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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Parallel-Group Study Comparing the Efficacy and Safety of 2 Dose Regimens (Intravenous/Subcutaneous and Subcutaneous) of TEV-48125 Versus Placebo for the Prevention of Chronic Cluster Headache

    Summary
    EudraCT number
    		 2016-003171-21
    Trial protocol
    		 GB   SE   DE   ES   IT   NL   PL   FI  
    Global end of trial date
    18 Jul 2018

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    TV48125-CNS-30057
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02964338
    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 18884838279, info.eraclinical@teva.de
    Scientific contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 18884838279, 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
    18 Jul 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Jul 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jul 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to demonstrate the efficacy of fremanezumab in the prevention of chronic cluster headache (CCH) in adult participants.
    Protection of trial subjects
    This study was conducted in full accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations (for example, Code of Federal Regulations [CFR] Title 21, Parts 50, 54, 56, 312, and 314; European Union (EU) Directive 2001/20/EC on the approximation of the laws, regulations, and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Jan 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 103
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Germany: 41
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    Finland: 8
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    Israel: 33
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    Netherlands: 17
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Sweden: 3
    Worldwide total number of subjects
    259
    EEA total number of subjects
    118
    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)
    245
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants with a history of CCH were enrolled. Eligible participants entered baseline cluster headache (CH) attack information into an electronic diary device daily for greater than or equal to (≥)4 weeks during the Baseline Period.

    Pre-assignment
    Screening details
    		 A total of 259 participants were randomly assigned with stratification based on sex, country, and baseline concomitant preventive medication use (yes/no) to either placebo, fremanezumab 675/225/225 milligrams (mg), or fremanezumab 900/225/225 mg treatment groups in a 1:1:1 ratio.

    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
    		 Placebo
    Arm description
    		 Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use, Intravenous use
    Dosage and administration details
    Placebo matching to fremanezumab will be administered as per the schedule specified in the respective arms.

    Arm title
    		 Fremanezumab 675/225/225 mg
    Arm description
    		 Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 milliliters [mL]) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fremanezumab
    Investigational medicinal product code
    Other name
    TEV-48125
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use, Intravenous use
    Dosage and administration details
    Fremanezumab will be administered as per the dose and schedule specified in the respective arms.

    Arm title
    		 Fremanezumab 900/225/225 mg
    Arm description
    		 Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fremanezumab
    Investigational medicinal product code
    Other name
    TEV-48125
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use, Intravenous use
    Dosage and administration details
    Fremanezumab will be administered as per the dose and schedule specified in the respective arms.

    Number of subjects in period 1
    		Placebo Fremanezumab 675/225/225 mg Fremanezumab 900/225/225 mg
    Started
    84
    88
    87
    Intent-to-Treat (ITT) Analysis Set
    84
    88
    87
    Safety Analysis Set
    83
    88
    87
    Full Analysis Set
    81
    86
    87
    Completed
    67
    64
    68
    Not completed
    17
    24
    19
         Consent withdrawn by subject
    1
    3
    1
         Adverse event, non-fatal
    2
    1
    1
         Non-compliant with e-diary
    -
    1
    -
         Did not meet criteria
    1
    -
    -
         Sponsor terminated study for futility
    12
    15
    14
         Lost to follow-up
    1
    -
    3
         Lack of efficacy
    -
    3
    -
         Protocol deviation
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.

    Reporting group title
    Fremanezumab 675/225/225 mg
    Reporting group description
    		 Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 milliliters [mL]) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.

    Reporting group title
    Fremanezumab 900/225/225 mg
    Reporting group description
    		 Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.

    Reporting group values
    		 Placebo Fremanezumab 675/225/225 mg Fremanezumab 900/225/225 mg Total
    Number of subjects
    		 84 88 87 259
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 81 83 81 245
        From 65-84 years
    		 3 5 6 14
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 46.3 ± 11.29 45.3 ± 11.40 43.8 ± 12.92 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 35 36 36 107
        Male
    		 49 52 51 152
    Race
    Units: Subjects
        White
    		 79 83 79 241
        Black or African American
    		 4 4 8 16
        Asian
    		 0 1 0 1
        American Indian or Alaska native
    		 0 0 0 0
        Native Hawaiian or other Pacific Islander
    		 0 0 0 0
        Middle Eastern
    		 1 0 0 1
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 77 78 83 238
        Hispanic or Latino
    		 5 9 4 18
        Missing Ethnicity
    		 2 1 0 3
    Number of CH Attacks During the Baseline Period
    CH attack defined as a severe/very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15-180 minutes (min) with either or both of following 2 categories: 1) ≥1 of following symptoms/signs, ipsilateral to headache: -conjunctival injection and/or lacrimation; -nasal congestion and/or rhinorrhea; -eyelid edema; -forehead and facial sweating; -forehead and facial flushing; -fullness in ear sensation; -miosis and/or ptosis. 2) sense of restlessness or agitation. Baseline period (≥4 weeks [wk]) defined as date informed consent was signed up to day before first dose of study drug.
    Units: CH attacks
        arithmetic mean (standard deviation)
    		 38.0 ± 33.88 33.9 ± 27.37 44.0 ± 43.78 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.

    Reporting group title
    Fremanezumab 675/225/225 mg
    Reporting group description
    		 Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 milliliters [mL]) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.

    Reporting group title
    Fremanezumab 900/225/225 mg
    Reporting group description
    		 Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.

    Primary: Mean Change From Baseline in the Overall Monthly Average Number of CH Attacks Up to Week 12

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    End point title
    		 Mean Change From Baseline in the Overall Monthly Average Number of CH Attacks Up to Week 12
    End point description
    CH: severe/very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15-180min with either/both of following 2 categories: 1) ≥1 of following symptoms/signs, ipsilateral to headache: -conjunctival injection and/or lacrimation; -nasal congestion and/or rhinorrhea; -eyelid edema; -forehead and facial sweating; -forehead and facial flushing; -fullness in ear sensation; -miosis and/or ptosis. 2) sense of restlessness or agitation. Least Squares mean calculated by analysis of covariance (ANCOVA) model with baseline preventive medication use (yes/no), sex, region (United States/Canada/other) and treatment as fixed effects & baseline number of CH attacks as a covariate. Change from baseline in overall monthly average number of CH attacks during 12-wk period after first dose of study drug (based on Wk0-12 data) is reported. Full analysis set: randomized participants, received ≥1 dose of study drug, had at least 10days of postbaseline efficacy assessments by Wk12 assessment.
    End point type
    Primary
    End point timeframe
    Baseline Period (from at least Week -4 to Week 0), Up to Week 12
    End point values
    		 Placebo Fremanezumab 675/225/225 mg Fremanezumab 900/225/225 mg
    Number of subjects analysed
    81
    86
    87
    Units: CH attacks
        least squares mean (standard error)
    -12.2 ± 2.32
    -8.7 ± 2.26
    -15.5 ± 2.24
    Statistical analysis title
    		 Placebo versus Fremanezumab 675/225/225 mg
    Comparison groups
    Placebo v Fremanezumab 675/225/225 mg
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2741 [1]
    Method
    		 ANCOVA
    Parameter type
    		 Least square (LS) mean difference
    Point estimate
    3.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.8
         upper limit
    		 9.82
    Notes
    [1] - Threshold for significance at 0.05 level.
    Statistical analysis title
    		 Placebo versus Fremanezumab 900/225/225 mg
    Comparison groups
    Placebo v Fremanezumab 900/225/225 mg
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3047 [2]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -3.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.59
         upper limit
    		 3.01
    Notes
    [2] - Threshold for significance at 0.05 level.

    Secondary: Percentage of Participants With a ≥50% Reduction from Baseline in the Monthly Average Number of CH Attacks Up to Week 12

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    End point title
    		 Percentage of Participants With a ≥50% Reduction from Baseline in the Monthly Average Number of CH Attacks Up to Week 12
    End point description
    A CH attack was defined as a severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes with either or both of the following 2 categories: 1) at least 1 of the following symptoms or signs, ipsilateral to the headache: -conjunctival injection and/or lacrimation; -nasal congestion and/or rhinorrhea; -eyelid edema; -forehead and facial sweating; -forehead and facial flushing; -sensation of fullness in the ear; -miosis and/or ptosis. 2) a sense of restlessness or agitation. Full analysis set included all randomized participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessments by the Week 12 assessment.
    End point type
    Secondary
    End point timeframe
    Baseline Period (from at least Week -4 to Week 0) up to Week 12
    End point values
    		 Placebo Fremanezumab 675/225/225 mg Fremanezumab 900/225/225 mg
    Number of subjects analysed
    81
    86
    87
    Units: percentage of participants
    40
    40
    45
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in the Monthly Average Number of CH Attacks at Week 4 and Week 12

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    End point title
    		 Mean Change From Baseline in the Monthly Average Number of CH Attacks at Week 4 and Week 12
    End point description
    CH attack defined as a severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15-180 min with either or both of following 2 categories: 1) ≥1 of following symptoms or signs, ipsilateral to the headache: -conjunctival injection and/or lacrimation; -nasal congestion and/or rhinorrhea; -eyelid edema; -forehead and facial sweating; -forehead and facial flushing; -fullness in ear sensation; -miosis and/or ptosis. 2) a sense of restlessness or agitation. Mean change from baseline in monthly average number of CH attacks during 4-wk period after administration of first dose of study drug (based on Wk 0-4 data) and during 4-week period after administration of third dose of study drug (based on Wk 8-12 data) is reported. Full analysis set: all randomized participants who received ≥1 dose of study drug and had ≥10 days of postbaseline efficacy assessments by the Wk 12 assessment. Here, 'N' signifies participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline Period (from at least Week -4 to Week 0), Week 4 and Week 12
    End point values
    		 Placebo Fremanezumab 675/225/225 mg Fremanezumab 900/225/225 mg
    Number of subjects analysed
    81
    86
    87
    Units: CH attacks
    arithmetic mean (standard deviation)
        Change at Week 4 (n=81, 86, 87)
    -10.4 ± 17.22
    -7.7 ± 19.53
    -15.0 ± 24.17
        Change at Week 12 (n=67, 62, 72)
    -12.6 ± 25.72
    -3.1 ± 34.42
    -17.9 ± 25.98
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in the Overall Weekly Average Number of Days with Use of Cluster-Specific Acute Headache Medications (Triptans and Ergot Compounds) Up to Week 12

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    End point title
    		 Mean Change From Baseline in the Overall Weekly Average Number of Days with Use of Cluster-Specific Acute Headache Medications (Triptans and Ergot Compounds) Up to Week 12
    End point description
    A maximum of 2 concomitant preventive medications for CH were allowed during the study. Participants must have been on a stable dose and regimen of the concomitant medication for at least 2 weeks before screening and throughout the study. Baseline data and the mean change from baseline in the overall weekly average number of days with the use of cluster-specific acute headache medications (triptans and ergot compounds) during the 12-week period after administration of the first dose of study drug (based on Week 0 to 12 data) is reported. Full analysis set included all randomized participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessments by the Week 12 assessment.
    End point type
    Secondary
    End point timeframe
    Baseline Period (from at least Week -4 to Week 0), Up to Week 12
    End point values
    		 Placebo Fremanezumab 675/225/225 mg Fremanezumab 900/225/225 mg
    Number of subjects analysed
    81
    86
    87
    Units: days
    arithmetic mean (standard deviation)
        Baseline
    2.4 ± 2.42
    2.4 ± 2.18
    2.2 ± 2.27
        Change at Week 12
    -0.7 ± 1.34
    -0.8 ± 1.57
    -0.8 ± 1.20
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in the Weekly Average Number of Days Oxygen was Used to Treat CCH Up to Week 12

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    End point title
    		 Mean Change From Baseline in the Weekly Average Number of Days Oxygen was Used to Treat CCH Up to Week 12
    End point description
    Baseline data and the mean change from baseline in the overall weekly average number of days oxygen was used to treat CCH during the 12-week period after administration of the first dose of study drug (based on Week 0 to 12 data) is reported. Full analysis set included all randomized participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessments by the Week 12 assessment.
    End point type
    Secondary
    End point timeframe
    Baseline Period (from at least Week -4 to Week 0), Up to Week 12
    End point values
    		 Placebo Fremanezumab 675/225/225 mg Fremanezumab 900/225/225 mg
    Number of subjects analysed
    81
    86
    87
    Units: days
    arithmetic mean (standard deviation)
        Baseline
    2.2 ± 2.59
    1.9 ± 2.53
    1.9 ± 2.59
        Change at Week 12
    -0.5 ± 1.35
    -0.5 ± 1.35
    -0.5 ± 1.09
    No statistical analyses for this end point

    Secondary: Number of Participants who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12

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    End point title
    		 Number of Participants who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12
    End point description
    The PPSI assessment was developed to measure pain intensity and was adjusted for CH symptoms improvement. Participants marked the level of CH-associated pain and indicated if pain is “1=much worse,” “2=moderately worse,” “3=slightly worse,” “4=unchanged,” “5=slightly improved,” “6=moderately improved,” or “much improved” compared with 4 weeks prior. PPSI was defined as the change in pain that corresponds with a minimal rating of “7=slightly improved.” Data at Week 1 was recorded on Day 7 in the electronic diary device at home. Week 12 data also included assessment at the early withdrawal visit for participants who discontinued the study early. Full analysis set included all randomized participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessments by the Week 12 assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 1, 4, 8, and 12
    End point values
    		 Placebo Fremanezumab 675/225/225 mg Fremanezumab 900/225/225 mg
    Number of subjects analysed
    81
    86
    87
    Units: participants
        Much worse, Baseline
    3
    1
    1
        Moderately worse, Baseline
    1
    4
    4
        Slightly worse, Baseline
    1
    5
    4
        Unchanged, Baseline
    69
    72
    75
        Slightly improved, Baseline
    5
    3
    3
        Moderately improved, Baseline
    1
    1
    0
        Much improved, Baseline
    1
    0
    0
        Missing, Baseline
    0
    0
    0
        Much worse, Week 1
    0
    3
    3
        Moderately worse, Week 1
    0
    2
    1
        Slightly worse, Week 1
    0
    2
    5
        Unchanged, Week 1
    35
    31
    26
        Slightly improved, Week 1
    23
    20
    32
        Moderately improved, Week 1
    5
    4
    8
        Much improved, Week 1
    6
    13
    8
        Missing, Week 1
    12
    11
    4
        Much worse, Week 4
    0
    1
    0
        Moderately worse, Week 4
    1
    2
    3
        Slightly worse, Week 4
    1
    2
    2
        Unchanged, Week 4
    24
    24
    25
        Slightly improved, Week 4
    30
    17
    25
        Moderately improved, Week 4
    5
    9
    12
        Much improved, Week 4
    12
    18
    11
        Missing, Week 4
    8
    13
    9
        Much worse, Week 8
    3
    2
    0
        Moderately worse, Week 8
    1
    3
    3
        Slightly worse, Week 8
    3
    4
    5
        Unchanged, Week 8
    27
    18
    24
        Slightly improved, Week 8
    18
    12
    13
        Moderately improved, Week 8
    10
    13
    14
        Much improved, Week 8
    4
    12
    15
        Missing, Week 8
    15
    22
    13
        Much worse, Week 12
    0
    2
    1
        Moderately worse, Week 12
    3
    5
    3
        Slightly worse, Week 12
    4
    6
    6
        Unchanged, Week 12
    29
    27
    31
        Slightly improved, Week 12
    21
    18
    15
        Moderately improved, Week 12
    8
    11
    11
        Much improved, Week 12
    13
    14
    12
        Missing, Week 12
    3
    3
    8
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events (AEs)

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    End point title
    		 Number of Participants with Adverse Events (AEs)
    End point description
    An AE was defined as any untoward medical occurrence that develops or worsens in severity during conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the Investigator on a scale of mild, moderate and severe, with severe as an AE that prevents usual activities. Relationship of AE to treatment was determined by the Investigator. Serious AEs include death, a life-threatening adverse event, 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 the participant and required medical intervention to prevent the previously listed serious outcomes. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Safety population included all randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    		 Placebo Fremanezumab 675/225/225 mg Fremanezumab 900/225/225 mg
    Number of subjects analysed
    83
    88
    87
    Units: participants
        Any AE
    43
    51
    49
        Severe AE
    3
    1
    3
        Treatment-related AE
    17
    23
    28
        Serious AE
    2
    2
    3
        AE leading to discontinuation
    2
    1
    2
    No statistical analyses for this end point

    Secondary: Number of Participants with Potentially Clinically Significant Laboratory (Serum Chemistry, Hematology, and Urinalysis) Abnormal Results

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    End point title
    		 Number of Participants with Potentially Clinically Significant Laboratory (Serum Chemistry, Hematology, and Urinalysis) Abnormal Results
    End point description
    Laboratory tests with potentially clinically significant abnormal findings included: Alanine Aminotransferase (units/liter [U/L]) ≥3*upper limit of normal (ULN); Aspartate Aminotransferase (U/L) ≥3*ULN; Bilirubin (Total) ≥34.2 micromoles/liter (umol/L); Blood Urea Nitrogen ≥10.71millimole/L; Creatinine ≥177 umol/L; Gamma Glutamyl Transferase (U/L) ≥3*ULN; hemoglobin less than (<)115grams (g)/L (males) or less than or equal to (≤)95g/L (females); leukocytes ≥20*10^9/L or ≤3*10^9/L; Eosinophils/Leukocytes ≥10%; Hematocrit <0.37L/L (males) and <0.32L/L (females); platelets ≥700*10^9/L or ≤75*10^9/L; blood ≥2 U increase from baseline; urine glucose (milligrams/decilitre [mg/dL]) ≥2 U increase from baseline; ketones (mg/dL) ≥2 U increase from baseline; urine protein (mg/dL) ≥2 U increase from baseline. Summary of other non-serious AEs and all serious AEs, regardless of causality located in Reported AE section. Safety population: randomized participants and received ≥1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    		 Placebo Fremanezumab 675/225/225 mg Fremanezumab 900/225/225 mg
    Number of subjects analysed
    83
    88
    87
    Units: participants
        With at least 1 serum chemistry abnormality
    1
    2
    0
        With at least 1 hematology abnormality
    2
    1
    3
        With at least 1 urinalysis abnormality
    0
    0
    0
    No statistical analyses for this end point

    Secondary: 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
    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 randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    		 Placebo Fremanezumab 675/225/225 mg Fremanezumab 900/225/225 mg
    Number of subjects analysed
    83
    88
    87
    Units: participants
        PT: Low-Low
    0
    0
    0
        PT: Low-Normal
    0
    0
    0
        PT: Low-High
    0
    0
    0
        PT: Normal-Low
    0
    0
    0
        PT: Normal-Normal
    68
    69
    62
        PT: Normal-High
    3
    2
    5
        PT: High-Low
    0
    0
    0
        PT: High-Normal
    5
    8
    11
        PT: High-High
    5
    4
    3
        PT: Missing
    2
    5
    6
        Prothrombin INR: Low-Low
    0
    0
    0
        Prothrombin INR: Low-Normal
    0
    0
    0
        Prothrombin INR: Low-High
    0
    0
    0
        Prothrombin INR: Normal-Low
    0
    0
    0
        Prothrombin INR: Normal-Normal
    70
    71
    69
        Prothrombin INR: Normal-High
    4
    2
    5
        Prothrombin INR: High-Low
    0
    0
    0
        Prothrombin INR: High-Normal
    5
    7
    6
        Prothrombin INR: High-High
    2
    3
    1
        Prothrombin INR: Missing
    2
    5
    6
    No statistical analyses for this end point

    Secondary: 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
    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 ≤50 mmHg and decrease of ≥15 mmHg, or ≥105 mmHg and increase of ≥15 mmHg; respiratory rate <10 breaths/minute; and body temperature ≥38.3 degrees 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 randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    		 Placebo Fremanezumab 675/225/225 mg Fremanezumab 900/225/225 mg
    Number of subjects analysed
    83
    88
    87
    Units: participants
    3
    0
    0
    No statistical analyses for this end point

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

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    End point title
    		 Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters
    End point description
    ECG parameters included: heart rate, PR interval, QRS interval, QT interval corrected using the Fridericia formula (QTcF), QT interval corrected using the Bazett's formula (QTcB) and RR interval. Shifts represented as Baseline - 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 randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo Fremanezumab 675/225/225 mg Fremanezumab 900/225/225 mg
    Number of subjects analysed
    83
    88
    87
    Units: participants
        Normal / Normal
    47
    46
    45
        Normal / NCS
    8
    11
    14
        Normal / CS
    0
    0
    0
        NCS / Normal
    10
    7
    8
        NCS / NCS
    15
    20
    12
        NCS / CS
    0
    0
    0
        CS / Normal
    0
    0
    0
        CS / NCS
    0
    0
    0
        CS / CS
    0
    0
    0
        Missing
    3
    4
    8
    No statistical analyses for this end point

    Secondary: Number of Participants with Injection Site Reactions

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    End point title
    		 Number of Participants with Injection Site Reactions
    End point description
    Number of participants who reported treatment-emergent injection site reactions are summarized. Preferred terms from Medical Dictionary for Regulatory Activities (MedDRA) version 18.1 were offered without a threshold applied. Injection site reactions included injection site erythema, induration, pain, haemorrhage, bruising, hypersensitivity, swelling, rash, and flushing. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Safety population included all randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    		 Placebo Fremanezumab 675/225/225 mg Fremanezumab 900/225/225 mg
    Number of subjects analysed
    83
    88
    87
    Units: participants
        Injection site erythema
    3
    7
    5
        Injection site induration
    3
    6
    6
        Injection site pain
    6
    5
    2
        Injection site haemorrhage
    0
    0
    2
        Injection site bruising
    0
    0
    1
        Injection site hypersensitivity
    0
    1
    0
        Injection site swelling
    2
    0
    0
        Injection site rash
    1
    0
    0
        Injection site flushing
    0
    1
    0
    No statistical analyses for this end point

    Secondary: 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)
    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 randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    		 Placebo Fremanezumab 675/225/225 mg Fremanezumab 900/225/225 mg
    Number of subjects analysed
    83
    88
    87
    Units: participants
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Week 12
    Adverse event reporting additional description
    Safety population included all randomized participants who received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.

    Reporting group title
    Fremanezumab 900/225/225 mg
    Reporting group description
    		 Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.

    Reporting group title
    Fremanezumab 675/225/225 mg
    Reporting group description
    		 Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.

    Serious adverse events
    		 Placebo Fremanezumab 900/225/225 mg Fremanezumab 675/225/225 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 83 (2.41%)
    3 / 87 (3.45%)
    2 / 88 (2.27%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Surgical and medical procedures
    Hospitalisation
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 87 (1.15%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Infusion site necrosis
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 87 (1.15%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 87 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric haemorrhage
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 87 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 87 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 87 (1.15%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Conversion disorder
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 87 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 87 (1.15%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 87 (1.15%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Fremanezumab 900/225/225 mg Fremanezumab 675/225/225 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 83 (21.69%)
    19 / 87 (21.84%)
    22 / 88 (25.00%)
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    3 / 83 (3.61%)
    5 / 87 (5.75%)
    7 / 88 (7.95%)
         occurrences all number
    4
    6
    15
    Injection site induration
         subjects affected / exposed
    3 / 83 (3.61%)
    6 / 87 (6.90%)
    6 / 88 (6.82%)
         occurrences all number
    8
    12
    12
    Injection site pain
         subjects affected / exposed
    6 / 83 (7.23%)
    2 / 87 (2.30%)
    5 / 88 (5.68%)
         occurrences all number
    11
    2
    9
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    4 / 83 (4.82%)
    3 / 87 (3.45%)
    5 / 88 (5.68%)
         occurrences all number
    4
    4
    5
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 83 (7.23%)
    8 / 87 (9.20%)
    6 / 88 (6.82%)
         occurrences all number
    7
    9
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 May 2017
    The primary reason for this amendment was to provide clarification based on feedback from participating Investigators and regulatory agencies.

    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.
    Futility analysis revealed that the primary endpoint is unlikely to be met. There were no safety concerns observed with fremanezumab treatment in the trial.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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