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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study Comparing the Efficacy, Safety, and Tolerability of Subcutaneous Administration of Fremanezumab Versus Placebo for the Preventive Treatment of Episodic Migraine in Pediatric Patients 6 to 17 Years of Age

    Summary
    EudraCT number
    2019-002055-42
    Trial protocol
    DE   FI   PL   NL   IT  
    Global end of trial date
    13 Mar 2024

    Results information
    Results version number
    v1(current)
    This version publication date
    26 Sep 2024
    First version publication date
    26 Sep 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TV48125-CNS-30083
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04458857
    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., MedInfo@tevaeu.com
    Scientific contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., MedInfo@tevaeu.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001877-PIP01-15
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Apr 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Mar 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Mar 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the efficacy of fremanezumab as compared to placebo for the preventive treatment of episodic migraine (EM).
    Protection of trial subjects
    This trial was conducted in full accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and ISO 14155: Clinical investigation of medical devices for human subjects – Good clinical practice and any applicable national and local laws and regulations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    15 Jul 2020
    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
    Germany: 11
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    Finland: 36
    Country: Number of subjects enrolled
    Israel: 20
    Country: Number of subjects enrolled
    Italy: 23
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Poland: 56
    Country: Number of subjects enrolled
    United States: 70
    Worldwide total number of subjects
    235
    EEA total number of subjects
    135
    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)
    64
    Adolescents (12-17 years)
    171
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 411 participants were screened; of which 235 participants were randomized and included in the analysis.

    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 matched to fremanezumab subcutaneously (SC) for 3 months (Days 1, 29, and 57).
    Arm type
    Placebo

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

    Arm title
    Fremanezumab Dose A
    Arm description
    Participants weighing <threshold weight received fremanezumab SC at dose A for 3 months (Days 1, 29, and 57).
    Arm type
    Experimental

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

    Arm title
    Fremanezumab Dose B
    Arm description
    Participants weighing ≥threshold weight received fremanezumab SC at dose B for 3 months (Days 1, 29, and 57).
    Arm type
    Experimental

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

    Number of subjects in period 1
    Placebo Fremanezumab Dose A Fremanezumab Dose B
    Started
    112
    36
    87
    Received at least 1 dose of study drug
    112
    36
    87
    Completed
    106
    33
    86
    Not completed
    6
    3
    1
         Consent withdrawn by subject
    2
    -
    -
         Adverse event, non-fatal
    -
    1
    -
         Non-compliance with study drug
    -
    1
    -
         Lost to follow-up
    4
    1
    -
         Withdrawal by parent/guardian
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received placebo matched to fremanezumab subcutaneously (SC) for 3 months (Days 1, 29, and 57).

    Reporting group title
    Fremanezumab Dose A
    Reporting group description
    Participants weighing <threshold weight received fremanezumab SC at dose A for 3 months (Days 1, 29, and 57).

    Reporting group title
    Fremanezumab Dose B
    Reporting group description
    Participants weighing ≥threshold weight received fremanezumab SC at dose B for 3 months (Days 1, 29, and 57).

    Reporting group values
    Placebo Fremanezumab Dose A Fremanezumab Dose B Total
    Number of subjects
    112 36 87 235
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    13.4 ( 2.99 ) 11.0 ( 2.27 ) 14.2 ( 2.34 ) -
    Sex: Female, Male
    Units: participants
        Female
    64 16 50 130
        Male
    48 20 37 105
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0
        Asian
    0 0 2 2
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        Black or African American
    4 1 4 9
        White
    84 28 68 180
        More than one race
    0 0 0 0
        Unknown or Not Reported
    24 7 13 44
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    9 4 8 21
        Not Hispanic or Latino
    102 31 75 208
        Unknown or Not Reported
    1 1 4 6
    Number of Migraine Days
    A migraine day was defined as a calendar day where the participant reported either of the following: A calendar day (0:00 to 23:59) demonstrating at least 2 consecutive hours of a headache that was accompanied by ≥1 migraine symptom(s) or a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was treated with migraine specific medications (non-steroidal anti-inflammatory drugs [NSAIDs], paracetamol or triptans and ergot compounds).
    Units: days
        arithmetic mean (standard deviation)
    7.5 ( 2.84 ) 7.6 ( 2.92 ) 7.9 ( 3.21 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received placebo matched to fremanezumab subcutaneously (SC) for 3 months (Days 1, 29, and 57).

    Reporting group title
    Fremanezumab Dose A
    Reporting group description
    Participants weighing <threshold weight received fremanezumab SC at dose A for 3 months (Days 1, 29, and 57).

    Reporting group title
    Fremanezumab Dose B
    Reporting group description
    Participants weighing ≥threshold weight received fremanezumab SC at dose B for 3 months (Days 1, 29, and 57).

    Subject analysis set title
    Fremanezumab
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants received fremanezumab SC for 3 months (Days 1, 29, and 57).

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

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    End point title
    Mean Change From Baseline in Monthly Average Number of Migraine Days During 12-Week Period After the First Dose of Study Drug [1]
    End point description
    A migraine day was defined as a calendar day where a participant reported either of the following: A calendar day (0:00 to 23:59) demonstrating at least 2 consecutive hours of a headache that was accompanied by ≥1 migraine symptom(s) or a calendar day demonstrating a headache of any duration that was treated with migraine specific medications (NSAIDs, paracetamol or triptans and ergot compounds). Monthly averages were derived and normalized to 28 days equivalent by formula: (number of days of efficacy variable over 12-week period/number of days with assessments recorded in e-diary for 12-week period) * 28. Least square (LS) mean was calculated using analysis of covariance (ANCOVA). Full analysis set (FAS): all randomized participants who received at least 1 dose of study drug and had at least 10 days of diary entries postbaseline for efficacy assessments on primary endpoint. Efficacy analysis was planned to be evaluated combined for both fremanezumab dose treatment groups.
    End point type
    Primary
    End point timeframe
    Baseline (Day -28 to Day -1), up to Week 12
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Efficacy analysis was planned to be evaluated combined for fremanezumab low and high dose treatment groups.
    End point values
    Placebo Fremanezumab
    Number of subjects analysed
    111
    123
    Units: days/month
        least squares mean (standard error)
    -1.4 ( 0.39 )
    -2.5 ( 0.38 )
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Fremanezumab
    Number of subjects included in analysis
    234
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.021
    Method
    ANCOVA
    Parameter type
    LS mean Difference
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.9
         upper limit
    -0.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.44

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

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    End point title
    Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
    End point description
    An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious AEs (SAEs) were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. AEs were considered TEAEs if onset occurred on or after the first dose date. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. The safety analysis set included all randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 3
    End point values
    Placebo Fremanezumab Dose A Fremanezumab Dose B
    Number of subjects analysed
    112
    36
    87
    Units: participants
    55
    20
    48
    No statistical analyses for this end point

    Secondary: Number of Participants With Shift From Baseline to Last Assessment in Electrocardiogram (ECG) Findings (Assessed by Investigator)

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    End point title
    Number of Participants With Shift From Baseline to Last Assessment in Electrocardiogram (ECG) Findings (Assessed by Investigator)
    End point description
    The number of participants with a shift from Baseline (Normal, Abnormal CS [Clinically Significant], or Abnormal NCS [Not Clinically Significant]) in any of the following ECG parameters is reported by treatment group: Heart rate, PR interval, QRS interval, RR interval, QT interval, QT interval corrected using the Bazett's formula (QTcB), and QT interval corrected using the Fridericia formula (QTcF). Last assessment was defined as the last observed postbaseline interpretation. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. The safety analysis set included all randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline to last assessment (up to Month 3)
    End point values
    Placebo Fremanezumab Dose A Fremanezumab Dose B
    Number of subjects analysed
    112
    36
    87
    Units: participants
        Normal/Normal
    92
    32
    74
        Abnormal NCS/Normal
    13
    0
    4
        Abnormal CS/Normal
    0
    0
    0
        Normal/Abnormal NCS
    2
    2
    6
        Abnormal NCS/Abnormal NCS
    4
    1
    3
        Abnormal CS/Abnormal NCS
    0
    0
    0
        Normal/Abnormal CS
    0
    0
    0
        Abnormal NCS/Abnormal CS
    0
    0
    0
        Abnormal CS/Abnormal CS
    0
    0
    0
        Missing
    1
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Shift From Baseline to Last Assessment in ECG Findings (Assessed by Cardiologist)

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    End point title
    Number of Participants With Shift From Baseline to Last Assessment in ECG Findings (Assessed by Cardiologist)
    End point description
    The number of participants with a shift from Baseline (Normal or Abnormal) in any of the following ECG parameters is reported by treatment group: Heart rate, PR interval, QRS interval, RR interval, QT interval, QTcB, and QTcF. Last assessment was defined as the last observed postbaseline interpretation. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. The safety analysis set included all randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline to last assessment (up to Month 3)
    End point values
    Placebo Fremanezumab Dose A Fremanezumab Dose B
    Number of subjects analysed
    112
    36
    87
    Units: participants
        Normal/Normal
    88
    29
    72
        Abnormal/Normal
    14
    0
    5
        Normal/Abnormal
    2
    4
    4
        Abnormal/Abnormal
    6
    2
    6
        Missing
    2
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With One or More Potentially Clinically Significant Vital Signs Abnormalities

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    End point title
    Number of Participants With One or More Potentially Clinically Significant Vital Signs Abnormalities
    End point description
    Potentially clinically significant abnormal vital signs findings included: Pulse rate ≥120 beats per minute (bpm) and increase from baseline of ≥15 bpm, or ≤50 bpm and decrease from baseline of ≥15 bpm; Systolic blood pressure ≤85 millimeters of mercury (mmHg) and decrease from baseline of ≥20 mmHg; Diastolic blood pressure ≥100 mmHg and increase from baseline of ≥15 mmHg; Respiratory rate <15 breaths/minute. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. The safety analysis set included all randomized participants who received at least 1 dose of study drug. Here, 'Overall number of participants analyzed' = participants with at least one Baseline and post-baseline vital sign assessment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 3
    End point values
    Placebo Fremanezumab Dose A Fremanezumab Dose B
    Number of subjects analysed
    112
    35
    87
    Units: participants
    14
    3
    5
    No statistical analyses for this end point

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

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    End point title
    Number of Participants With Potentially Clinically Significant Abnormal Laboratory (Serum Chemistry, Hematology, Coagulation, and Urinalysis) Results
    End point description
    Potentially clinically significant abnormal findings included- Serum chemistry tests: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) both ≥2*upper limit of normal (ULN); and bilirubin ≥34.2 micromole/liter (umol/L). Hematology tests: hemoglobin ≤100 grams (g)/L, leukocytes ≤3*10^9 cells/L, neutrophils ≤1*10^9 cells/L, eosinophils/leukocytes ≥10%, and platelets ≥700*10^9 cells/L or ≤75*10^9 cells/L. Coagulation parameter test: prothrombin international normalized ratio (INR) >1.5. Urinalysis laboratory tests: urine protein ≥2 units (U) increase from baseline. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. The safety analysis set included all randomized participants who received at least 1 dose of study drug. Here, 'Overall number of participants analyzed' and 'n'= participants with at least one Baseline and post-baseline assessment of the specified laboratory parameters.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 3
    End point values
    Placebo Fremanezumab Dose A Fremanezumab Dose B
    Number of subjects analysed
    111
    35
    87
    Units: participants
        Serum chemistry abnormality (n=111,35,87)
    2
    1
    3
        Hematology abnormality (n=110,34,87)
    6
    2
    3
        Coagulation abnormality (n=110,35,87)
    3
    0
    1
        Urinalysis abnormality (n=111,35,87)
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Abnormal Physical Examination Findings as Identified by the Investigator

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    End point title
    Number of Participants With Abnormal Physical Examination Findings as Identified by the Investigator
    End point description
    A complete physical examination included the following organ systems: general appearance; head, eyes, ears, nose, and throat (HEENT); chest and lungs; heart; abdomen; musculoskeletal; skin; lymph nodes; and neurological. Only the organ systems with abnormal physical findings in at least one treatment group have been reported. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. The safety analysis set included all randomized participants who received at least 1 dose of study drug. Here, 'Overall number of participants analyzed' = participants with at least one Baseline and post-baseline physical examination.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 3
    End point values
    Placebo Fremanezumab Dose A Fremanezumab Dose B
    Number of subjects analysed
    109
    34
    87
    Units: participants
        General Appearance
    0
    0
    1
        HEENT
    1
    0
    1
        Musculoskeletal
    2
    0
    1
        Skin
    5
    1
    2
        Neurological
    1
    0
    0
        Extremities/Back
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With Suicidal Ideation or Suicidal Behavior as Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS)

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    End point title
    Number of Participants With Suicidal Ideation or Suicidal Behavior as Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS)
    End point description
    C-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. The ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' = participants with both Baseline and Month 3 assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and Month 3
    End point values
    Placebo Fremanezumab Dose A Fremanezumab Dose B
    Number of subjects analysed
    105
    33
    86
    Units: participants
        Baseline
    0
    1
    0
        Month 3
    1
    0
    0
    No statistical analyses for this end point

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

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    End point title
    Mean Change From Baseline in Monthly Average Number of Headache Days of at Least Moderate Severity During 12-Week Period After the First Dose of Study Drug [2]
    End point description
    A headache day of at least moderate severity was defined as a calendar day (00:00 to 23:59) where the participant reported either of the following: A day with headache pain that lasted ≥2 hours with a peak severity of at least moderate severity or a day where the participant used acute medication (triptans, ergots, NSAIDs or paracetamol) to treat a headache of any severity or duration. Monthly averages were derived and normalized to 28 days equivalent by formula: (number of days of efficacy variable over 12-week period/number of days with assessments recorded in e-diary for 12-week period) * 28. LS mean was calculated using ANCOVA. The FAS included all randomized participants who received at least 1 dose of study drug and had at least 10 days of diary entries postbaseline for efficacy assessments on the primary endpoint. Efficacy analysis was planned to be evaluated combined for both fremanezumab dose treatment groups.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -28 to Day -1), up to Week 12
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Efficacy analysis was planned to be evaluated combined for fremanezumab low and high dose treatment groups.
    End point values
    Placebo Fremanezumab
    Number of subjects analysed
    111
    123
    Units: days/month
        least squares mean (standard error)
    -1.5 ( 0.42 )
    -2.6 ( 0.40 )
    No statistical analyses for this end point

    Secondary: Number of Participants Reaching at Least 50% Reduction in the Monthly Average Number of Migraine Days during the 12-week Period After the First Dose of Study Drug

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    End point title
    Number of Participants Reaching at Least 50% Reduction in the Monthly Average Number of Migraine Days during the 12-week Period After the First Dose of Study Drug [3]
    End point description
    A migraine day was defined as a calendar day where the participant reported either of the following: A calendar day (0:00 to 23:59) demonstrating at least 2 consecutive hours of a headache that was accompanied by ≥1 migraine symptom(s) or a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was treated with migraine specific medications (NSAIDs, paracetamol or triptans and ergot compounds). Monthly averages were derived and normalized to 28 days equivalent by formula: (number of days of efficacy variable over 12-week period/number of days with assessments recorded in e-diary for 12-week period) * 28. The FAS included all randomized participants who received at least 1 dose of study drug and had at least 10 days of diary entries postbaseline for efficacy assessments on the primary endpoint. Efficacy analysis was planned to be evaluated combined for both fremanezumab dose treatment groups.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -28 to Day -1) up to Week 12
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Efficacy analysis was planned to be evaluated combined for fremanezumab low and high dose treatment groups.
    End point values
    Placebo Fremanezumab
    Number of subjects analysed
    111
    123
    Units: participants
    111
    123
    No statistical analyses for this end point

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

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    End point title
    Mean Change From Baseline in Monthly Average Number of Days of Use of Any Acute Headache Medications During 12-Week Period After the First Dose of Study Drug [4]
    End point description
    Participants recorded any headache medications (name of drug, number of tablets/capsules, and the dose in milligrams per tablet/capsule) taken each day in their electronic headache diary device. Acute headache medication included triptans and ergot compounds, NSAIDs or paracetamol. Monthly averages were derived and normalized to 28 days equivalent by formula: (number of days of efficacy variable over 12-week period/number of days with assessments recorded in e-diary for 12-week period) * 28. LS mean was calculated using ANCOVA. The FAS included all randomized participants who received at least 1 dose of study drug and had at least 10 days of diary entries postbaseline for efficacy assessments on the primary endpoint. Efficacy analysis was planned to be evaluated combined for both fremanezumab dose treatment groups.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -28 to Day -1), up to Week 12
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Efficacy analysis was planned to be evaluated combined for fremanezumab low and high dose treatment groups.
    End point values
    Placebo Fremanezumab
    Number of subjects analysed
    111
    123
    Units: days/month
        least squares mean (standard error)
    -1.0 ( 0.30 )
    -2.1 ( 0.29 )
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Migraine-related Disability Score at Week 12, as Measured by the Pediatric Migraine Disability Assessment (PedMIDAS) Questionnaire

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    End point title
    Mean Change From Baseline in Migraine-related Disability Score at Week 12, as Measured by the Pediatric Migraine Disability Assessment (PedMIDAS) Questionnaire [5]
    End point description
    PedMIDAS questionnaire is a 6-item instrument developed to assess headache-related disability. It has been validated in participants aged 4 through 18 years and includes questions related to the impact of headache on school performance, disability at home (for example, inability to do chores or homework), and social/sport functioning. Total score: that is, the sum of 6 questions, was used for grading of disability, with scores of 0 to 10, 11 to 30, 31 to 50, and >50 interpreted as disability grades 1 (little or no disability), 2 (mild disability), 3 (moderate disability), and 4 (severe disability), respectively. Higher scores indicated severe disability. LS mean was calculated using ANCOVA. FAS included all randomized participants who received at least 1 dose of study drug and had at least 10 days of diary entries postbaseline for efficacy assessments on the primary endpoint. Efficacy analysis was planned to be evaluated combined for both fremanezumab dose treatment groups.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Efficacy analysis was planned to be evaluated combined for fremanezumab low and high dose treatment groups.
    End point values
    Placebo Fremanezumab
    Number of subjects analysed
    111
    123
    Units: units on a scale
        least squares mean (standard error)
    -15.3 ( 3.37 )
    -21.6 ( 3.29 )
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Quality of Life at Week 12, as Measured by Pediatric Quality of Life Inventory (PedsQL) Questionnaire

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    End point title
    Mean Change From Baseline in Quality of Life at Week 12, as Measured by Pediatric Quality of Life Inventory (PedsQL) Questionnaire [6]
    End point description
    PedsQL 4.0 (23-item health-related quality of life [QoL]) evaluates QoL in 4 areas: physical, emotional, social, and school functioning. For child and adolescent (8-18 years) and parent, a 5-point Likert scale was used to rate item severity (0=never a problem;1=almost never a problem; 2=sometimes a problem; 3=often a problem; 4=almost always a problem). For younger children (5-7 years), a 3-point Likert scale, anchored with a happy and a sad face, was used (0=not at all a problem; 2=sometimes a problem; 4=a lot of a problem). PedsQL yields a total QoL score and 2 summary scores: Physical Health Summary Score and Psychosocial Health Summary Score. To obtain scores, items were reverse scored, transformed to a 0 to 100 scale (0=100, 1=75, 2=50, 3=25, 4=0), and averaged; total scores near 0 indicated lower QoL, while scores approaching 100 indicated higher QoL. Analysis population: FAS. Efficacy analysis was planned to be evaluated combined for both fremanezumab dose groups.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Efficacy analysis was planned to be evaluated combined for fremanezumab low and high dose treatment groups.
    End point values
    Placebo Fremanezumab
    Number of subjects analysed
    111
    123
    Units: units on a scale
    least squares mean (standard error)
        Child-Physical Health Summary Score
    8.3 ( 1.61 )
    7.8 ( 1.57 )
        Child-Psychosocial Health Summary Score
    5.3 ( 1.38 )
    4.7 ( 1.35 )
        Child-Total Scale Score
    6.2 ( 1.37 )
    5.7 ( 1.33 )
        Parent-Physical Health Summary Score
    7.3 ( 2.69 )
    7.3 ( 2.35 )
        Parent-Psychosocial Health Summary Score
    6.8 ( 2.28 )
    4.3 ( 1.96 )
        Parent-Total Scale Score
    7.2 ( 2.28 )
    5.2 ( 1.97 )
    No statistical analyses for this end point

    Secondary: Number of Participants Developing Anti-drug Antibodies (ADAs) Throughout the Study

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    End point title
    Number of Participants Developing Anti-drug Antibodies (ADAs) Throughout the Study [7]
    End point description
    Number of participants who developed ADAs were reported. The FAS included all randomized participants who received at least 1 dose of study drug and had at least 10 days of diary entries postbaseline for efficacy assessments on the primary endpoint. Here, 'Overall number of participants analyzed' = Participants who had Baseline and at least 1 postbaseline ADA assessment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 3
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is reporting statistics for the specified arms only.
    End point values
    Fremanezumab Dose A Fremanezumab Dose B
    Number of subjects analysed
    35
    87
    Units: participants
    1
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Month 3
    Adverse event reporting additional description
    The safety analysis set 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
    26.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received placebo matched to fremanezumab SC for 3 months (Days 1, 29, and 57).

    Reporting group title
    Fremanezumab Dose B
    Reporting group description
    Participants weighing ≥threshold weight received fremanezumab SC at dose B for 3 months (Days 1, 29, and 57).

    Reporting group title
    Fremanezumab Dose A
    Reporting group description
    Participants weighing <threshold weight received fremanezumab SC at dose A for 3 months (Days 1, 29, and 57).

    Serious adverse events
    Placebo Fremanezumab Dose B Fremanezumab Dose A
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 112 (2.68%)
    1 / 87 (1.15%)
    1 / 36 (2.78%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Hemiparesis
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 87 (0.00%)
    0 / 36 (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
    Migraine
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 87 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Immune thrombocytopenia
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 87 (0.00%)
    0 / 36 (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
    Hepatitis infectious mononucleosis
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 87 (1.15%)
    0 / 36 (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 Dose B Fremanezumab Dose A
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 112 (23.21%)
    29 / 87 (33.33%)
    8 / 36 (22.22%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 112 (1.79%)
    0 / 87 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    3
    0
    3
    Dizziness
         subjects affected / exposed
    0 / 112 (0.00%)
    5 / 87 (5.75%)
    0 / 36 (0.00%)
         occurrences all number
    0
    5
    0
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    6 / 112 (5.36%)
    11 / 87 (12.64%)
    1 / 36 (2.78%)
         occurrences all number
    9
    18
    2
    Injection site pain
         subjects affected / exposed
    6 / 112 (5.36%)
    6 / 87 (6.90%)
    0 / 36 (0.00%)
         occurrences all number
    10
    9
    0
    Injection site swelling
         subjects affected / exposed
    1 / 112 (0.89%)
    5 / 87 (5.75%)
    1 / 36 (2.78%)
         occurrences all number
    1
    6
    1
    Vaccination site pain
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 87 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    1
    0
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 112 (7.14%)
    8 / 87 (9.20%)
    3 / 36 (8.33%)
         occurrences all number
    10
    10
    4
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 112 (4.46%)
    4 / 87 (4.60%)
    2 / 36 (5.56%)
         occurrences all number
    6
    5
    2
    COVID-19
         subjects affected / exposed
    6 / 112 (5.36%)
    5 / 87 (5.75%)
    2 / 36 (5.56%)
         occurrences all number
    6
    5
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Jun 2019
    The primary reasons for this amendment were to improve the feasibility of the diary compliance requirement, to clarify the exclusion criterion for nerve stimulation or device, and to clarify the timing of injection site reaction assessment.
    05 Dec 2019
    The primary reason for this amendment was to update the protocol with the dose to be used for participants <45.0 kg (120 mg SC monthly) following the completion of the Phase 1 pediatric pharmacokinetic study (TV48125-CNS-10141).
    20 Apr 2020
    The primary reason for this amendment was to revise an exclusion criterion to exclude participants with a history of Stevens-Johnson Syndrome or toxic epidermal necrolysis syndrome.
    20 Aug 2020
    The primary reason for this amendment was to provide guidance for remote assessments to minimize the time that participants and caregivers were required to spend at the study site. This consideration was triggered by the COVID-19 pandemic; however, remote assessments could be carried out on a regular basis to provide flexibility for participants, caregivers, and site staff. Patient reported outcomes assessed in this study, including the PedMIDAS, PedsQL, and Patient Global Impression of Improvement (PGI-I), as well as the C-SSRS, were valid to be conducted remotely, as confirmed by the scale authors. Instructions on remote data collection were available in the site operational manual.
    09 Dec 2021
    The primary reason for this amendment was to revise the protocol to allow combined oral progestin and estrogen contraceptives, to expand the body mass index (BMI) upper limit to 120% of the 95th percentile in order reflect the real-world participant population, and to clarify potential sample size changes subsequent to the planned interim analysis.
    24 Sep 2023
    - The primary reason for this amendment was to reduce the size of the study population and to update the inclusion criteria in order to help with enrollment and study completion. - Updated study timelines according to new projections and reduced study population.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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