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    Summary
    EudraCT Number:2019-001989-15
    Sponsor's Protocol Code Number:TV48125-MH-40142
    National Competent Authority:Greece - EOF
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2019-11-01
    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 ConcernedGreece - EOF
    A.2EudraCT number2019-001989-15
    A.3Full title of the trial
    A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Followed by an Open-Label Extension to Evaluate the Efficacy and Safety of Fremanezumab for Preventive Treatment of Migraine in Patients with Major Depressive Disorder
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Assess if Fremanezumab is Effective in Preventing Migraine in Patients with Major Depressive Disorder
    A.3.2Name or abbreviated title of the trial where available
    UNITE
    A.4.1Sponsor's protocol code numberTV48125-MH-40142
    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 organisationMerckle GmbH
    B.5.2Functional name of contact pointClinical Trial Information Desk
    B.5.3 Address:
    B.5.3.1Street AddressGraf-Arco-Str.3
    B.5.3.2Town/ cityUlm
    B.5.3.3Post code89079
    B.5.3.4CountryGermany
    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 Yes
    D.2.1.1.1Trade name AJOVY
    D.2.1.1.2Name of the Marketing Authorisation holderTEVA GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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
    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.3.9.4EV 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
    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
    Migraine and major depressive disorder (MDD)
    E.1.1.1Medical condition in easily understood language
    Migraine and major depressive disorder (MDD)
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10025453
    E.1.2Term Major depressive disorder NOS
    E.1.2System Organ Class 100000004873
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of monthly 225 mg sc fremanezumab in adult patients with migraine and MDD
    E.2.2Secondary objectives of the trial
    -To evaluate the efficacy of monthly 225 mg sc of fremanezumab in adult patients with migraine and on the reduction of MDD symptoms
    -To evaluate the efficacy of monthly 225 mg sc fremanezumab in adult patients with migraine and MDD in terms of responder rates in monthly migraine days
    -To evaluate the efficacy of monthly 225 mg sc fremanezumab in adult patients with migraine and MDD in terms of improving quality of life
    -To evaluate the efficacy of monthly 225 mg sc fremanezumab in adult patients with migraine and MDD in terms of improving disability
    -To evaluate the safety and tolerability of monthly 225 mg sc and quarterly 675 mg sc fremanezumab in adult patients with migraine and MDD
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    a. The patient is capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in this protocol.
    b. The patient is male or female and 18 to 70 years of age, inclusive.
    c. The patient has a diagnosis of migraine with onset at ≤50 years of age.
    d. Prior to the screening visit (V1), the patient has a 12-month history of either:
    -migraine (according to ICHD-3 criteria) or
    -headache consistent with migraine (ie, migraine diagnosis not better accounted for by another ICHD-3 diagnosis)
    e. The patient fulfills the following criteria for migraine in a prospectively collected diary during the 28-day baseline period:
    -on ≥4 days, headache attacks qualified as migraine based on the following ICHD-3 criteria:
    -ICHD-3 diagnostic criteria C and D for 1.1 Migraine without aura
    -headache has at least 2 of the following 4 characteristics: unilateral location; pulsating quality; moderate or severe pain intensity;
    and aggravation by, or causing avoidance of, routine physical activity (eg, walking or climbing stairs)
    -during headache, at least one of the following: nausea and/or vomiting; photophobia and phonophobia
    -ICHD-3 criteria B and C for 1.2 Migraine with aura
    -1 or more of the following fully reversible aura symptoms: visual, sensory, speech and/or language, motor, brainstem, retinal
    -at least 2 of the following 4 characteristics: at least 1 aura symptom spreads gradually over ≥5 minutes, and/or 2 or more symptoms
    occur in succession; each individual aura symptom lasts 5 to 60 minutes; at least 1 aura symptom is unilateral; the aura is
    accompanied, or followed within 60 minutes, by headache not better accounted for by another ICHD-3 diagnosis, and transient
    ischemic attack has been excluded
    -probable migraine (a migraine subtype where only 1 migraine criterion is missing)
    -triptan or ergot derivative used to treat an established headache.
    f. The patient agrees not to initiate any migraine preventive medications during the study. Up to 30% of patients, however, may take a single such medication previously prescribed for the treatment of migraine.
    g. The patient has a history of MDD according to the DSM-V criteria at least 12 months prior to the screening visit (V1). Patients may take a single medication prescribed for the treatment of depression as long as the dose of that medication has been stable for at least 8 weeks prior to the screening visit (V1) and expects to remain at the stable dose throughout the study.
    h. The patient has a PHQ-9 score of at least 10 at the screening visit (V1).
    i. The patient has a Mini Mental State Examination score of at least 26 points at the screening visit (V1).
    j. The patient is in good health in the opinion of the investigator as determined by medical evaluation, including medical and psychiatric history, physical examination, laboratory tests, and cardiac monitoring.
    k. The patient has a body weight >-45 kg and a body mass index within the range of 17.5 to 34.9 kg/m2, inclusive.
    l. The patient demonstrated compliance with the electronic headache diary during the 28-day baseline period by entry of headache data on a minimum of 21 days cumulative during the 28-day baseline period (~75% diary compliance).
    m. Women may be included only if they have a negative serum beta-human chorionic gonadotropin test at the screening visit (V1), are sterile or postmenopausal, and are not lactating (not applicable for patients participating in safety follow-up only).
    n. Women of child-bearing potential whose male partners are potentially fertile (ie, no vasectomy) must use highly effective birth control methods for the duration of the study and for 6 months after discontinuation of IMP.
    o. Men must be sterile or, if they are potentially fertile/reproductively competent (not congenitally sterile) and their female partners are of child-bearing potential, must use a condom for the duration of the study and for 6 months after discontinuation of IMP. For the purpose of this study, vasectomized men must use a condom if their partners are of child-bearing potential.
    p. The patient must be willing and able to comply with study restrictions, to remain at the clinic for the required duration during the study, and to return to the clinic for the follow-up evaluations, as specified in this protocol.
    E.4Principal exclusion criteria
    a. The patient uses medications containing opioids (incl. codeine), barbiturates (incl. butalbital/aspirin/caffeine,
    butalbital/paracetamol/caffeine or any other combination containing butalbital) on more than 4 days during the 28-day baseline period for the treatment of migraine or for any other reason.
    b. The patient has failed 4 or more different medication classes to treat depression
    c. If in the clinical judgment of the investigator/qualified psychiatrist, the patient's antidepressant medication needs to be changed or dose-adjusted during the 28-day baseline period
    d.The patient has used an intervention/device for migraine/depression 2 months prior screening
    e.The patient has used electroconvulsive therapy at any time
    f.The patient suffers from constant/nearly constant headache, 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
    g.The patient has clinically significant disease/complications of an infection
    h.The patient has a clinical history of a severe/uncontrolled psychiatric disorder or any clinically significant psychiatric history that would likely interfere with full participation in the study such as suicide attempt (lifetime exclusion) and suicidal ideation/other psychoactive spectrum disorders incl. schizoaffective/delusional disorder, depression with psychotic features/catatonic disorder (in the past 6 months exclusion)
    i.The patient has a history of clinically significant cardiovascular disease/vascular ischemia or thromboembolic events, e.g. cerebrovascular accident, deep vein thrombosis, or pulmonary embolism
    j.The patient has a known infection/history of HIV, tuberculosis, any history of Lyme disease or chronic hepatitis B/C infection.
    k.The patient has a past/current history of cancer, except for appropriately treated non-melanoma skin carcinoma.
    l.The patient is a pregnant/nursing female or plans to become pregnant during the study, incl. the 6-month period after the administration of the last dose.
    m.The patient has a history of hypersensitivity reactions to injected proteins, incl. monoclonal antibodies/Stevens-Johnson Syndrome/toxic epidermal necrolysis syndrome.
    n. The patient has participated in a clinical study of a new chemical entity or a prescription medicine within 2 months of the screening visit (V1) 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 a medical device).
    o.The patient has failed treatment with any monoclonal antibodies targeting the CGRP pathway or have taken the medications within 5 half-lives of the screening visit or take them during the study.
    p.The patient has any finding in the baseline 12-lead electrocardiogram considered clinically significant.
    q.The patient has any finding that, in the judgment of the investigator, is a clinically significant abnormality, incl. serum chemistry, hematology, coagulation, and urinalysis test values.
    r. The patient has hepatic enzymes (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase) >1.5 × the upper limit of the normal range after confirmation in a repeat test or suspected hepatocellular damage that fulfills the criteria for Hy's law at the screening visit.
    s.The patient has serum creatinine >1.5 × the upper limit of normal range, clinically significant proteinuria, or evidence of renal disease at the screening visit.
    t.The patient has any clinically significant uncontrolled medical condition (treated/ untreated).
    u.The patient has a history of alcohol/drug abuse in the opinion of the investigator
    v.The patient cannot participate/successfully complete the study, in the opinion of their healthcare provider/investigator, for reasons as:
    w.The patient is a study center/sponsor employee who is directly involved in the study or the relative of such an employee.
    x.The patient has any disorder that may interfere with the absorption, distribution, metabolism, or excretion of IMP.
    y.The patient is vulnerable.
    z.The patient previously participated in this study.
    aa. The patient has evidence/medical history of psychotic symptoms as per DSM-V criteria such as delusions, hallucinations/disorganized speech in the past 1 month
    bb. Patient has received onabotulinumtoxinA for migraine/for any medical or cosmetic reasons requiring injections in the head, face, or neck during the 3 months before screening visit
    E.5 End points
    E.5.1Primary end point(s)
    Mean change in the monthly average number of migraine days from the 28-day baseline period during the 12-week period after the first dose of study drug
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 weeks after the first dose of study drug
    E.5.2Secondary end point(s)
    Efficacy:
    -Mean change in depression symptoms from randomization visit (day 1) to week 8 after the first dose of study drug as measured by HAM-D 17
    -Number of patients with 50% or more reduction from the 28-day baseline period until 12 weeks after the first dose of study drug, in the monthly average number of migraine days
    -Mean change in quality of life from randomization visit (day 1) to week 12 after the first dose of study drug as measured by the MSQoL questionnaire, role functionrestrictive and role function-preventive domains
    -Mean change from randomization visit (day 1) in disability score for overall impact, as measured by CGI-S and HIT-6, to the following time points after administration of the first dose of study drug:
     -weeks 4 and 8 (CGI-S)
     -week 12 (CGI-S and HIT-6)

    Safety and tolerability:
    -occurrence of adverse events throughout the study
    -changes from randomization visit (day 1) in vital signs (pulse, systolic and diastolic blood pressure, body temperature, and respiratory rate) measurements
    -abnormal physical examination findings including body weight
    -use of concomitant medication for adverse events during the study
    -number (%) of patients who did not complete the study due to adverse events
    -occurrence of severe hypersensitivity/anaphylaxis reactions
    -suicidal ideation and behavior as suggested by eC-SSRS
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy:
    -Mean change in depression symptoms: week 8 after the first dose of study drug
    -Number of patients with 50% or more reduction in the monthly average number of migraine days: 12 weeks after the first dose of study drug
    -Mean change in quality of life: week 12 after the first dose of study drug
    -Mean change in disability score for overall impact after administration of the first dose of study drug: weeks 4 and 8 (CGI-S), week 12 (CGI-S and HIT-6)

    Safety and tolerability: throughout the study
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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
    The 12-week double-blind treatment phase is followed by a 12-week open-label extension phase
    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 trial2
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA36
    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
    Czech Republic
    Finland
    France
    Germany
    Greece
    Israel
    Italy
    Poland
    Russian Federation
    Spain
    Ukraine
    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 years1
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    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: 306
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 34
    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 state35
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 172
    F.4.2.2In the whole clinical trial 340
    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)
    Not applicable
    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 Decision2019-11-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-01-17
    P. End of Trial
    P.End of Trial StatusCompleted
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