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    Summary
    EudraCT Number:2017-002441-30
    Sponsor's Protocol Code Number:TV48125-CNS-30068
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-01-22
    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 ConcernedSpain - AEMPS
    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
    Estudio multicéntrico, aleatorizado, doble ciego, de grupos paralelos, controlado con placebo con un período abierto, para evaluar la eficacia y la seguridad de fremanezumab en el tratamiento profiláctico de la migraña en pacientes con una respuesta inadecuada a los tratamientos preventivos anteriores
    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
    Estudio para probar si Fremanezumab es eficaz en la prevención de la migraña en pacientes que no respondieron a los tratamientos preventivos anteriores de migraña
    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
    Migraña crónica y episódica
    E.1.1.1Medical condition in easily understood language
    episodic and chronic migraine
    Migraña crónica y episódica
    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
    El objetivo principal del estudio es demostrar la eficacia de fremanezumab administrado en forma de inyecciones subcutáneas (s.c.) mensuales y trimestrales a pacientes adultos con migraña y una respuesta insuficiente a entre 2 y 4 clases de tratamientos preventivos previos en comparación con el 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.
    El objetivo secundario del estudio es seguir evaluando la eficacia de fremanezumab administrado en forma de inyecciones s.c. mensuales y trimestrales a pacientes adultos con migraña y una respuesta insuficiente a entre 2 y 4 clases de tratamientos preventivos previos en comparación con el placebo.
    Un objetivo secundario del estudio es evaluar la seguridad y la tolerabilidad de fremanezumab administrado en forma de inyecciones s.c. mensuales y trimestrales a pacientes adultos con migraña y una respuesta insuficiente a entre 2 y 4 clases de tratamientos preventivos previos en comparación con el 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.
    a. Paciente capaz de dar el cons infor por escrito.
    b. Mujer o varón de 18 a 70 años de edad, ambos inclu.
    c. Diagn de migraña con inicio a una edad ≤50 años.
    d. En opin de los invest, el paciente cuenta con un buen edo de salud, determinado mediante los antec médicos, la explo física, los anál clíniy el ECG.
    e. Peso corporal 45 kg e índice masa corp(IMC) dentro del intervalo compr entre 17,5 y 34,9 kg/m2 (ambos inclui.
    f. Paciente con antec de migraña (según los criterios de la ICHD-3 [IHS 2013]), o el crit clín apunta a un diagnó de migraña (no explicado mejor por otro diagnós de la ICHD-3) durante un plazo ≥12 meses antes de la selec.
    g.Paciente que cumple los siguientes crit de MC o ME conforme a la inform basal recopilada de forma prospectiva durante el período de preinclusión de 28 días:
    Pacientes con MC:
    Cefalea durante un perí ≥15 días.
    Durante un período ≥8 días, cumpliendo alguno de los sig:
    Crit diagnósticos C y D de la ICHD-3 de 1.1 Migraña sin aura.
    Critdiagnósticos B y C de la ICHD-3 de 1.2 Migraña con aura.
    Migraña probable (un subtipo de migraña en el que solo se incumple 1 crit).
    El paciente utilizaba un triptano o un derivado ergotamínico para tratar una cefalea establecida.
    Pacientes con ME:
    Cefalea durante un perí ≥6 días pero <15 días.
    Durante un perí≥4 días, cumpliendo alguno de los sigui:
    Crit diagnósticos C y D de la ICHD-3 de 1.1 Migraña sin aura.
    Crit diagnósticos B y C de la ICHD-3 de 1.2 Migraña con aura.
    Migraña probable (un subtipo de migraña en el que solo se incumple 1 criterio).
    El paciente utilizaba un triptano o un derivado ergotamínico para tratar una cefalea establecida.
    h. En el momento de la selec, el paciente debe haber tenido una resp insuficiente document a entre 2 y 4 clases de medicprevios para la prevención de la migraña (conforme a la defi del Anexo H) en los últimos 10 años (en la hist clínica o por confirmación del médi responsable del tratam; véase en el Anexo I) la doc aceptable del fracaso terapéutico previo). Una respuesta insuficiente a los med previos para la prevención de la migraña (incluido el ácido valproico) se define de la siguiente manera: ausencia de mejora clínicamente relevante, según el criterio del médico responsable del tratamiento, después de al menos 3 meses de tratamiento a una dosis estable considerada apropiada para la preve de la migraña conforme a las directrices naci vig; necesidad de interrumpir el tratam debido a acontecimientos adversos que lo hicieron intolerable para el paciente; o contraindicación o inadecuación del medicamento (tal y como se define en el Anexo H) para el tratami profiláctico de la migraña en el caso de un paciente dado. El período de 3 meses no es aplicable si el fármaco es intolerable o está contraindicado. Si onabotulinumtoxin A es el med preve anterior, deben haber transcurrido como mín 2 series de inyecciones y 3 meses desde la última serie de inyecciones antes de la visita de selec.
    I. El paciente acepta no empezar a utilizar ningún medic preven para la migraña (según la definición del Anexo H) durante los períodos de preinclusión, de tratamiento doble ciego y abierto. En la visita de selec, deben haber transcurrido como mín 5 semividas de estos medica desde que el paciente los utilizara por última vez, tal y como se def en el Anexo H.
    j. Con resp a otros med de venta con receta que no figuren en el Anexo H, el paciente debe haber estado recib una dosis estable durante al menos 2 meses antes de la visita de selec, sin expectativas de cambio dur el perí de trat doble ciego del estudio.
    k. Paciente que ha mostrado cumpl con el diario electrónico de cefaleas durante el perí de preinclusión, introduciendo los datos sobre las cefaleas en un mín de 24 días acum durante dicho período (cumpl con el diario ~85 %).
    l. Las mujeres solo pueden ser incluidas si cuentan con un resultado negativo en la prueba de detección de β-gonadotropina coriónica humana (β-HCG) en la selec, o si son estériles o posmenopá. Las defi de mujeres estériles y posmenopáusicas se encuentran en ‎Anex E.
    m. Las mujeres con cap de concebir cuyas parejas sean potencialm fértiles ( sin vasectomía) deben utilizar mét anticonceptivos muy eficaces durante el estudio y el perí de segui ( a partir de la selección), y en los 6 meses posteriores a la interrupción de la adm del PEI (véanse los detalles sobre mujeres con cap de concebir, estériles y posmenop en Anexo E).
    n. Los hombres deben ser estériles o, si son potenc fértiles/reproductiv competentes (sin esterilidad quir [p. ej., vasectomía] ni congénita) y sus parejas tienen capacidad de concebir, deben utilizar, junto con sus parejas, mét anticonceptivos aceptables durante el est y en los 6 meses posteriores a la interrup de la admin del PEI.
    o. Paciente con disposición y capacidad para obedecer las restricciones del est, permanecer en el centro el tiempo exigido durante el perí del est y acudir al centro para las evalua del seguimi especificadas en este protocolo.
    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
    a.En el mom de la visita de sele, el paciente ha estado recib algún med preve para la migraña, independientemente de la indic médica (tal y como se define en el Anexo H), durante más de 5 días y espera conti recibiendo dicho medicamento.
    b.El pacient ha recib onabotulinumtoxin A para la migraña, o por cualquier motivo médico o estético, que ha requerido la admin de inyecciones en la cabeza, la cara o el cuello durante los 3 meses anter a la visi de selec.
    c.El pacient ha utilizado medic que conti opioides (como codeína) o barbitúricos (como butalbital/ácido acetilsal/cafeína [Fiorinal®, Actavis plc], butalbital/paracetamol/cafeína [Fioricet®, Cardinal Health], o alg otra comb que contenga butalbital) durante más de 4 días durante el perí de preinclus p el tratam de la migraña o por cualq otro motiv.
    d.El pacient ha utilizado una intervención/dispos (p. ej., bloq nerviosos programados y estimul magnética transcraneal) p la migraña durante los 2 meses anteria la selec.
    e.El pacient utiliza triptanos o derivados ergotamínicos como tratam para la preve de la migraña.
    f.El pacient utiliza antiinflamat no esteroideos (AINE) como tratam preventivo contra la migraña casi a diario p otras indicac. Nota: se permite el uso de ácido acetilsal en dosis bajas (p. ej., 81 mg) para la prev de enfermed cardiovasculares.
    g.El pacient padece cefaleas que no remiten, esto es, cefaleas durant más del 80 % del tiempo de vigilia, y pasa menos de 4 días al mes sin cefaleas. La cefalea diar es aceptable si el pacient tiene cefaleas durant el 80 % o menos del tiempo de vigilia la mayor parte de los días.
    h.Enfer de import clíni hematológica, cardíaca, renal, endocri, pulmonar, gastroint, genitouri, neurológi, hepátic u ocular que, en opinión del inv, podría mermar o comprometer la cap del pacient p participar en este est
    i.Indicios o antec méd de trastornos psiquiát de impor clíni que, en opinión del invest, podrían mermar o comprometer la capa del pacient p participar en este estud, por ej, depresión mayor, trast de pánico, trast de ansiedad generalizada, intento previ de suicidio o ideas suicidas con un plan espec en los dos años anteri a la selecci o ideas suicidas en curso, según la C-SSRS electrón
    j.Antec de enfermedad cardiovasc o isquemia vascular (miocárdica, neurológica [p. ej., isquemia cerebral], isquemia de las extremidades perifér u otro episodio isquémico) o acontec tromboembólicos (acontecimientos trombóticos o embólicos arteriales o venosos), como accide cerebrovascular (incluidos los accidentes isquémicos transitorios), trombosis venosa profunda o embolia pulmonar, de impor clín
    k.Antec de infec por el virus de la inmunod humana, de tuberculosis o de infec crónica por el virus de la hep B o C
    l.Cáncer o antec de cáncer en los últi 5 años, excepto carcinoma de piel distinto del melanoma debidam tratado
    m.Paci embar, en período de lactan, o que tienen previsto quedarse embar durante el estu
    n. artici en un estu clín de un nuevo producto quím o un medic de vta con receta en los 2 meses antera la selec (o 3 meses en el caso de prod biológsi se desconoce su semivida) o en un período de 5 semividas, lo que suponga más tiempo, o participa en curso en otro est de un PEI (o prod sanitario)
    o.Exposi previa a un anticuerp monoclonal dirig a la vía del CGRP (como AMG 334, ALD304, LY2951742 o fremanezumab)
    p.Resultado en el ECG de 12 derivaciones basal que el investconsidere clínicamente significativo
    q.Resultado que, según el crit del invest, constituye una anomalía de impor clín, por ej, valores anormales en los análisis de bioquímica séric, de hematología, de la coagulac y de orina (en caso de resultads anómalos se pueden repetir los anális para su confirma)
    r.Enzimas hepáticas (alanina-aminotransferasa, aspartato-aminotransferasa y fosfatasa alcalina) >1,5 × lím sup de la normalidad (LSN) tras su confirma en la repetición del anális o sospecha de lesión hepatocelular que cumpla los crit ley de Hy en la selec
    s.Creatinina sérica >1,5 × LSN, proteinuria clínicame significa o indicios de enfermedad renal en la selecc
    t.Antec de abuso de alcohol en los 2 años anteriores a la selecu.
    Antecedentes de toxicomanía en los 2 años anteriores o de farmacodependencia en los últimos 5 años
    v.El paciente no puede parti o completar el estudio de forma satisfactoria, en opinión de su proveedor de asistencia sanitaria o del investigador, por alguna de las siguientes razones:
    Incapacidad mental o legal o incapacidad de dar su cons por cualquier razón
    En custodia por una decisión adminis o legal, en tutelaje o ingresado en un centro sanitario o social.Imposibilidad de contactar con él en caso de emerg
    - Tiene otra enfermedad que, en opinión del invest, hace que no sea apto para su inclusión en el est.
    w. El paciente es un trabajador del centro del estu o del promo que está directamente implic en el estudio o es un familiar de ese tipo de emplea
    x. El paciente no ha superado el proced de selección del est anteriorm
    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
    El criterio de valoración principal de la eficacia es la variación media con respecto al valor basal (período de preinclusión de 28 días) del número promedio de días del mes con migraña durante el período de 12 semanas siguiente a la 1.a dosis de 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.
    Las evaluaciones finales del estudio se realizarán en la visita 8 (visita de fin del tratamiento [FdT]), aproximadamente 4 semanas después de la administración de la última dosis de 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
    - Proporción de pacientes que alcanzan una reducción del número promedio de días del mes con migraña de por lo menos el 50 % durante el período de 12 semanas siguiente a la 1.a dosis de fremanezumab.
    - Variación media con respecto al valor basal (período de preinclusión de 28 días) del número promedio de días del mes con cefalea de intensidad al menos moderada durante el período de 12 semanas siguiente a la 1.a dosis de fremanezumab.
    - Variación media con respecto al valor basal (período de preinclusión de 28 días) del número promedio de días del mes con migraña durante el período de 4 semanas siguiente a la 1.ª dosis de fremanezumab.
    - Proporción de pacientes que alcanzan una reducción del número promedio de días del mes con migraña de por lo menos el 50 % durante el período de 4 semanas siguiente a la 1.ª dosis de fremanezumab.
    - Variación media con respecto al valor basal (período de preinclusión de 28 días) del número promedio de días del mes de utilización de algún medicamento para la cefalea aguda durante el período de 12 semanas siguiente a la 1.ª dosis de fremanezumab.
    - Variación media con respecto al valor basal (período de preinclusión de 28 días) del número de días con cefalea de intensidad al menos moderada durante el período de 4 semanas siguiente a la 1.ª dosis de fremanezumab.
    - Incidencia de acontecimientos adversos a lo largo del estudio.
    - Resultados de los análisis clínicos (bioquímica sérica, hematología, coagulación y análisis de orina) en puntos temporales especificados.
    - Mediciones de las constantes vitales (tensión arterial sistólica y diastólica, temperatura oral y pulso) en cada visita. Nota: además, se medirán la saturación de oxígeno y la frecuencia respiratoria en caso de sospecha de anafilaxia e hipersensibilidad grave.
    - Resultados del ECG de 12 derivaciones en puntos temporales especificados.
    - Uso de medicamentos concomitantes por acontecimientos adversos durante el estudio.
    - Número (%) de pacientes que no finalicen el estudio debido a los acontecimientos adversos.
    - Cambios de importancia clínica en las exploraciones físicas, incluido el peso corporal.
    - Incidencia de reacciones de anafilaxia o de hipersensibilidad graves.
    - Ideas y conductas suicidas determinadas mediante la C-SSRS electrónica
    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.
    Las evaluaciones finales del estudio se realizarán en la visita 8 (visita de fin del tratamiento [FdT]), aproximadamente 4 semanas después de la administración de la última dosis de 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 concerned12
    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
    UVUP
    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 state71
    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.
    Al final del período de tratamiento de 24 semanas, se espera que los pacientes vuelvan a la atención de sus médicos tratantes.
    El promotor no planea ningún tratamiento después de completar el período de tratamiento de 24 semanas y el estudio. Los pacientes deben ser tratados con el estándar de atención después de la retirada o la terminación del período de tratamiento de 24 semanas, según proceda.
    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 Decision2018-01-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-01-12
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-05-29
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