection of placebo 1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).

    Reporting group title
    TEV-48125 675 mg Quarterly: Active Rollover Participants
    Reporting group description
    		 Participants with CM or EM who were randomized to the active treatment group (Fremanezumab 675 mg) in the pivotal efficacy study, received fremanezumab 675 mg SC once every 3 months for 12 months for a total of 4 doses (3 injections of fremanezumab 225 mg/1.5 mL on Days 0, 84, 168, and 252; and 1 injection of placebo 1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).

    Reporting group values
    		 TEV-48125 225 mg Monthly: New/Placebo Rollover Participants TEV-48125 225 mg Monthly: Active Rollover Participants TEV-48125 675 mg Quarterly: New/Placebo Rollover Participants TEV-48125 675 mg Quarterly: Active Rollover Participants Total
    Number of subjects
    		 419 526 420 525 1890
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.1 ± 12.09 42.9 ± 11.97 44.0 ± 11.67 43.2 ± 11.73 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 365 454 369 457 1645
        Male
    		 54 72 51 68 245
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 29 45 34 38 146
        Not Hispanic or Latino
    		 387 481 386 484 1738
        Unknown or Not Reported
    		 3 0 0 3 6
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 351 424 343 412 1530
        Black
    		 32 38 38 40 148
        Asian
    		 29 62 36 64 191
        American Indian or Alaskan Native
    		 1 2 0 3 6
        Native Hawaiian or other Pacific Islander
    		 1 0 0 2 3
        Other
    		 5 0 3 4 12
    Number of Migraine Days
    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 (for CM participants) or at least 2 consecutive hours (for EM participants) of a headache meeting criteria for migraine with or without aura; a calendar day demonstrating at least 4 consecutive hours (for CM participants) or at least 2 consecutive hours (for EM participants) of a headache meeting criteria for probable migraine; a calendar day demonstrating a headache of any duration that was treated with migraine-specific medications.
    Units: days
        arithmetic mean (standard deviation)
    		 13.9 ± 5.99 13.1 ± 5.49 13.6 ± 5.86 13.2 ± 5.26 -
    Number of Headache Days of Any Severity
    Headaches were subjectively rated by participants as mild, moderate or severe. A headache day of any severity for both CM and EM participants was defined as a calendar day (00:00 to 23:59) where the participant (using the electronic headache diary device) reports: a day with headache pain that lasts at least 4 hours with a peak severity of any severity or; a day when the participant used acute migraine-specific medication (triptans or ergots) to treat a headache of any severity or duration.
    Units: days
        arithmetic mean (standard deviation)
    		 13.6 ± 6.68 12.7 ± 6.20 13.2 ± 6.32 12.9 ± 6.02 -

    End points

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    End points reporting groups
    Reporting group title
    TEV-48125 225 mg Monthly: New/Placebo Rollover Participants
    Reporting group description
    		 Participants with CM who were randomized to the placebo treatment group or participants who did not rollover from the pivotal efficacy study, received fremanezumab (TEV-48125) 675 milligrams (mg) subcutaneously (SC) as loading dose (3 injections of fremanezumab 225 mg/1.5 milliliters [mL] on Day 0) followed by 11 monthly SC doses of fremanezumab at 225 mg (1 injection of fremanezumab 225 mg/1.5mL and 2 injections of placebo 1.5 mL on Days 84, 168, and 252; and 1 injection of fremanezumab 225 mg/1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308). Participants with EM who were randomized to the placebo treatment group or participants who did not rollover from the pivotal efficacy study, received 12 monthly SC doses of fremanezumab at 225 mg (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL on Days 0, 84, 168, and 252; and 1 injection of fremanezumab 225 mg/1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).

    Reporting group title
    TEV-48125 225 mg Monthly: Active Rollover Participants
    Reporting group description
    		 Participants with CM who were randomized to the active treatment group (Fremanezumab 675/225 mg) in the pivotal efficacy study, received fremanezumab 675 mg SC as loading dose (3 injections of fremanezumab 225 mg/1.5 mL on Day 0) followed by 11 monthly SC doses of fremanezumab at 225 mg (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL on Days 84, 168, and 252; and 1 injection of fremanezumab 225 mg/1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308). Participants with EM who were randomized to the active treatment group (Fremanezumab 225 mg) in the pivotal efficacy study, received 12 monthly SC doses of fremanezumab at 225 mg (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL on Days 0, 84, 168, and 252; and 1 injection of fremanezumab 225 mg/1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).

    Reporting group title
    TEV-48125 675 mg Quarterly: New/Placebo Rollover Participants
    Reporting group description
    		 Participants with CM or EM who were randomized to the placebo treatment group or participants who did not rollover from the pivotal efficacy study, received fremanezumab 675 mg SC once every 3 months for 12 months for a total of 4 doses (3 injections of fremanezumab 225 mg/1.5 mL on Days 0, 84, 168, and 252; and 1 injection of placebo 1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).

    Reporting group title
    TEV-48125 675 mg Quarterly: Active Rollover Participants
    Reporting group description
    		 Participants with CM or EM who were randomized to the active treatment group (Fremanezumab 675 mg) in the pivotal efficacy study, received fremanezumab 675 mg SC once every 3 months for 12 months for a total of 4 doses (3 injections of fremanezumab 225 mg/1.5 mL on Days 0, 84, 168, and 252; and 1 injection of placebo 1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).

    Subject analysis set title
    TEV-48125 225 mg Monthly: New/Placebo Rollover CM Participants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with CM who were randomized to the placebo treatment group or participants who did not rollover from the pivotal efficacy study, received fremanezumab 675 mg SC as loading dose (3 injections of fremanezumab 225 mg/1.5 mL on Day 0) followed by 11 monthly SC doses of fremanezumab at 225 mg (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL on Days 84, 168, and 252; and 1 injection of fremanezumab 225 mg/1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).

    Subject analysis set title
    TEV-48125 225 mg Monthly: Active Rollover CM Participants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with CM who were randomized to the active treatment group (Fremanezumab 675/225 mg) in the pivotal efficacy study, received fremanezumab 675 mg SC as loading dose (3 injections of fremanezumab 225 mg/1.5 mL on Day 0) followed by 11 monthly SC doses of fremanezumab at 225 mg (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL on Days 84, 168, and 252; and 1 injection of fremanezumab 225 mg/1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).

    Subject analysis set title
    TEV-48125 675mg Quarterly:New/Placebo Rollover CM Participants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with CM who were randomized to the placebo treatment group or participants who did not rollover from the pivotal efficacy study, received fremanezumab 675 mg SC once every 3 months for 12 months for a total of 4 doses (3 injections of fremanezumab 225 mg/1.5 mL on Days 0, 84, 168, and 252; and 1 injection of placebo 1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).

    Subject analysis set title
    TEV-48125 675 mg Quarterly: Active Rollover CM Participants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with CM who were randomized to the active treatment group (Fremanezumab 675 mg) in the pivotal efficacy study, received fremanezumab 675 mg SC once every 3 months for 12 months for a total of 4 doses (3 injections of fremanezumab 225 mg/1.5 mL on Days 0, 84, 168, and 252; and 1 injection of placebo 1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).

    Subject analysis set title
    TEV-48125 225 mg Monthly: New/Placebo Rollover EM Participants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with EM who were randomized to the placebo treatment group or participants who did not rollover from the pivotal efficacy study, received 12 monthly SC doses of fremanezumab at 225 mg (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL on Days 0, 84, 168, and 252; and 1 injection of fremanezumab 225 mg/1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).

    Subject analysis set title
    TEV-48125 225 mg Monthly: Active Rollover EM Participants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with EM who were randomized to the active treatment group (Fremanezumab 225 mg) in the pivotal efficacy study, received 12 monthly SC doses of fremanezumab at 225 mg (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL on Days 0, 84, 168, and 252; and 1 injection of fremanezumab 225 mg/1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).

    Subject analysis set title
    TEV-48125 675mg Quarterly:New/Placebo Rollover EM Participants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with EM who were randomized to the placebo treatment group or participants who did not rollover from the pivotal efficacy study, received fremanezumab 675 mg SC once every 3 months for 12 months for a total of 4 doses (3 injections of fremanezumab 225 mg/1.5 mL on Days 0, 84, 168, and 252; and 1 injection of placebo 1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).

    Subject analysis set title
    TEV-48125 675 mg Quarterly: Active Rollover EM Participants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with EM who were randomized to the active treatment group (Fremanezumab 675 mg) in the pivotal efficacy study, received fremanezumab 675 mg SC once every 3 months for 12 months for a total of 4 doses (3 injections of fremanezumab 225 mg/1.5 mL on Days 0, 84, 168, and 252; and 1 injection of placebo 1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).

    Primary: Number of Participants With Adverse Events (AEs)

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    End point title
    		 Number of Participants With Adverse Events (AEs) [1]
    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. Safety population included all participants who received at least 1 dose of fremanezumab.
    End point type
    Primary
    End point timeframe
    Baseline (Day 0) up to follow-up visit (Day 533)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Safety analyses were descriptive in nature.
    End point values
    		 TEV-48125 225 mg Monthly: New/Placebo Rollover Participants TEV-48125 225 mg Monthly: Active Rollover Participants TEV-48125 675 mg Quarterly: New/Placebo Rollover Participants TEV-48125 675 mg Quarterly: Active Rollover Participants
    Number of subjects analysed
    418
    526
    419
    525
    Units: participants
        Any AEs
    365
    456
    365
    426
        Severe AEs
    47
    51
    45
    50
        Treatment-related AEs
    263
    288
    242
    270
        Serious AEs
    27
    29
    36
    23
        AEs leading to discontinuation from study
    18
    18
    22
    18
    No statistical analyses for this end point

    Primary: Number of Participants With Shift From Baseline to Endpoint in Electrocardiogram (ECG) Parameters

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    End point title
    		 Number of Participants With Shift From Baseline to Endpoint in Electrocardiogram (ECG) Parameters [2]
    End point description
    ECG parameters included: 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 - endpoint value (last observed post-baseline 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. Safety population included all participants who received at least 1 dose of fremanezumab. Here, 'Overall number of participants analyzed' = participants with both baseline and endpoint electrocardiogram findings.
    End point type
    Primary
    End point timeframe
    Baseline (Day 0), endpoint (Day 336)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Safety analyses were descriptive in nature.
    End point values
    		 TEV-48125 225 mg Monthly: New/Placebo Rollover Participants TEV-48125 225 mg Monthly: Active Rollover Participants TEV-48125 675 mg Quarterly: New/Placebo Rollover Participants TEV-48125 675 mg Quarterly: Active Rollover Participants
    Number of subjects analysed
    386
    492
    391
    489
    Units: participants
        Normal - Normal
    239
    295
    230
    296
        Normal - Abnormal NCS
    45
    64
    49
    67
        Normal - Abnormal CS
    0
    0
    0
    1
        Abnormal NCS - Normal
    42
    53
    43
    60
        Abnormal NCS - Abnormal NCS
    60
    79
    69
    65
        Abnormal NCS - Abnormal CS
    0
    1
    0
    0
        Abnormal CS - Normal
    0
    0
    0
    0
        Abnormal CS - Abnormal NCS
    0
    0
    0
    0
        Abnormal CS - Abnormal CS
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results

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    End point title
    		 Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results [3]
    End point description
    Coagulation parameters included: prothrombin time (PT) (seconds), prothrombin international normalized ratio (INR), activated partial thromboplastin time (aPTT) (seconds). Shifts represented as Baseline - endpoint value (last observed post-baseline value). Shifts from baseline to endpoint were summarized using participant counts grouped into three categories: - Low (below normal range) - Normal (within the normal range of 9.4 to 12.5 seconds) - High (above normal range). A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Safety population included all participants who received at least 1 dose of fremanezumab. Here, 'Overall number of participants analyzed' = participants with both baseline and endpoint coagulation laboratory test results. 'n' = participants evaluable for specified categories.
    End point type
    Primary
    End point timeframe
    Baseline (Day 0), endpoint (Day 336)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Safety analyses were descriptive in nature.
    End point values
    		 TEV-48125 225 mg Monthly: New/Placebo Rollover Participants TEV-48125 225 mg Monthly: Active Rollover Participants TEV-48125 675 mg Quarterly: New/Placebo Rollover Participants TEV-48125 675 mg Quarterly: Active Rollover Participants
    Number of subjects analysed
    407
    516
    410
    513
    Units: participants
        PT: Low-Low (n=407,516,410,513)
    0
    0
    0
    0
        PT: Low-Normal (n=407,516,410,513)
    0
    0
    0
    0
        PT: Low-High (n=407,516,410,513)
    0
    0
    0
    0
        PT: Normal-Low (n=407,516,410,513)
    0
    0
    0
    0
        PT: Normal-Normal (n=407,516,410,513)
    0
    0
    0
    0
        PT: Normal-High (n=407,516,410,513)
    0
    0
    0
    0
        PT: High-Low (n=407,516,410,513)
    0
    0
    0
    0
        PT: High-Normal (n=407,516,410,513)
    0
    0
    0
    0
        PT: High-High (n=407,516,410,513)
    0
    0
    0
    0
        Prothrombin INR: Low-Low (n=406,516,410,513)
    0
    1
    4
    1
        Prothrombin INR: Low-Normal (n=406,516,410,513)
    11
    11
    11
    9
        Prothrombin INR: Low-High (n=406,516,410,513)
    0
    0
    0
    0
        Prothrombin INR: Normal-Low (n=406,516,410,513)
    12
    15
    9
    4
        Prothrombin INR: Normal-Normal (n=406,516,410,513)
    366
    468
    372
    473
        Prothrombin INR: Normal-High (n=406,516,410,513)
    6
    5
    4
    4
        Prothrombin INR: High-Low (n=406,516,410,513)
    0
    0
    0
    1
        Prothrombin INR: High-Normal (n=406,516,410,513)
    7
    11
    6
    13
        Prothrombin INR: High-High (n=406,516,410,513)
    4
    5
    4
    6
        aPTT: Low-Low (n=406,516,410,513)
    2
    2
    1
    0
        aPTT: Low-Normal (n=406,516,410,513)
    4
    1
    7
    7
        aPTT: Low-High (n=406,516,410,513)
    0
    1
    0
    0
        aPTT: Normal-Low (n=406,516,410,513)
    3
    11
    7
    10
        aPTT: Normal-Normal (n=406,516,410,513)
    341
    423
    234
    414
        aPTT: Normal-High (n=406,516,410,513)
    14
    18
    19
    22
        aPTT: High-Low (n=406,516,410,513)
    0
    0
    0
    1
        aPTT: High-Normal (n=406,516,410,513)
    26
    43
    26
    37
        aPTT: High-High (n=406,516,410,513)
    16
    17
    16
    22
    No statistical analyses for this end point

    Primary: Number of Participants With Injection Site Reactions

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    End point title
    		 Number of Participants With Injection Site Reactions [4]
    End point description
    Number of participants who reported treatment-emergent injection site reactions are summarized. Preferred terms from MedDRA version 18.1 were offered without a threshold applied. Injection site reactions included injection site induration, pain, erythema, haemorrhage, pruritus, swelling, bruising, rash, urticaria, warmth, dermatitis, haematoma, inflammation, discolouration, discomfort, hypersensitivity, hypoaesthesia, irritation, oedema, papule, paraesthesia, vesicles and pallor. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Safety population included all participants who received at least 1 dose of fremanezumab.
    End point type
    Primary
    End point timeframe
    Baseline (Day 0) up to follow-up visit (Day 533)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Safety analyses were descriptive in nature.
    End point values
    		 TEV-48125 225 mg Monthly: New/Placebo Rollover Participants TEV-48125 225 mg Monthly: Active Rollover Participants TEV-48125 675 mg Quarterly: New/Placebo Rollover Participants TEV-48125 675 mg Quarterly: Active Rollover Participants
    Number of subjects analysed
    418
    526
    419
    525
    Units: participants
        Injection site induration
    167
    174
    144
    134
        Injection site pain
    149
    156
    135
    140
        Injection site erythema
    130
    144
    99
    124
        Injection site haemorrhage
    34
    38
    21
    38
        Injection site pruritus
    31
    43
    17
    24
        Injection site swelling
    7
    10
    6
    8
        Injection site bruising
    2
    2
    4
    3
        Injection site rash
    4
    2
    5
    2
        Injection site urticaria
    4
    2
    3
    2
        Injection site warmth
    3
    2
    1
    1
        Injection site dermatitis
    0
    1
    0
    1
        Injection site haematoma
    1
    0
    0
    1
        Injection site inflammation
    0
    1
    1
    0
        Injection site discolouration
    0
    1
    0
    0
        Injection site discomfort
    0
    0
    0
    1
        Injection site hypersensitivity
    1
    0
    0
    0
        Injection site hypoaesthesia
    1
    1
    0
    0
        Injection site irritation
    0
    0
    0
    1
        Injection site oedema
    1
    1
    1
    0
        Injection site papule
    1
    0
    0
    0
        Injection site paraesthesia
    0
    0
    1
    0
        Injection site vesicles
    0
    1
    1
    0
        Injection site pallor
    0
    0
    0
    1
    No statistical analyses for this end point

    Primary: Number of Participants With Suicidal Ideation and Suicidal Behavior as Assessed by the Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS)

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    End point title
    		 Number of Participants With Suicidal Ideation and Suicidal Behavior as Assessed by the Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) [5]
    End point description
    eC-SSRS is a questionnaire to assess suicidal ideation and suicidal behavior. Suicidal behavior was defined as a "yes" answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation was defined as a "yes" answer to any one of 5 suicidal ideation questions: wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent, any self-injurious behavior with no suicidal intent. Safety population included all participants who received at least 1 dose of fremanezumab.
    End point type
    Primary
    End point timeframe
    Baseline (Day 0) up to follow-up visit (Day 533)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Safety analyses were descriptive in nature.
    End point values
    		 TEV-48125 225 mg Monthly: New/Placebo Rollover Participants TEV-48125 225 mg Monthly: Active Rollover Participants TEV-48125 675 mg Quarterly: New/Placebo Rollover Participants TEV-48125 675 mg Quarterly: Active Rollover Participants
    Number of subjects analysed
    418
    526
    419
    525
    Units: participants
        Suicidal ideation
    2
    0
    2
    1
        Suicidal attempt
    0
    0
    1
    0
    No statistical analyses for this end point

    Primary: Number of Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results

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    End point title
    		 Number of Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results [6]
    End point description
    Potentially clinically significant abnormal serum chemistry findings included: Blood Urea Nitrogen (BUN): greater than or equal to (>=) 10.71 millimoles/liter (mmol/L), creatinine: >=177 micromoles/liter (µmol/L), bilirubin: >=34.2 µmol/L, Alanine Aminotransferase (ALT) (units/liter [U/L]): >=3*upper limit of normal (ULN) Aspartate Aminotransferase (AST) (U/L): >=3*ULN, and Gamma Glutamyl Transferase (GGT) (U/L): >=3*ULN. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Safety population included all participants who received at least 1 dose of fremanezumab. Here, 'Overall number of participants analysed'=participants with both baseline and post-baseline serum chemistry values.
    End point type
    Primary
    End point timeframe
    Baseline (Day 0) up to end of treatment (EOT) visit (Day 336)
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Safety analyses were descriptive in nature.
    End point values
    		 TEV-48125 225 mg Monthly: New/Placebo Rollover Participants TEV-48125 225 mg Monthly: Active Rollover Participants TEV-48125 675 mg Quarterly: New/Placebo Rollover Participants TEV-48125 675 mg Quarterly: Active Rollover Participants
    Number of subjects analysed
    408
    518
    412
    513
    Units: participants
    27
    26
    11
    23
    No statistical analyses for this end point

    Primary: Number of Participants With Potentially Clinically Significant Abnormal Hematology Results

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    End point title
    		 Number of Participants With Potentially Clinically Significant Abnormal Hematology Results [7]
    End point description
    Potentially clinically significant abnormal hematology findings included: hemoglobin: less than (<) 115 grams/liter (g/L) (in males) or <=95 g/L (in females), hematocrit: <0.37 L/L (in males) or <0.32 L/L (in females), leukocytes: >=20*10^9/L or <=3*10^9/L, eosinophils/leukocytes: >=10%, and platelets: >=700*10^9/L or <=75*10^9/L. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Safety population included all participants who received at least 1 dose of fremanezumab. Here, 'Overall number of participants analysed'=participants with both baseline and post-baseline hematology parameter values.
    End point type
    Primary
    End point timeframe
    Baseline (Day 0) up to end of treatment (EOT) visit (Day 336)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Safety analyses were descriptive in nature.
    End point values
    		 TEV-48125 225 mg Monthly: New/Placebo Rollover Participants TEV-48125 225 mg Monthly: Active Rollover Participants TEV-48125 675 mg Quarterly: New/Placebo Rollover Participants TEV-48125 675 mg Quarterly: Active Rollover Participants
    Number of subjects analysed
    408
    518
    412
    513
    Units: participants
    34
    39
    27
    40
    No statistical analyses for this end point

    Primary: Number of Participants With Potentially Clinically Significant Abnormal Urinalysis Laboratory Tests Results

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    End point title
    		 Number of Participants With Potentially Clinically Significant Abnormal Urinalysis Laboratory Tests Results [8]
    End point description
    Potentially clinically significant abnormal urinalysis findings included: blood: >=2 unit increase from baseline, urine glucose (milligrams/decilitre [mg/dL]): >=2 unit increase from baseline, ketones (mg/dL): >=2 unit increase from baseline, urine protein (mg/dL): >=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. Safety population included all participants who received at least 1 dose of fremanezumab. Here, 'Overall number of participants analysed'=participants with both baseline and post-baseline urinalysis values.
    End point type
    Primary
    End point timeframe
    Baseline (Day 0) up to (EOT visit (Day 336)
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Safety analyses were descriptive in nature.
    End point values
    		 TEV-48125 225 mg Monthly: New/Placebo Rollover Participants TEV-48125 225 mg Monthly: Active Rollover Participants TEV-48125 675 mg Quarterly: New/Placebo Rollover Participants TEV-48125 675 mg Quarterly: Active Rollover Participants
    Number of subjects analysed
    408
    517
    412
    513
    Units: participants
    128
    170
    120
    146
    No statistical analyses for this end point

    Primary: Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Values

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    End point title
    		 Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Values [9]
    End point description
    Potentially clinically significant abnormal vital signs findings 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: >=105 mmHg and increase of >=15 mmHg, or <=50 mmHg and decrease of >=15 mmHg; respiratory rate: <10 breaths/minute; and body temperature >=38.3 degrees centigrade and change of >=1.1 degrees centigrade. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Safety population included all participants who received at least 1 dose of fremanezumab. Here, 'Overall number of participants analysed'=participants with both baseline and post-baseline vital signs values.
    End point type
    Primary
    End point timeframe
    Baseline (Day 0) up to EOT visit (Day 336)
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Safety analyses were descriptive in nature.
    End point values
    		 TEV-48125 225 mg Monthly: New/Placebo Rollover Participants TEV-48125 225 mg Monthly: Active Rollover Participants TEV-48125 675 mg Quarterly: New/Placebo Rollover Participants TEV-48125 675 mg Quarterly: Active Rollover Participants
    Number of subjects analysed
    415
    520
    414
    519
    Units: participants
    20
    33
    24
    40
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Monthly Average Number of Migraine Days During the 4-Week Period at Month 12

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    End point title
    		 Change From Baseline in Monthly Average Number of Migraine Days During the 4-Week Period at Month 12
    End point description
    A migraine day: when at least 1 of following situations occurred: A calendar day(0:00 to 23:59) demonstrating >= 4 consecutive hours (hrs) (for CM participants) or >= 2 consecutive hrs (for EM participants) of a headache meeting criteria for migraine with or without aura; or of a headache meeting criteria for probable migraine; and a calendar day demonstrating a headache of any duration that was treated with migraine-specific medications. 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. Full analysis set (FAS):all participants who received at least 1 dose of fremanezumab, had at least 10 days of efficacy assessments by e-diary after first injection. Data for this endpoint was collected and reported separately for CM and EM participants.‘Overall number of participants analysed'=participants evaluable for this endpoint.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Day -28 to Day -1), Month 12
    End point values
    		 TEV-48125 225 mg Monthly: New/Placebo Rollover CM Participants TEV-48125 225 mg Monthly: Active Rollover CM Participants TEV-48125 675mg Quarterly:New/Placebo Rollover CM Participants TEV-48125 675 mg Quarterly: Active Rollover CM Participants TEV-48125 225 mg Monthly: New/Placebo Rollover EM Participants TEV-48125 225 mg Monthly: Active Rollover EM Participants TEV-48125 675mg Quarterly:New/Placebo Rollover EM Participants TEV-48125 675 mg Quarterly: Active Rollover EM Participants
    Number of subjects analysed
    192
    233
    194
    230
    124
    173
    138
    173
    Units: days/month
        arithmetic mean (standard deviation)
    -7.8 ± 6.98
    -8.2 ± 6.14
    -7.6 ± 6.87
    -7.0 ± 6.54
    -4.5 ± 4.20
    -5.5 ± 4.01
    -5.5 ± 3.65
    -5.0 ± 3.78
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Monthly Average Number of Headache Days of Any Severity During the 4-Week Period at Month 12

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    End point title
    		 Change From Baseline in Monthly Average Number of Headache Days of Any Severity During the 4-Week Period at Month 12
    End point description
    Headaches were subjectively rated by participants as mild, moderate or severe. A headache day of any severity for both CM and EM participants was defined as a calendar day (00:00 to 23:59) where participant reports: a day with headache pain that lasts >=4 hours with a peak severity of any severity or; a day when participant used acute migraine-specific medication to treat a headache of any severity or duration. 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. FAS: all participants who received at least 1 dose of fremanezumab, and had at least 10 days of efficacy assessments by electronic diary after first injection. Data for this endpoint was collected and reported separately for CM and EM participants. ‘Overall number of participants analysed'=participants evaluable for this endpoint.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Day -28 to Day -1), Month 12
    End point values
    		 TEV-48125 225 mg Monthly: New/Placebo Rollover CM Participants TEV-48125 225 mg Monthly: Active Rollover CM Participants TEV-48125 675mg Quarterly:New/Placebo Rollover CM Participants TEV-48125 675 mg Quarterly: Active Rollover CM Participants TEV-48125 225 mg Monthly: New/Placebo Rollover EM Participants TEV-48125 225 mg Monthly: Active Rollover EM Participants TEV-48125 675mg Quarterly:New/Placebo Rollover EM Participants TEV-48125 675 mg Quarterly: Active Rollover EM Participants
    Number of subjects analysed
    192
    233
    194
    230
    124
    173
    138
    173
    Units: days/month
        arithmetic mean (standard deviation)
    -7.7 ± 6.79
    -7.9 ± 6.01
    -7.2 ± 6.48
    -7.1 ± 6.88
    -4.4 ± 4.25
    -5.0 ± 3.90
    -5.0 ± 3.63
    -4.8 ± 3.74
    No statistical analyses for this end point

    Other pre-specified: Percentage of Participants With At Least 50% Reduction From Baseline in Monthly Average Number of Migraine Days During the 4-Week Period

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    End point title
    		 Percentage of Participants With At Least 50% Reduction From Baseline in Monthly Average Number of Migraine Days During the 4-Week Period
    End point description
    A migraine day: when at least 1 of following situations occurred: A calendar day (0:00 to 23:59) demonstrating >= 4 consecutive hours (hrs) (for CM participants) or >= 2 consecutive hrs (for EM participants) of a headache meeting criteria for migraine with or without aura; or of a headache meeting criteria for probable migraine; and a calendar day demonstrating a headache of any duration that was treated with migraine-specific medications. 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. FAS: all participants who received at least 1 dose of fremanezumab, had at least 10 days of efficacy assessments by e-diary after first injection. Data for this endpoint was collected and reported separately for CM and EM participants.‘Overall number of participants analysed'=participants evaluable for this endpoint.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Day -28 to Day -1), Month 12
    End point values
    		 TEV-48125 225 mg Monthly: New/Placebo Rollover CM Participants TEV-48125 225 mg Monthly: Active Rollover CM Participants TEV-48125 675mg Quarterly:New/Placebo Rollover CM Participants TEV-48125 675 mg Quarterly: Active Rollover CM Participants TEV-48125 225 mg Monthly: New/Placebo Rollover EM Participants TEV-48125 225 mg Monthly: Active Rollover EM Participants TEV-48125 675mg Quarterly:New/Placebo Rollover EM Participants TEV-48125 675 mg Quarterly: Active Rollover EM Participants
    Number of subjects analysed
    195
    240
    197
    237
    125
    174
    139
    174
    Units: percentage of participants
        number (not applicable)
    54
    59
    52
    54
    58
    75
    68
    64
    No statistical analyses for this end point

    Other pre-specified: Percentage of Participants With At Least 50% Reduction From Baseline in Monthly Average Number of Headache Days of at Least Moderate Severity During the 4-Week Period

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    End point title
    		 Percentage of Participants With At Least 50% Reduction From Baseline in Monthly Average Number of Headache Days of at Least Moderate Severity During the 4-Week Period
    End point description
    Headaches were subjectively rated by participants as mild, moderate or severe. A headache day of any severity for both CM and EM participants was defined as a calendar day (00:00 to 23:59) where participant reports: a day with headache pain that lasts >=4 hours with a peak severity of any severity or; a day when participant used acute migraine-specific medication to treat a headache of any severity or duration. 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. FAS: all participants who received at least 1 dose of fremanezumab, and had at least 10 days of efficacy assessments by electronic diary after first injection. Data for this endpoint was collected and reported separately for CM and EM participants. ‘Overall number of participants analysed'=participants evaluable for this endpoint.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Day -28 to Day -1), Month 12
    End point values
    		 TEV-48125 225 mg Monthly: New/Placebo Rollover CM Participants TEV-48125 225 mg Monthly: Active Rollover CM Participants TEV-48125 675mg Quarterly:New/Placebo Rollover CM Participants TEV-48125 675 mg Quarterly: Active Rollover CM Participants TEV-48125 225 mg Monthly: New/Placebo Rollover EM Participants TEV-48125 225 mg Monthly: Active Rollover EM Participants TEV-48125 675mg Quarterly:New/Placebo Rollover EM Participants TEV-48125 675 mg Quarterly: Active Rollover EM Participants
    Number of subjects analysed
    193
    240
    197
    237
    124
    174
    138
    174
    Units: percentage of participants
        number (not applicable)
    56
    62
    54
    54
    58
    72
    67
    68
    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 (Day 533)
    Adverse event reporting additional description
    Safety population included all participants who received at least 1 dose of fremanezumab.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    TEV-48125 225 mg Monthly: New/Placebo Rollover Participants
    Reporting group description
    		 Participants with CM who were randomized to the placebo treatment group or participants who did not rollover from the pivotal efficacy study, received fremanezumab 675 mg SC as loading dose (3 injections of fremanezumab 225 mg/1.5 mL on Day 0) followed by 11 monthly SC doses of fremanezumab at 225 mg (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL on Days 84, 168, and 252; and 1 injection of fremanezumab 225 mg/1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308). Participants with EM who were randomized to the placebo treatment group or participants who did not rollover from the pivotal efficacy study, received 12 monthly SC doses of fremanezumab at 225 mg (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL on Days 0, 84, 168, and 252; and 1 injection of fremanezumab 225 mg/1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).

    Reporting group title
    TEV-48125 225 mg Monthly: Active Rollover Participants
    Reporting group description
    		 Participants with CM who were randomized to the active treatment group (Fremanezumab 675/225 mg) in the pivotal efficacy study, received fremanezumab 675 mg SC as loading dose (3 injections of fremanezumab 225 mg/1.5 mL on Day 0) followed by 11 monthly SC doses of fremanezumab at 225 mg (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL on Days 84, 168, and 252; and 1 injection of fremanezumab 225 mg/1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308). Participants with EM who were randomized to the active treatment group (Fremanezumab 225 mg) in the pivotal efficacy study, received 12 monthly SC doses of fremanezumab at 225 mg (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL on Days 0, 84, 168, and 252; and 1 injection of fremanezumab 225 mg/1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).

    Reporting group title
    TEV-48125 675 mg Quarterly: Active Rollover Participants
    Reporting group description
    		 Participants with CM or EM who were randomized to the active treatment group (Fremanezumab 675 mg) in the pivotal efficacy study, received fremanezumab 675 mg SC once every 3 months for 12 months for a total of 4 doses (3 injections of fremanezumab 225 mg/1.5 mL on Days 0, 84, 168, and 252; and 1 injection of placebo 1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).

    Reporting group title
    TEV-48125 675 mg Quarterly: New/Placebo Rollover Participants
    Reporting group description
    		 Participants with CM or EM who were randomized to the placebo treatment group or participants who did not rollover from the pivotal efficacy study, received fremanezumab 675 mg SC once every 3 months for 12 months for a total of 4 doses (3 injections of fremanezumab 225 mg/1.5 mL on Days 0, 84, 168, and 252; and 1 injection of placebo 1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).

    Serious adverse events
    		 TEV-48125 225 mg Monthly: New/Placebo Rollover Participants TEV-48125 225 mg Monthly: Active Rollover Participants TEV-48125 675 mg Quarterly: Active Rollover Participants TEV-48125 675 mg Quarterly: New/Placebo Rollover Participants
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 418 (6.46%)
    29 / 526 (5.51%)
    23 / 525 (4.38%)
    36 / 419 (8.59%)
         number of deaths (all causes)
    0
    0
    0
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 418 (0.00%)
    2 / 526 (0.38%)
    0 / 525 (0.00%)
    2 / 419 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign breast neoplasm
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer stage III
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    High grade B-cell lymphoma Burkitt-like lymphoma
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    1 / 525 (0.19%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    1 / 525 (0.19%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Phyllodes tumour
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pituitary tumour
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superficial spreading melanoma stage unspecified
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    1 / 525 (0.19%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Salpingo-oophorectomy
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    1 / 525 (0.19%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foetal death
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Premature baby
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Premature separation of placenta
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    1 / 525 (0.19%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Allergy to arthropod sting
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    1 / 525 (0.19%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometriosis
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic ovarian cyst
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst ruptured
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    1 / 525 (0.19%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian mass
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    1 / 525 (0.19%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngeal oedema
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    1 / 525 (0.19%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung consolidation
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Adjustment disorder with mixed disturbance of emotion and conduct
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    1 / 525 (0.19%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Ammonia increased
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Abdominal wound dehiscence
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    1 / 525 (0.19%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    1 / 525 (0.19%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Arteriovenous malformation
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    1 / 525 (0.19%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular arteriovenous malformation
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    1 / 525 (0.19%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital cyst
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    1 / 525 (0.19%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital cystic disease of liver
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hereditary haemochromatosis
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    1 / 525 (0.19%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Central nervous system lesion
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    1 / 525 (0.19%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cluster headache
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    1 / 525 (0.19%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    1 / 525 (0.19%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Migraine
         subjects affected / exposed
    0 / 418 (0.00%)
    3 / 526 (0.57%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nerve compression
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parkinsonism
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perineurial cyst
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Primary progressive multiple sclerosis
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status migrainosus
         subjects affected / exposed
    2 / 418 (0.48%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient global amnesia
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Sudden hearing loss
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    1 / 525 (0.19%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Macular degeneration
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 418 (0.24%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal tear
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    1 / 525 (0.19%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 418 (0.48%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Barrett's oesophagus
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    1 / 525 (0.19%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileal stenosis
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    1 / 525 (0.19%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis alcoholic
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fibromyalgia
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    1 / 525 (0.19%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 418 (0.24%)
    1 / 526 (0.19%)
    1 / 525 (0.19%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    1 / 525 (0.19%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periarthritis
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    1 / 525 (0.19%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Synovial cyst
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertebral osteophyte
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    1 / 525 (0.19%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    2 / 418 (0.48%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Petrositis
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 418 (0.24%)
    1 / 526 (0.19%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 418 (0.00%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    2 / 419 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 526 (0.00%)
    0 / 525 (0.00%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 TEV-48125 225 mg Monthly: New/Placebo Rollover Participants TEV-48125 225 mg Monthly: Active Rollover Participants TEV-48125 675 mg Quarterly: Active Rollover Participants TEV-48125 675 mg Quarterly: New/Placebo Rollover Participants
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    300 / 418 (71.77%)
    367 / 526 (69.77%)
    329 / 525 (62.67%)
    284 / 419 (67.78%)
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    130 / 418 (31.10%)
    144 / 526 (27.38%)
    124 / 525 (23.62%)
    99 / 419 (23.63%)
         occurrences all number
    430
    446
    386
    284
    Injection site haemorrhage
         subjects affected / exposed
    34 / 418 (8.13%)
    38 / 526 (7.22%)
    38 / 525 (7.24%)
    21 / 419 (5.01%)
         occurrences all number
    43
    66
    62
    38
    Injection site induration
         subjects affected / exposed
    167 / 418 (39.95%)
    174 / 526 (33.08%)
    134 / 525 (25.52%)
    144 / 419 (34.37%)
         occurrences all number
    717
    753
    666
    543
    Injection site pain
         subjects affected / exposed
    149 / 418 (35.65%)
    156 / 526 (29.66%)
    140 / 525 (26.67%)
    135 / 419 (32.22%)
         occurrences all number
    980
    982
    811
    981
    Injection site pruritus
         subjects affected / exposed
    31 / 418 (7.42%)
    43 / 526 (8.17%)
    24 / 525 (4.57%)
    17 / 419 (4.06%)
         occurrences all number
    101
    107
    64
    64
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    24 / 418 (5.74%)
    15 / 526 (2.85%)
    24 / 525 (4.57%)
    20 / 419 (4.77%)
         occurrences all number
    25
    16
    26
    22
    Influenza
         subjects affected / exposed
    14 / 418 (3.35%)
    27 / 526 (5.13%)
    25 / 525 (4.76%)
    8 / 419 (1.91%)
         occurrences all number
    18
    29
    28
    9
    Nasopharyngitis
         subjects affected / exposed
    43 / 418 (10.29%)
    69 / 526 (13.12%)
    68 / 525 (12.95%)
    37 / 419 (8.83%)
         occurrences all number
    61
    107
    108
    58
    Sinusitis
         subjects affected / exposed
    30 / 418 (7.18%)
    27 / 526 (5.13%)
    31 / 525 (5.90%)
    28 / 419 (6.68%)
         occurrences all number
    40
    28
    38
    35
    Upper respiratory tract infection
         subjects affected / exposed
    55 / 418 (13.16%)
    62 / 526 (11.79%)
    63 / 525 (12.00%)
    73 / 419 (17.42%)
         occurrences all number
    65
    76
    78
    97
    Urinary tract infection
         subjects affected / exposed
    25 / 418 (5.98%)
    27 / 526 (5.13%)
    33 / 525 (6.29%)
    26 / 419 (6.21%)
         occurrences all number
    38
    43
    37
    29

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Mar 2016
    The following major procedural changes (not all-inclusive) were made to the protocol: - Incorporation of required revisions based on health authority input from the European Medicines Agency, Food and Drug Administration, and Pharmaceuticals and Medical Devices Agency; - Provision of clarifying language for the inclusion and exclusion criteria; - Clarification of allowed and disallowed preventive medications; - Revision of protocol-defined adverse events of special interest and to add clinical criteria for diagnosing anaphylaxis; - Update and/or clarification of versions of certain exploratory endpoints, including the EuroQol-5 Dimension (EQ-5D) (now EuroQol-5 Dimension, 5 response level version [EQ-5D-5L]) and Patient Global Impression of Change (PGIC).

    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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