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    Summary
    EudraCT Number:2017-002441-30
    Sponsor's Protocol Code Number:TV48125-CNS-30068
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-11-09
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2017-002441-30
    A.3Full title of the trial
    A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study with an Open-Label Period to Evaluate the Efficacy and Safety of Fremanezumab for the Prophylactic Treatment of Migraine in Patients with Inadequate Response to Prior Preventive Treatments
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Test if Fremanezumab is Effective in Preventing Migraine in Patients Who Did Not Respond to Prior Preventive Migraine Treatments
    A.4.1Sponsor's protocol code numberTV48125-CNS-30068
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorTeva Branded Pharmaceutical Products R&D, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportTeva Branded Pharmaceutical Products R&D, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTeva GmbH
    B.5.2Functional name of contact pointClinical Trial Information Desk
    B.5.3 Address:
    B.5.3.1Street AddressGraf-Arco-Strasse-3
    B.5.3.2Town/ cityUlm
    B.5.3.3Post code89079
    B.5.3.4CountryGermany
    B.5.4Telephone number000000000000
    B.5.5Fax number000000000000
    B.5.6E-mailInfo-era-clinical@teva.de
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namefremanezumab
    D.3.2Product code TEV-48125
    D.3.4Pharmaceutical form Solution for injection in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNfremanezumab
    D.3.9.1CAS number 1655501-53-3
    D.3.9.2Current sponsor codeTEV-48125
    D.3.9.3Other descriptive namefremanezumab
    D.3.9.4EV Substance CodeSUB181665
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection in pre-filled syringe
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    episodic and chronic migraine
    E.1.1.1Medical condition in easily understood language
    episodic and chronic migraine
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10027603
    E.1.2Term Migraine headaches
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to demonstrate the efficacy of Fremanezumab administered as monthly and quarterly subcutaneous (sc) injections to adult patients with migraine with inadequate response to 2 to 4 classes of prior preventive treatments as compared with placebo
    E.2.2Secondary objectives of the trial
    A secondary objective of the study is to further evaluate the efficacy of Fremanezumab administered as monthly and quarterly sc injections to adult patients with migraine with inadequate response to 2 to 4 classes of prior preventive treatments as compared with placebo.
    A further secondary objective of the study is to evaluate the safety and tolerability of fremanezumab administered as monthly and quarterly sc injections to adult patients with migraine with inadequate response to 2 to 4 classes of prior preventive treatments as compared with placebo.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    a. The patient is capable of giving signed informed consent
    b. Male or female patient aged 18 to 70 years, inclusive.
    c. The patient has a diagnosis of migraine with onset at ≤50 years of age.
    d. The patient is in good health in the opinion of the investigators as determined by medical history, physical examination, laboratory tests, and ECG.
    e. Body weight greater than 45 kg and body mass index (BMI) within the range 17.5 to 34.9 kg/m2 (inclusive).
    f. The patient has a history of migraine (according to ICHD-3 criteria [IHS 2013]) or clinical judgment suggests a migraine diagnosis (not better accounted for by another ICHD-3 diagnosis) for ≥12 months prior to screening.
    g. The patient fulfills the following criteria for CM or EM in prospectively collected baseline information during the 28-day run-in period:
    For patients with CM:
     - Headache occurring on ≥15 days
    - On ≥8 days, fulfilling any of the following:
    ○ ICHD-3 diagnostic criteria C and D for 1.1 Migraine without aura
    ○ ICHD-3 criteria B and C for 1.2 Migraine with aura
    ○ Probable migraine (a migraine subtype where only 1 migraine criterion is
    missing)
    ○ The patient used a triptan or ergot derivative to treat an established headache
    For patients with EM:
    -Headache occurring on ≥6 days but <15
    -On ≥4 days, fulfilling any of the following:
    ○ ICHD-3 diagnostic criteria C and D for 1.1 Migraine without aura
    ○ ICHD-3 criteria B and C for 1.2 Migraine with aura
    ○ Probable migraine (a migraine subtype where only 1 migraine criterion is
    missing)
    ○ The patient used a triptan or ergot derivative to treat an established headache
    h. At the time of screening, the patient must have documented inadequate response to 2 to 4 classes of prior preventive migraine medications (as defined in Appendix H) within the past 10 years (in medical chart or by treating physician’s confirmation; see Appendix I for acceptable documentation of previous treatment failure). Inadequate response to prior preventive migraine medications (including valproic acid) is defined as: no clinically meaningful improvement per treating physician’s judgment, after at
    least 3 months of therapy at a stable dose considered appropriate for migraine prevention according to accepted country guidelines, or when treatment has to be interrupted because of adverse events that made it intolerable for the patient, or the medication (as defined in Appendix H) is contraindicated or unsuitable for the prophylactic treatment of migraine for the patient. The 3- month period does not apply if the drug is intolerable or contraindicated. If onabotulinumtoxinA is the previous preventive medication, at least 2 sets of injections and 3 months must have
    passed since the last set of injections prior to the screening visit.
    i. The patient agrees not to initiate any preventive migraine medications (as defined in Appendix H) during the run-in period double-blind treatment periodand open-label period. At the screening visit, at least 5 half-lives of these medications must have passed since the patient has been on any migraine preventive medication as defined in Appendix H.
    j. Other prescription medications not in Appendix H must have been on stable doses for at least 2 months at the screening visit with no expectation to change during the double-blind treatment period of the study.
    k. The patient demonstrated compliance with the electronic headache diary during the run-in period by entry of headache data on a minimum of 24 days cumulative during the run-in period (~85% diary compliance).
    l. Women may be included only if they have a negative serum beta-human chorionic gonadotropin (β-HCG) test at screening, are sterile, or postmenopausal. Definitions of sterile and postmenopausal are given in Appendix E.
    m. Women of childbearing potential (WOCBP) whose male partners are potentially fertile (ie, no vasectomy) must use highly effective birth control methods for the duration of the study and the follow-up period (ie, starting at screening) and for 6.0 months after discontinuation of IMP (for details of WOCBP, sterile, and
    postmenopausal women, see Appendix E).
    n. Men must be sterile, or if they are potentially fertile/reproductively competent (not surgically [eg, vasectomy] or congenitally sterile) and their female partners are of childbearing potential, must use, together with their female partners, acceptable birth control methods for the duration of the study and for 6.0 months after discontinuation of the IMP.
    o. The patient must be willing and able to comply with study restrictions, to remain at the clinic for the required duration during the study period and to return to the clinic for the follow-up evaluations, as specified in this protocol.
    E.4Principal exclusion criteria
    a. At time of screening visit, patient is receiving any preventive migraine medications, regardless of the medical indication (as defined in Appendix H) for more than 5 days and expects to continue with these medications
    b. Patient has received onabotulinumtoxinA for migraine or for any medical or cosmetic reasons requiring injections in the head, face, or neck during the 3 months before screening visit
    c. Patient uses medications containing opioids (including codeine) or barbiturates (including butalbital/aspirin/caffeine [Fiorinal®, Actavis plc], butalbital/paracetamol/caffeine [Fioricet®, Cardinal Health], or any other combination containing butalbital) on more than 4 days during the run-in period for the treatment of migraine or for any other reason
    d. Patient has used an intervention/device (eg, scheduled nerve blocks and transcranial magnetic stimulation) for migraine during the 2 months prior to screening
    e. Patient uses triptans/ergots as preventive therapies for migraine
    f. Patient uses non-steroidal anti-inflammatory drugs (NSAIDs) as preventive therapy for migraine on nearly daily basis for other indications. Note: Low dose aspirin (eg, 81 mg) used for cardiovascular disease prevention is allowed
    g. Patient suffers from unremitting headaches, defined as having headaches for more than 80% of the time he/she is awake, and less than 4 days without headache per month. Daily headache is acceptable if patient has headaches 80% or less of the time he/she is awake on most days
    h. Patient has a clinically significant hematological, cardiac, renal, endocrine, pulmonary, gastrointestinal, genitourinary, neurologic, hepatic, or ocular disease that, in opinion of investigator, could jeopardize or would compromise the patient’s ability to participate in this study
    i. Evidence or medical history of clinically significant psychiatric issues that, in opinion of investigator, could jeopardize or would compromise patient’s ability to participate in this study including major depression, panic disorder, or generalized anxiety disorder, any suicide attempt in the past or suicidal ideation with a specific plan the past two years prior to screening or current suicidal ideation as measured by eC-SSRS
    j. History of clinically significant cardiovascular disease or vascular ischemia (such as myocardial, neurological [e.g., cerebral ischemia], peripheral extremity ischemia, or other ischemic event) or thromboembolic events (arterial or venous thrombotic or embolic events), such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism
    k. History of human immunodeficiency virus, tuberculosis, or chronic hepatitis B or C infection
    l. Past or current history of cancer, except for appropriately treated non-melanoma skin carcinoma in last 5 years
    m. Pregnant or lactating female patients or female patients who plan to become pregnant during the study
    n. Participation in clinical study of a new chemical entity or a prescription medicine within 2 months before screening (or 3 months in case of biologics if the half-life of the biologics is unknown) or 5 half-lives, whichever is longer, or is currently participating in another study of an IMP (or medical device)
    o. Any prior exposure to a monoclonal antibody targeting the CGRP pathway (such as AMG 334, ALD304, LY2951742, or fremanezumab)
    p. Any finding in the baseline 12-lead ECG considered clinically significant in the judgment of the investigator
    q. Any finding that, in judgment of the investigator, is a clinically significant abnormality, including serum chemistry, hematology, coagulation, and urinalysis test values (abnormal tests may be repeated for confirmation)
    r. Hepatic enzymes (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase) >1.5 × the upper limit of the normal (ULN) range after confirmation in a repeat test or suspected hepatocellular damage that fulfills criteria for Hy’s law at screening
    s. Serum creatinine >1.5 × the ULN, clinically significant proteinuria, or evidence of renal disease at screening
    t. Patient has history of alcohol abuse during 2 years prior to screening
    u. Patient has history of drug abuse during past 2 years or drug dependence during past 5 years
    v. Patient cannot participate or successfully complete study, in opinion of their healthcare provider or investigator, for any of the following reasons: -mentally or legally incapacitated or unable to give consent for any reason, -in custody due to an administrative or a legal decision, under tutelage, or being admitted to a sanitarium or social institution, -unable to be contacted in case of emergency, -has any other condition, which, in the opinion of the investigator, makes the patient inappropriate for inclusion in study
    w. Patient is a study center or sponsor employee who is directly involved in study or the relative of such an employee
    x. Patient has been previously screen failed for study
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is the mean change from
    baseline (28-day run-in period) in the monthly average number
    of migraine days during the 12-week period after the 1st dose
    of fremanezumab
    E.5.1.1Timepoint(s) of evaluation of this end point
    Final study assessments will be performed at visit 8 (end-of-treatment
    [EOT] visit), approximately 4 weeks after administration of last dose of fremanezumab.
    E.5.2Secondary end point(s)
    - proportion of patients reaching at least 50% reduction in the monthly average number of migraine days during the 12-week period after the
    1st dose of fremanezumab
    - mean change from baseline (28-day run-in period) in the monthly average -number of headache days of at least moderate severity during the 12-week
    period after the 1st dose of fremanezumab
    - mean change from baseline (28-day run-in period) in the monthly average number of migraine days during the 4-week period after the 1st dose of
    fremanezumab
    -proportion of patients reaching at least 50% reduction in the monthly average number of migraine days during the 4-week period after the
    1st dose of fremanezumab
    - mean change from baseline (28-day run-in period) in the monthly average number of days of use of any acute headache medications during the 12-week period after the 1st dose of fremanezumab
    - mean change from baseline (28-day run-in period) in the number of headache days of at least moderate severity during the 4-week period after the 1st dose of fremanezumab
    -occurrence of adverse events throughout the study
    -clinical laboratory (serum chemistry, hematology, coagulation and urinalysis) test results at specified time points
    -vital signs (systolic and diastolic blood pressure, oral temperature, and pulse rate) measurements at each visit. Note: In addition, oxygen saturation and respiratory rate will be measured in cases of suspected anaphylaxis and severe hypersensitivity
    -12-lead ECG findings at specified time points
    -use of concomitant medication for adverse events during the study
    -number (%) of patients who did not complete the
    study due to adverse events
    -clinically significant changes in physical examinations, including body weight
    -occurrence of severe hypersensitivity/anaphylaxis reactions
    -suicidal ideations and behaviors as measured by the eC-SSRS
    E.5.2.1Timepoint(s) of evaluation of this end point
    Final study assessments will be performed at visit 8 (end-of-treatment
    [EOT] visit), approximately 4 weeks after administration of last dose of fremanezumab.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    a 12-week double-blind, placebo-controlled treatment period followed by a 12-week open-label period
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial6
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA93
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    Czech Republic
    Denmark
    Finland
    France
    Germany
    Italy
    Netherlands
    Poland
    Spain
    Sweden
    Switzerland
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 764
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state31
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 500
    F.4.2.2In the whole clinical trial 804
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    At the end of the 24-week treatment period, it is expected that patients should return to the care of their treating physicians.
    No treatment is planned by the sponsor after completion of the 24-week treatment period and the study. Patients should be treated with standard of care after withdrawal from or termination of the 24-week treatment period, as appropriate.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-11-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-01-23
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-05-29
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