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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 Episodic Cluster Headache

    Summary
    EudraCT number
    2016-003278-42
    Trial protocol
    GB   SE   DE   ES   IT   NL   PL   FI  
    Global end of trial date
    13 May 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    01 May 2020
    First version publication date
    01 May 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TV48125-CNS-30056
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02945046
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Teva Branded Pharmaceutical Products, R&D Inc.
    Sponsor organisation address
    145 Brandywine Parkway, West Chester, United States, 19380
    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
    27 Jun 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 May 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    13 May 2019
    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 episodic cluster headache (ECH) 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 Title 21, Parts 50, 54, 56, 312, and 314; European Union Directive 2001/20/EC on the approximation of the laws, regulations, and administrative provisions of the Member States relating to the implementation of GCP in the conduct of clinical trials on medicinal products for human use).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    19 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
    Australia: 1
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Finland: 7
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Israel: 25
    Country: Number of subjects enrolled
    Italy: 44
    Country: Number of subjects enrolled
    Poland: 6
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    United States: 61
    Worldwide total number of subjects
    169
    EEA total number of subjects
    80
    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)
    164
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 169 participants were randomized in a 1:1:1 ratio to placebo, fremanezumab 675 milligrams (mg)/placebo/placebo, or fremanezumab 900/225/225 mg groups.

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

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

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

    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 matched to fremanezumab was administered per schedule specified in the arm.

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

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

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

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

    Number of subjects in period 1
    Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 900/225/225 mg
    Started
    59
    55
    55
    Safety analysis set
    59
    55
    55
    Full analysis set
    57
    53
    55
    Completed
    46
    42
    40
    Not completed
    13
    13
    15
         Protocol deviation
    2
    3
    2
         Other than specified
    5
    4
    7
         Lack of efficacy
    1
    2
    1
         Adverse event, non-fatal
    1
    -
    2
         Consent withdrawn by subject
    3
    3
    3
         Lost to follow-up
    1
    1
    -

    Baseline characteristics

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

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

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

    Reporting group values
    Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 900/225/225 mg Total
    Number of subjects
    59 55 55 169
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    43.1 ± 10.39 45.4 ± 11.23 43.5 ± 11.48 -
    Sex: Female, Male
    Units: participants
        Female
    16 17 17 50
        Male
    43 38 38 119
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0
        Asian
    1 0 1 2
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        Black or African American
    3 0 2 5
        White
    54 55 51 160
        More than one race
    0 0 0 0
        Unknown or Not Reported
    1 0 1 2
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    2 3 5 10
        Not Hispanic or Latino
    56 52 49 157
        Unknown or Not Reported
    1 0 1 2
    Number of CH Attacks
    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.
    Units: CH attacks
        arithmetic mean (standard deviation)
    14.8 ± 10.50 15.9 ± 9.18 14.5 ± 7.55 -

    End points

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

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

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

    Primary: Mean Change From Baseline in the Weekly Average Number of Cluster Headache (CH) Attacks During the 4-Week Period After Administration of the First Dose of the IMP

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    End point title
    Mean Change From Baseline in the Weekly Average Number of Cluster Headache (CH) Attacks During the 4-Week Period After Administration of the First Dose of the IMP
    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. Least Squares (LS) mean calculated using analysis of covariance (ANCOVA) model with baseline preventive medication use (yes or no), sex, region (United States [US]/Canada or other), and treatment as fixed effects and the baseline number of CH attacks as a covariate. Full analysis set included all randomized participants who received at least 1 dose of IMP and had at least 10 days of postbaseline efficacy assessment in the first 4 weeks on the primary endpoint.
    End point type
    Primary
    End point timeframe
    Baseline (Week 0), up to Week 4
    End point values
    Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 900/225/225 mg
    Number of subjects analysed
    57
    53
    55
    Units: CH attacks/week
        least squares mean (standard error)
    -5.7 ± 1.00
    -5.8 ± 1.02
    -7.6 ± 1.01
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Fremanezumab 675 mg/Placebo/Placebo v Placebo
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.9093 [1]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.72
         upper limit
    2.42
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.3
    Notes
    [1] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Fremanezumab 900/225/225 mg v Placebo
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1345 [2]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -1.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.49
         upper limit
    0.61
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.29
    Notes
    [2] - Threshold for significance at 0.05 level.

    Secondary: Percentage of Participants With a ≥50% Reduction From Baseline in the Weekly Average Number of CH Attacks During the 4-Week Period After the First Dose of the IMP

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    End point title
    Percentage of Participants With a ≥50% Reduction From Baseline in the Weekly Average Number of CH Attacks During the 4-Week Period After the First Dose of the IMP
    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 IMP and had at least 10 days of postbaseline efficacy assessment in the first 4 weeks on the primary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), up to Week 4
    End point values
    Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 900/225/225 mg
    Number of subjects analysed
    57
    53
    55
    Units: percentage of participants
    60
    55
    75
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Weekly Average Number of CH Attacks During the 12-Week Period After Administration of the First Dose of the IMP

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    End point title
    Mean Change From Baseline in Weekly Average Number of CH Attacks During the 12-Week Period After Administration of the First Dose of the IMP
    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. LS mean calculated using mixed model for repeated measures (MMRM) with baseline preventive medication use (yes or no), gender, region (US/Canada or other), treatment, month, and month-by-treatment interaction as fixed effects and baseline number of CH attacks as a covariate. Full analysis set included all randomized participants who received at least 1 dose of IMP and had at least 10 days of postbaseline efficacy assessment in the first 4 weeks on the primary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), up to Week 12
    End point values
    Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 900/225/225 mg
    Number of subjects analysed
    57
    53
    55
    Units: CH attacks/week
        least squares mean (standard error)
    -8.4 ± 0.66
    -8.9 ± 0.68
    -9.6 ± 0.67
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Weekly Average Number of CH Attacks During the 4-Week Period After Administration of the Third Dose of the IMP

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    End point title
    Mean Change From Baseline in Weekly Average Number of CH Attacks During the 4-Week Period After Administration of the Third Dose of the IMP
    End point description
    CH attack: a severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes with either or both of following 2 categories: 1) at least 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; -sensation of fullness in ear; -miosis and/or ptosis. 2) a sense of restlessness or agitation. LS mean calculated using MMRM with baseline preventive medication use (yes/no), gender, region (US/Canada or other), treatment, month, and month-by-treatment interaction as fixed effects and baseline number of CH attacks as a covariate. Full analysis set: all randomized participants who received at least 1 dose of IMP and had at least 10 days of postbaseline efficacy assessment in first 4 weeks on primary endpoint. Here, 'overall number of participants analyzed'=participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Week 8 up to Week 12
    End point values
    Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 900/225/225 mg
    Number of subjects analysed
    46
    42
    40
    Units: CH attacks/week
        least squares mean (standard error)
    -10.8 ± 0.75
    -10.8 ± 0.78
    -10.9 ± 0.78
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in the Weekly Average Number of Days with Use of Cluster-Specific Acute Headache Medications (Triptans and Ergot Compounds) During the 12-Week Period After the First Dose of the IMP

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    End point title
    Mean Change From Baseline in the Weekly Average Number of Days with Use of Cluster-Specific Acute Headache Medications (Triptans and Ergot Compounds) During the 12-Week Period After the First Dose of the IMP
    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. LS mean calculated using ANCOVA model with baseline preventive medication use (yes or no), gender, region (US/Canada or other), and treatment as fixed effects and the baseline number of cluster headache attacks as a covariate. 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 IMP and had at least 10 days of postbaseline efficacy assessment in the first 4 weeks on the primary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), up to Week 12
    End point values
    Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 900/225/225 mg
    Number of subjects analysed
    57
    53
    55
    Units: days of use/week
        least squares mean (standard error)
    -1.6 ± 0.36
    -2.4 ± 0.36
    -2.8 ± 0.36
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in the Weekly Average Number of Days Oxygen was Used to Treat Episodic Cluster Headache (ECH) During the 12-Week Period After the First Dose of the IMP

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    End point title
    Mean Change From Baseline in the Weekly Average Number of Days Oxygen was Used to Treat Episodic Cluster Headache (ECH) During the 12-Week Period After the First Dose of the IMP
    End point description
    LS mean calculated using ANCOVA model with baseline preventive medication use (yes or no), gender, region (US/Canada or other), and treatment as fixed effects and the baseline number of cluster headache attacks as a covariate. Baseline data and the mean change from baseline in the overall weekly average number of days oxygen was used to treat ECH during the 12-week period after administration of the first dose of IMP (based on Week 0 to 12 data) is reported. Full analysis set included all randomized participants who received at least 1 dose of IMP and had at least 10 days of postbaseline efficacy assessment in the first 4 weeks on the primary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), up to Week 12
    End point values
    Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 900/225/225 mg
    Number of subjects analysed
    57
    53
    55
    Units: days of use/week
        least squares mean (standard error)
    -1.1 ± 0.30
    -1.5 ± 0.31
    -1.0 ± 0.30
    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 “7=much improved” compared with 4 weeks prior. PPSI was defined as the change in pain that corresponds with a minimal rating of “5=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 IMP and had at least 10 days of postbaseline efficacy assessment in the first 4 weeks on the primary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 1, 4, 8, and 12
    End point values
    Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 900/225/225 mg
    Number of subjects analysed
    57
    53
    55
    Units: participants
        Baseline|Much worse
    10
    14
    7
        Week 1|Much worse
    2
    4
    1
        Week 4|Much worse
    1
    1
    2
        Week 8|Much worse
    1
    1
    0
        Week 12|Much worse
    3
    2
    2
        Baseline|Moderately worse
    3
    5
    8
        Week 1|Moderately worse
    2
    2
    1
        Week 4|Moderately worse
    3
    0
    1
        Week 8|Moderately worse
    3
    0
    1
        Week 12|Moderately worse
    0
    0
    1
        Baseline|Slightly worse
    3
    3
    3
        Week 1|Slightly worse
    5
    3
    2
        Week 4|Slightly worse
    4
    2
    0
        Week 8|Slightly worse
    0
    1
    1
        Week 12|Slightly worse
    2
    1
    0
        Baseline|Unchanged
    37
    31
    28
        Week 1|Unchanged
    19
    11
    9
        Week 4|Unchanged
    8
    11
    5
        Week 8|Unchanged
    13
    8
    12
        Week 12|Unchanged
    16
    16
    16
        Baseline|Slightly improved
    3
    0
    6
        Week 1|Slightly improved
    11
    8
    14
        Week 4|Slightly improved
    9
    9
    8
        Week 8|Slightly improved
    1
    6
    5
        Week 12|Slightly improved
    5
    5
    4
        Baseline|Moderately improved
    1
    0
    1
        Week 1|Moderately improved
    5
    3
    6
        Week 4|Moderately improved
    5
    7
    8
        Week 8|Moderately improved
    7
    6
    7
        Week 12|Moderately improved
    8
    7
    5
        Baseline|Much improved
    0
    0
    2
        Week 1|Much improved
    6
    12
    12
        Week 4|Much improved
    23
    19
    27
        Week 8|Much improved
    20
    20
    17
        Week 12|Much improved
    17
    19
    24
        Baseline|Missing
    0
    0
    0
        Week 1|Missing
    7
    10
    10
        Week 4|Missing
    4
    4
    4
        Week 8|Missing
    12
    11
    12
        Week 12|Missing
    6
    3
    3
    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 the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. 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 analysis set included all randomized participants who received at least 1 dose of the IMP.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 900/225/225 mg
    Number of subjects analysed
    59
    55
    55
    Units: participants
        Any AEs
    28
    26
    28
        Treatment-related AEs
    8
    11
    13
        Serious AEs
    5
    0
    1
        AEs leading to discontinuation
    1
    0
    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
    Serum chemistry, hematology, urinalysis tests with potentially clinically significant abnormal findings: alanine aminotransferase (ALP), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), lactate dehydrogenase (LDH) each ≥3*upper limit of normal(ULN); blood urea nitrogen ≥10.71 millimole (mmol)/L; Bilirubin ≥34.2 micromole/liter (umol/L); creatinine ≥177 umol/L; hemoglobin ≤115 grams(g)/L (males) or ≤95 g/L (females); leukocytes ≥20*10^9/L or ≤3*10^9/L; eosinophils ≥10%; hematocrit <0.37 L/L (males) and <0.32 L/L (females); platelets ≥700*10^9/L or ≤75*10^9/L; haemoglobin, urine glucose, ketones, total protein each ≥2 unit(U) increase from baseline. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Safety analysis set: all randomized participants who received at least 1 dose of the IMP. Here, 'overall number of participants analyzed'=participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 900/225/225 mg
    Number of subjects analysed
    56
    54
    54
    Units: participants
        With at least 1 serum chemistry abnormality
    1
    1
    0
        With at least 1 hematology abnormality
    4
    1
    4
        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) and prothrombin international normalized ratio (INR). 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). Missing PT and prothrombin INR shift data are also presented. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Safety analysis set included all randomized participants who received at least 1 dose of the IMP.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 900/225/225 mg
    Number of subjects analysed
    59
    55
    55
    Units: participants
        PT|Low-Low
    0
    0
    0
        Prothrombin INR|Low-Low
    0
    0
    0
        PT|Low-Normal
    0
    0
    0
        Prothrombin INR|Low-Normal
    0
    0
    0
        PT|Low-High
    0
    0
    0
        Prothrombin INR|Low-High
    0
    0
    0
        PT|Normal-Low
    0
    0
    0
        Prothrombin INR|Normal-Low
    0
    0
    0
        PT|Normal-Normal
    47
    46
    44
        Prothrombin INR|Normal-Normal
    48
    48
    47
        PT|Normal-High
    2
    2
    3
        Prothrombin INR|Normal-High
    2
    2
    1
        PT|High-Low
    0
    0
    0
        Prothrombin INR|High-Low
    0
    0
    0
        PT|High-Normal
    4
    4
    4
        Prothrombin INR|High-Normal
    3
    3
    3
        PT|High-High
    1
    1
    2
        Prothrombin INR|High-High
    1
    0
    2
        PT|Missing
    5
    2
    2
        Prothrombin INR|Missing
    5
    2
    2
    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 ≥120 beats per minute (bpm) and increase of 15 bpm; systolic blood pressure ≤90 millimeters of mercury (mmHg) and decrease of 20 mmHg; diastolic blood pressure ≤50 mmHg and decrease of 15 mmHg, or ≥105 mmHg and increase of 15 mmHg. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Safety analysis set included all randomized participants who received at least 1 dose of the IMP. Here, 'overall number of participants analyzed'=participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 900/225/225 mg
    Number of subjects analysed
    56
    54
    54
    Units: participants
    3
    0
    1
    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. Missing ECG shift data are also presented. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Safety analysis set included all randomized participants who received at least 1 dose of the IMP.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 900/225/225 mg
    Number of subjects analysed
    59
    55
    55
    Units: participants
        Normal / Normal
    35
    33
    23
        Normal / Abnormal NCS
    6
    1
    5
        Normal / Abnormal CS
    0
    0
    0
        Abnormal NCS / Normal
    4
    9
    4
        Abnormal NCS / Abnormal NCS
    7
    9
    18
        Abnormal NCS / Abnormal CS
    0
    0
    0
        Abnormal CS / Normal
    0
    0
    0
        Abnormal CS / Abnormal NCS
    0
    0
    0
        Abnormal CS / Abnormal CS
    0
    0
    0
        Missing
    7
    3
    5
    No statistical analyses for this end point

    Secondary: Number of Participants Who Received Concomitant Medications

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    End point title
    Number of Participants Who Received Concomitant Medications
    End point description
    Concomitant medications included: agents acting on renin-angiotensin system, all other therapeutic products (for example: homeopathic preparation), allergens, analgesics, anesthetics, anti-parkinson drugs, antianemic preparations, antibacterials for systemic use, antibiotics and chemotherapeutics for dermatological use, antidiarrheals, intestinal antiinflammatory/antiinfective agents, antiemetic, antiepileptics, antifungals for dermatologiocal use, antigout preparations, antihemorrhagics, antihypertensives, antiinflammatory and antirheumatic products, antipruritics, antipsoriatics, antivirals for systemic use, beta blocking agents, cardiac therapy, corticosteroids, cough and cold preparations, diagnostic radiopharmaceuticals, diuretics, thyroid therapy, urologicals, vaccines, psycoleptics, ophthalmologicals, muscle relaxants, drugs used in diabetes etc. Safety analysis set included all randomized participants who received at least 1 dose of the IMP.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 900/225/225 mg
    Number of subjects analysed
    59
    55
    55
    Units: participants
    57
    52
    52
    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, swelling, and pruritus. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Safety analysis set included all randomized participants who received at least 1 dose of the IMP.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 900/225/225 mg
    Number of subjects analysed
    59
    55
    55
    Units: participants
        Injection site induration
    1
    3
    6
        Injection site pain
    4
    2
    6
        Injection site erythema
    2
    0
    2
        Injection site haemorrhage
    0
    0
    1
        Injection site pruritus
    1
    0
    1
        Injection site swelling
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Hypersensitivity/Anaphylaxis Reactions

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    End point title
    Number of Participants With Hypersensitivity/Anaphylaxis Reactions
    End point description
    A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Safety analysis set included all randomized participants who received at least 1 dose of the IMP.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 900/225/225 mg
    Number of subjects analysed
    59
    55
    55
    Units: participants
    0
    0
    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 analysis set included all randomized participants who received at least 1 dose of the IMP.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 900/225/225 mg
    Number of subjects analysed
    59
    55
    55
    Units: participants
    0
    1
    4
    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 analysis set included all randomized participants who received at least 1 dose of the IMP.
    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 administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.

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

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

    Serious adverse events
    Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 900/225/225 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 59 (8.47%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 55 (0.00%)
    0 / 55 (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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cluster headache
         subjects affected / exposed
    2 / 59 (3.39%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 55 (0.00%)
    0 / 55 (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
    Gastrointestinal disorders
    Duodenitis
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 900/225/225 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 59 (11.86%)
    9 / 55 (16.36%)
    16 / 55 (29.09%)
    General disorders and administration site conditions
    Injection site induration
         subjects affected / exposed
    1 / 59 (1.69%)
    3 / 55 (5.45%)
    6 / 55 (10.91%)
         occurrences all number
    1
    7
    10
    Injection site pain
         subjects affected / exposed
    4 / 59 (6.78%)
    2 / 55 (3.64%)
    6 / 55 (10.91%)
         occurrences all number
    6
    5
    17
    Infections and infestations
    Influenza
         subjects affected / exposed
    2 / 59 (3.39%)
    0 / 55 (0.00%)
    3 / 55 (5.45%)
         occurrences all number
    2
    0
    3
    Nasopharyngitis
         subjects affected / exposed
    1 / 59 (1.69%)
    4 / 55 (7.27%)
    4 / 55 (7.27%)
         occurrences all number
    1
    5
    4

    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 following major procedural changes (not all inclusive) were made to the protocol: - Clarification was provided based on feedback from participating investigators and regulatory agencies. - Table (Study Procedures and Assessments) was revised.

    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.
    Study was terminated as a result of a pre-specified futility analysis at the interim of 150 participants completing the efficacy analysis of the study.
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