Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   42782   clinical trials with a EudraCT protocol, of which   7047   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).


    Phase 1 trials conducted solely in adults and that are not part of an agreed PIP are not public in the EU CTR (refer to European Guidance 2008/C 168/02   Art. 3 par. 2 and   Commission Guideline 2012/C 302/03,   Art. 5) .

    Clinical Trials marked as "Trial now transitioned" were transitioned to the Clinical Trial Regulation 536/2014 and can be further followed in the Clinical Trial Information System  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Multicenter, Double-Blind, Double-Dummy Study to Explore the Long-Term Safety and Efficacy of TEV-48125 for the Prevention of Cluster Headache

    Summary
    EudraCT number
    2016-003172-43
    Trial protocol
    SE   GB   DE   ES   IT   NL   PL   FI  
    Global end of trial date
    11 Jun 2019

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

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    TV48125-CNS-30058
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03107052
    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
    02 Aug 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Jun 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the long-term safety of fremanezumab in adult participants with cluster headache (CH).
    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 (eg, 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
    27 Apr 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
    Canada: 4
    Country: Number of subjects enrolled
    Germany: 34
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    Finland: 10
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    Israel: 43
    Country: Number of subjects enrolled
    Italy: 34
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Poland: 9
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    United States: 106
    Worldwide total number of subjects
    275
    EEA total number of subjects
    122
    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)
    261
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    A total of 275 participants with episodic cluster headache (ECH) or chronic cluster headache (CCH) were enrolled in this study.

    Pre-assignment
    Screening details
    Participants were assigned to receive treatments in fremanezumab 225 milligrams (mg) monthly, fremanezumab 675/225 mg monthly, or fremanezumab 675 mg quarterly groups; based on their randomization in the pivotal studies TV48125-CNS-30056 (NCT02945046) and TV48125-CNS-30057 (NCT02964338).

    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
    Fremanezumab 225 mg Monthly
    Arm description
    Participants with ECH or CCH who received fremanezumab at 900 mg intravenous (IV) infusion at Week 0 and fremanezumab at 225 mg subcutaneous (SC) injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056 or TV48125-CNS-30057, and participants with CCH who received fremanezumab at 675 mg SC injection at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab at 225 mg SC injection monthly (approximately every 4 weeks, administered as single SC injection of fremanezumab at 225 mg [225 mg/1.5 milliliter {mL}] at Week 0 and 36; and 2 placebo SC injections at Weeks 0, 12, 24, and 36 for blinding in participants rolled over from Study TV48125-CNS-30056; fremanezumab at 225 mg as a single SC injection [225 mg/1.5 mL] at Week 0, 12, 24, and 36; 2 SC injections of placebo at Week 0 for blinding in participants rolled over from Study TV48125-CNS-30057) through Week 36 in this study.
    Arm type
    Experimental

    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.

    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.

    Arm title
    Fremanezumab 675/225 mg Monthly
    Arm description
    Participants with CCH who received placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab 675 mg SC injection as loading dose (administered as 3 SC injections of fremanezumab at 225 mg [225 mg/1.5 mL] at Week 0) followed by monthly (approximately every 4 weeks) fremanezumab at 225 mg SC injection (administered as single SC injection of fremanezumab at 225 mg [225 mg/1.5 mL] at Weeks 12, 24, and 36) through Week 36.
    Arm type
    Experimental

    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 675 mg Quarterly
    Arm description
    Participants with ECH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study; or placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056; received fremanezumab at 675 mg SC injection quarterly (approximately every 12 weeks, administered as 3 SC injections of fremanezumab at 225 mg [225 mg/1.5 mL] at Weeks 0 and 36; and single placebo SC injection at Weeks 4, 8, 16, 20, 28, and 32 for blinding) through Week 36.
    Arm type
    Experimental

    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.

    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.

    Number of subjects in period 1
    Fremanezumab 225 mg Monthly Fremanezumab 675/225 mg Monthly Fremanezumab 675 mg Quarterly
    Started
    145
    60
    70
    Completed
    26
    14
    29
    Not completed
    119
    46
    41
         Protocol deviation
    6
    -
    3
         Other than specified
    4
    2
    -
         Lack of efficacy
    23
    7
    4
         Study terminated due to futility
    67
    31
    23
         Adverse event, non-fatal
    6
    1
    2
         Consent withdrawn by subject
    9
    5
    8
         Lost to follow-up
    4
    -
    1

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Fremanezumab 225 mg Monthly
    Reporting group description
    Participants with ECH or CCH who received fremanezumab at 900 mg intravenous (IV) infusion at Week 0 and fremanezumab at 225 mg subcutaneous (SC) injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056 or TV48125-CNS-30057, and participants with CCH who received fremanezumab at 675 mg SC injection at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab at 225 mg SC injection monthly (approximately every 4 weeks, administered as single SC injection of fremanezumab at 225 mg [225 mg/1.5 milliliter {mL}] at Week 0 and 36; and 2 placebo SC injections at Weeks 0, 12, 24, and 36 for blinding in participants rolled over from Study TV48125-CNS-30056; fremanezumab at 225 mg as a single SC injection [225 mg/1.5 mL] at Week 0, 12, 24, and 36; 2 SC injections of placebo at Week 0 for blinding in participants rolled over from Study TV48125-CNS-30057) through Week 36 in this study.

    Reporting group title
    Fremanezumab 675/225 mg Monthly
    Reporting group description
    Participants with CCH who received placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab 675 mg SC injection as loading dose (administered as 3 SC injections of fremanezumab at 225 mg [225 mg/1.5 mL] at Week 0) followed by monthly (approximately every 4 weeks) fremanezumab at 225 mg SC injection (administered as single SC injection of fremanezumab at 225 mg [225 mg/1.5 mL] at Weeks 12, 24, and 36) through Week 36.

    Reporting group title
    Fremanezumab 675 mg Quarterly
    Reporting group description
    Participants with ECH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study; or placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056; received fremanezumab at 675 mg SC injection quarterly (approximately every 12 weeks, administered as 3 SC injections of fremanezumab at 225 mg [225 mg/1.5 mL] at Weeks 0 and 36; and single placebo SC injection at Weeks 4, 8, 16, 20, 28, and 32 for blinding) through Week 36.

    Reporting group values
    Fremanezumab 225 mg Monthly Fremanezumab 675/225 mg Monthly Fremanezumab 675 mg Quarterly Total
    Number of subjects
    145 60 70 275
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    45.2 ± 12.25 46.1 ± 11.14 43.2 ± 11.40 -
    Sex: Female, Male
    Units: participants
        Female
    51 20 25 96
        Male
    94 40 45 179
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0
        Asian
    0 0 0 0
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        Black or African American
    9 3 2 14
        White
    136 56 68 260
        More than one race
    0 0 0 0
        Unknown or Not Reported
    0 1 0 1

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Fremanezumab 225 mg Monthly
    Reporting group description
    Participants with ECH or CCH who received fremanezumab at 900 mg intravenous (IV) infusion at Week 0 and fremanezumab at 225 mg subcutaneous (SC) injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056 or TV48125-CNS-30057, and participants with CCH who received fremanezumab at 675 mg SC injection at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab at 225 mg SC injection monthly (approximately every 4 weeks, administered as single SC injection of fremanezumab at 225 mg [225 mg/1.5 milliliter {mL}] at Week 0 and 36; and 2 placebo SC injections at Weeks 0, 12, 24, and 36 for blinding in participants rolled over from Study TV48125-CNS-30056; fremanezumab at 225 mg as a single SC injection [225 mg/1.5 mL] at Week 0, 12, 24, and 36; 2 SC injections of placebo at Week 0 for blinding in participants rolled over from Study TV48125-CNS-30057) through Week 36 in this study.

    Reporting group title
    Fremanezumab 675/225 mg Monthly
    Reporting group description
    Participants with CCH who received placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab 675 mg SC injection as loading dose (administered as 3 SC injections of fremanezumab at 225 mg [225 mg/1.5 mL] at Week 0) followed by monthly (approximately every 4 weeks) fremanezumab at 225 mg SC injection (administered as single SC injection of fremanezumab at 225 mg [225 mg/1.5 mL] at Weeks 12, 24, and 36) through Week 36.

    Reporting group title
    Fremanezumab 675 mg Quarterly
    Reporting group description
    Participants with ECH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study; or placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056; received fremanezumab at 675 mg SC injection quarterly (approximately every 12 weeks, administered as 3 SC injections of fremanezumab at 225 mg [225 mg/1.5 mL] at Weeks 0 and 36; and single placebo SC injection at Weeks 4, 8, 16, 20, 28, and 32 for blinding) through Week 36.

    Subject analysis set title
    Fremanezumab 675 mg Quarterly
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants with ECH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study; or placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056; received fremanezumab at 675 mg SC injection quarterly (approximately every 12 weeks, administered as 3 SC injections of fremanezumab at 225 mg [225 mg/1.5 mL] at Weeks 0 and 36; and single placebo SC injection at Weeks 4, 8, 16, 20, 28, and 32 for blinding) through Week 36.

    Primary: Number of Participants With Adverse Events (AEs)

    Close Top of page
    End point title
    Number of Participants With Adverse Events (AEs) [1] [2]
    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. Baseline refers to the baseline values from the pivotal studies. Safety analysis set included all participants who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline up to follow-up (Week 68)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Safety analyses were descriptive in nature.
    [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: The endpoint is reporting statistics for specified arms only.
    End point values
    Fremanezumab 225 mg Monthly Fremanezumab 675/225 mg Monthly Fremanezumab 675 mg Quarterly
    Number of subjects analysed
    144
    60
    71
    Units: participants
        Any AEs
    87
    31
    42
        Treatment-related AEs
    26
    6
    10
        Serious AEs
    8
    2
    1
        AEs leading to discontinuation
    6
    1
    2
    No statistical analyses for this end point

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

    Close Top of page
    End point title
    Number of Participants with Potentially Clinically Significant Abnormal Laboratory Results: Serum Chemistry [3]
    End point description
    Serum chemistry tests with potentially clinically significant abnormal findings included: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), lactate dehydrogenase (LDH) each ≥3*upper limit of normal (ULN); Blood urea nitrogen (BUN) ≥10.71 millimole (mmol)/L; Bilirubin (Total) ≥34.2 micromole/liter (umol/L); and Creatinine ≥177 umol/L. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies. Safety analysis set included all participants who received at least 1 dose of study drug. Here, 'Overall number of participants analyzed' signifies participants with a laboratory result.
    End point type
    Primary
    End point timeframe
    Baseline up to end of treatment (Week 40)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Safety analyses were descriptive in nature.
    End point values
    Fremanezumab 225 mg Monthly Fremanezumab 675/225 mg Monthly Fremanezumab 675 mg Quarterly
    Number of subjects analysed
    129
    55
    67
    Units: participants
    2
    0
    1
    No statistical analyses for this end point

    Primary: Number of Participants with Potentially Clinically Significant Abnormal Laboratory Results: Hematology

    Close Top of page
    End point title
    Number of Participants with Potentially Clinically Significant Abnormal Laboratory Results: Hematology [4]
    End point description
    Hematology tests with potentially clinically significant abnormal findings included: hemoglobin less than or equal to (≤)115 grams (g)/L (males) or ≤95 g/L (females), leukocytes count ≥20*10^9/L or ≤3*10^9/L, eosinophils ≥10%, hematocrit <0.37 L/L (males) and <0.32 L/L (females), platelets count ≥700*10^9/L or ≤75*10^9/L, absolute neutrophil count (ANC) ≤1*10^9/L. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies. Safety analysis set included all participants who received at least 1 dose of study drug. Here, 'Overall number of participants analyzed' signifies participants with a laboratory result.
    End point type
    Primary
    End point timeframe
    Baseline up to end of treatment (Week 40)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Safety analyses were descriptive in nature.
    End point values
    Fremanezumab 225 mg Monthly Fremanezumab 675/225 mg Monthly Fremanezumab 675 mg Quarterly
    Number of subjects analysed
    129
    55
    67
    Units: participants
    6
    3
    0
    No statistical analyses for this end point

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

    Close Top of page
    End point title
    Number of Participants with Potentially Clinically Significant Abnormal Laboratory Results: Urinalysis [5]
    End point description
    Urinalysis laboratory tests with potentially clinically significant abnormal findings included: haemoglobin, urine glucose, ketones, urine 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. Baseline refers to the baseline values from the pivotal studies. Safety analysis set included all participants who received at least 1 dose of study drug. Here, 'Overall number of participants analyzed' signifies participants with a laboratory result.
    End point type
    Primary
    End point timeframe
    Baseline up to end of treatment (Week 40)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Safety analyses were descriptive in nature.
    End point values
    Fremanezumab 225 mg Monthly Fremanezumab 675/225 mg Monthly Fremanezumab 675 mg Quarterly
    Number of subjects analysed
    129
    55
    67
    Units: participants
    0
    0
    0
    No statistical analyses for this end point

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

    Close Top of page
    End point title
    Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Coagulation Laboratory Test Results [6] [7]
    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. Baseline refers to the baseline values from the pivotal studies. Safety analysis set included all participants who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline up to end of treatment (Week 40)
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Safety analyses were descriptive in nature.
    [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 endpoint is reporting statistics for specified arms only.
    End point values
    Fremanezumab 225 mg Monthly Fremanezumab 675/225 mg Monthly Fremanezumab 675 mg Quarterly
    Number of subjects analysed
    144
    60
    71
    Units: participants
        Prothrombin INR|Low-Low
    0
    0
    0
        PT|Low-Low
    0
    0
    0
        Prothrombin INR|Low-Normal
    0
    0
    0
        PT|Low-Normal
    0
    0
    0
        Prothrombin INR|Low-High
    0
    0
    0
        PT|Low-High
    0
    0
    0
        Prothrombin INR|Normal-Low
    1
    0
    0
        PT|Normal-Low
    1
    0
    0
        Prothrombin INR|Normal-Normal
    103
    42
    61
        PT|Normal-Normal
    99
    39
    59
        Prothrombin INR|Normal-High
    6
    4
    1
        PT|Normal-High
    6
    5
    1
        Prothrombin INR|High-Low
    0
    0
    0
        PT|High-Low
    0
    0
    0
        Prothrombin INR|High-Normal
    7
    4
    3
        PT|High-Normal
    11
    4
    5
        Prothrombin INR|High-High
    4
    2
    0
        PT|High-High
    4
    4
    0
        Prothrombin INR|Missing
    23
    8
    6
        PT|Missing
    23
    8
    6
    No statistical analyses for this end point

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

    Close Top of page
    End point title
    Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Values [8]
    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 ≤90 millimeters of mercury (mmHg) and decrease from baseline of ≥20 mmHg, or ≥180 mmHg and increase from baseline of ≥20 mmHg; Diastolic blood pressure ≤50 mmHg and decrease from baseline of ≥15 mmHg, or ≥105 mmHg and increase from baseline of ≥15 mmHg; Temperature >38.3 degrees celsius (°C). A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies. Safety analysis set included all participants who received at least 1 dose of study drug. Here, 'Overall number of participants analyzed' signifies participants with a vital sign result.
    End point type
    Primary
    End point timeframe
    Baseline up to follow-up (Week 68)
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Safety analyses were descriptive in nature.
    End point values
    Fremanezumab 225 mg Monthly Fremanezumab 675/225 mg Monthly Fremanezumab 675 mg Quarterly
    Number of subjects analysed
    139
    57
    68
    Units: participants
    6
    4
    2
    No statistical analyses for this end point

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

    Close Top of page
    End point title
    Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters [9] [10]
    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. Baseline refers to the baseline values from the pivotal studies. Safety analysis set included all participants who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline up to follow-up (Week 68)
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Safety analyses were descriptive in nature.
    [10] - 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 endpoint is reporting statistics for specified arms only.
    End point values
    Fremanezumab 225 mg Monthly Fremanezumab 675/225 mg Monthly Fremanezumab 675 mg Quarterly
    Number of subjects analysed
    144
    60
    71
    Units: participants
        Normal / Normal
    76
    30
    46
        Normal / Abnormal NCS
    16
    6
    4
        Normal / Abnormal CS
    1
    0
    0
        Abnormal NCS / Normal
    15
    7
    4
        Abnormal NCS / Abnormal NCS
    23
    12
    12
        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
    13
    5
    5
    No statistical analyses for this end point

    Primary: Number of Participants With Abnormal Physical Examination Findings

    Close Top of page
    End point title
    Number of Participants With Abnormal Physical Examination Findings [11]
    End point description
    A complete physical examination included the following organ systems: general appearance; head, eyes, ears, nose, and throat; chest and lungs; heart; abdomen; musculoskeletal; skin; lymph nodes; and neurological. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies. ITT analysis set included all participants who were enrolled in this study for long-term safety evaluation, regardless if they received study treatment or not.
    End point type
    Primary
    End point timeframe
    Baseline up to follow-up (Week 68)
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Safety analyses were descriptive in nature.
    End point values
    Fremanezumab 225 mg Monthly Fremanezumab 675/225 mg Monthly Fremanezumab 675 mg Quarterly
    Number of subjects analysed
    145
    60
    70
    Units: participants
    22
    8
    7
    No statistical analyses for this end point

    Primary: Number of Participants With Injection Site Reactions

    Close Top of page
    End point title
    Number of Participants With Injection Site Reactions [12] [13]
    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, rash, warmth, and pruritus. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies. Safety analysis set included all participants who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 36
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Safety analyses were descriptive in nature.
    [13] - 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 endpoint is reporting statistics for specified arms only.
    End point values
    Fremanezumab 225 mg Monthly Fremanezumab 675/225 mg Monthly Fremanezumab 675 mg Quarterly
    Number of subjects analysed
    144
    60
    71
    Units: participants
        Injection site induration
    13
    4
    5
        Injection site pain
    6
    1
    3
        Injection site erythema
    7
    1
    1
        Injection site haemorrhage
    2
    0
    0
        Injection site pruritus
    2
    0
    0
        Injection site bruising
    0
    1
    0
        Injection site rash
    0
    0
    1
        Injection site warmth
    1
    0
    0
    No statistical analyses for this end point

    Primary: Number of Participants With Hypersensitivity/Anaphylaxis Reactions

    Close Top of page
    End point title
    Number of Participants With Hypersensitivity/Anaphylaxis Reactions [14] [15]
    End point description
    A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies. Safety analysis set included all participants who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 36
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Safety analyses were descriptive in nature.
    [15] - 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 endpoint is reporting statistics for specified arms only.
    End point values
    Fremanezumab 225 mg Monthly Fremanezumab 675/225 mg Monthly Fremanezumab 675 mg Quarterly
    Number of subjects analysed
    144
    60
    71
    Units: participants
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Participants Who Received Concomitant Medications

    Close Top of page
    End point title
    Number of Participants Who Received Concomitant Medications [16] [17]
    End point description
    Concomitant medications included: agents acting on the renin-angiotensin system, all other therapeutic products (homeopathic), analgesics, anesthetics, anti-parkinson drugs, antibacterials, antibiotics and chemotherapeutics for dermatological use, antidiarrheals, intestinal antiinflammatory/antiinfective agents, antiemetic, antiepileptics, antifungals for dermatologiocal use, antihemorrhagics, antihistamines for systemic use, antihypertensives, antiinflammatory and antirheumatic products, antimycotics for systemic use, antipruritics, antipsoriatics, antivirals for systemic use, blood substitutes and perfusion solutions, cardiac therapy, corticosteroids, cough and cold preparations, diagnostic radiopharmaceuticals, diuretics, thyroid therapy, urologicals, vaccines, psycoleptics, psycoanaleptics, muscle relaxants, drugs used in diabetes. Baseline refers to values from the pivotal studies. Safety analysis set included all participants who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline up to follow-up (Week 68)
    Notes
    [16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Safety analyses were descriptive in nature.
    [17] - 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 endpoint is reporting statistics for specified arms only.
    End point values
    Fremanezumab 225 mg Monthly Fremanezumab 675/225 mg Monthly Fremanezumab 675 mg Quarterly
    Number of subjects analysed
    144
    60
    71
    Units: participants
    140
    56
    68
    No statistical analyses for this end point

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

    Close Top of page
    End point title
    Number of Participants With Suicidal Ideation and Suicidal Behavior as Assessed by the Electronic Columbia Suicide Severity Rating Scale (eC-SSRS) [18]
    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. Baseline refers to the baseline values from the pivotal studies. ITT analysis set included all participants who were enrolled in this study for long-term safety evaluation, regardless if they received study treatment or not.
    End point type
    Primary
    End point timeframe
    Baseline up to follow-up (Week 68)
    Notes
    [18] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Safety analyses were descriptive in nature.
    End point values
    Fremanezumab 225 mg Monthly Fremanezumab 675/225 mg Monthly Fremanezumab 675 mg Quarterly
    Number of subjects analysed
    145
    60
    70
    Units: participants
    7
    1
    3
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Week 68
    Adverse event reporting additional description
    Safety population included all 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
    Fremanezumab 225 mg Monthly
    Reporting group description
    Participants with ECH or CCH who received fremanezumab at 900 mg IV infusion at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056 or TV48125-CNS-30057, and participants with CCH who received fremanezumab at 675 mg SC injection at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab at 225 mg SC injection monthly (approximately every 4 weeks, administered as single SC injection of fremanezumab at 225 mg [225 mg/1.5 mL] at Week 0 and 36; and 2 placebo SC injections at Weeks 0, 12, 24, and 36 for blinding in participants rolled over from Study TV48125-CNS-30056; fremanezumab at 225 mg as a single SC injection [225 mg/1.5 mL] at Week 0, 12, 24, and 36; 2 SC injections of placebo at Week 0 for blinding in participants rolled over from Study TV48125-CNS-30057) through Week 36 in this study.

    Reporting group title
    Fremanezumab 675/225 mg Monthly
    Reporting group description
    Participants with CCH who received placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab 675 mg SC injection as loading dose (administered as 3 SC injections of fremanezumab at 225 mg [225 mg/1.5 mL] at Week 0) followed by monthly (approximately every 4 weeks) fremanezumab at 225 mg SC injection (administered as single SC injection of fremanezumab at 225 mg [225 mg/1.5 mL] at Weeks 12, 24, and 36) through Week 36.

    Reporting group title
    Fremanezumab 675 mg Quarterly
    Reporting group description
    Participants with ECH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study; or placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056; received fremanezumab at 675 mg SC injection quarterly (approximately every 12 weeks, administered as 3 SC injections of fremanezumab at 225 mg [225 mg/1.5 mL] at Weeks 0 and 36; and single placebo SC injection at Weeks 4, 8, 16, 20, 28, and 32 for blinding) through Week 36.

    Serious adverse events
    Fremanezumab 225 mg Monthly Fremanezumab 675/225 mg Monthly Fremanezumab 675 mg Quarterly
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 144 (5.56%)
    2 / 60 (3.33%)
    1 / 71 (1.41%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Intentional overdose
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 60 (0.00%)
    0 / 71 (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
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 60 (0.00%)
    0 / 71 (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
    Road traffic accident
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 60 (0.00%)
    0 / 71 (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
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 60 (0.00%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 60 (1.67%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 60 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cluster headache
         subjects affected / exposed
    3 / 144 (2.08%)
    0 / 60 (0.00%)
    0 / 71 (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
    Eye disorders
    Amaurosis fugax
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 60 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 60 (0.00%)
    0 / 71 (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
    Cholelithiasis
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 60 (0.00%)
    0 / 71 (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
    Musculoskeletal and connective tissue disorders
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 60 (1.67%)
    0 / 71 (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
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 60 (1.67%)
    0 / 71 (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
    Fremanezumab 225 mg Monthly Fremanezumab 675/225 mg Monthly Fremanezumab 675 mg Quarterly
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 144 (21.53%)
    11 / 60 (18.33%)
    14 / 71 (19.72%)
    General disorders and administration site conditions
    Injection site induration
         subjects affected / exposed
    13 / 144 (9.03%)
    4 / 60 (6.67%)
    5 / 71 (7.04%)
         occurrences all number
    44
    13
    10
    Oedema peripheral
         subjects affected / exposed
    0 / 144 (0.00%)
    3 / 60 (5.00%)
    0 / 71 (0.00%)
         occurrences all number
    0
    3
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 144 (1.39%)
    3 / 60 (5.00%)
    0 / 71 (0.00%)
         occurrences all number
    3
    4
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    16 / 144 (11.11%)
    5 / 60 (8.33%)
    7 / 71 (9.86%)
         occurrences all number
    18
    8
    8
    Sinusitis
         subjects affected / exposed
    4 / 144 (2.78%)
    3 / 60 (5.00%)
    2 / 71 (2.82%)
         occurrences all number
    4
    4
    2

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Apr 2018
    The following major procedural changes (not all-inclusive) were made to the protocol: - Provided clarification on concomitant preventive medications allowed in the treatment arm of this long-term safety study. - Extended the duration of the study by 6 months because the study recruitment rate into Studies TV48125-CNS-30056 and TV48125-CNS-30057 was lower than initially expected. - Clarified that pharmacogenomics samples were taken only during the pivotal studies and were not collected in Study TV48125-CNS-30058.
    28 Aug 2018
    The following major procedural changes (not all-inclusive) were made to the protocol: - Described the way in which participants who participated in the double-blind study for CCH (Study TV48125-CNS-30057) would continue to participate only in the ADA and safety arm of the long-term safety study (Study TV48125-CNS-30058), since the CCH study was terminated. - Updated standardized text.

    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.
    The study was terminated after the ECH study (TV48125-CNS-30056) was terminated due to a pre specified futility analyses.
    For support, visit the EMA Service Desk , log in using your EMA account and open a ticket specifying "EU CTR" in your request.
    If you do not have an account, please visit the EMA Account management page page click on "Create an EMA account" and follow the instructions.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2022 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA