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    Summary
    EudraCT Number:2016-003278-42
    Sponsor's Protocol Code Number:TV48125-CNS-30056
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2017-01-04
    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 number2016-003278-42
    A.3Full title of the trial
    A Multicenter, Randomized, Double-Blind, Double-Dummy, Placebo Controlled, Parallel Group Study Comparing the Efficacy and Safety of 2 Dose Regimens (Intravenous/Subcutaneous and Subcutaneous) of TEV-48125 versus Placebo for the Prevention of Episodic Cluster Headache
    Estudio multicéntrico, aleatorizado, de doble enmascaramiento, con doble placebo, controlado con placebo y de grupos paralelos que compara la eficacia y la seguridad con pautas de 2 dosis (intravenosa/subcutánea y subcutánea) de la administración de TEV-48125 frente a placebo para la prevención de la cefalea en racimos episódica
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical trial investigating the efficacy and safety of investigational drug TEV-48125 developed to prevent cluster headache
    Ensayo clínico que investiga la eficacia y la seguridad del fármaco en investigación,TEV-48125, desarrollado para prevenir la cefalea en racimos
    A.4.1Sponsor's protocol code numberTV48125-CNS-30056
    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.5.6E-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 IMPIntravenous 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.IMP: 2
    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 placeboIntravenous use
    D.8 Placebo: 2
    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 Cluster headache (ECH)
    Cefalea en racimos episódica (CRE)
    E.1.1.1Medical condition in easily understood language
    Episodic Cluster headache (ECH)
    Cefalea en racimos episódica (CRE)
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    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 this study is to demonstrate the efficacy of fremanezumab in the prevention of episodic cluster headache (ECH) in adult patients.
    El objetivo principal del estudio es demostrar la eficacia de fremanezumab para la prevención de la cefalea en racimos episódica (CRE) en pacientes adultos.
    E.2.2Secondary objectives of the trial
    A secondary objectives of this study are
    1. to further demonstrate the efficacy of fremanezumab in the prevention of ECH in adult patients.
    2. to evaluate the safety of fremanezumab in adult patients with ECH.
    Los objetivos secundarios del studio son
    1. demostrar con más detalle la eficacia de fremanezumab para la prevención de la CRE en pacientes adultos.
    2. evaluar la seguridad de fremanezumab en pacientes adultos con CRE.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    a.Patients are capable of giving signed informed consent as described in Appendix D which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
    b.The patient is a man or woman 18 to 70 years of age, inclusive.
    c.The patient has a history of ECH according to ICHD-3 beta criteria (Headache Classification Committee of the IHS 2013) for ≥12 months prior to screening including the following:
    -Attacks of severe, strictly unilateral pain which is orbital, supraorbital, temporal or in any combination of these sites, lasting 15 to 180 minutes and occurring from once daily every other day to 8 times a day for more than half of the time when the disorder is active
    -The pain is associated with at least 1 of the following symptoms or signs: ipsilateral conjunctival injection, lacrimation, nasal congestion, rhinorrhoea, forehead and facial sweating, miosis and/or ptosis and/or eyelid oedema, and/or sense of restlessness or agitation.
    -CH attacks occurring in periods lasting from 7 days to 1 year, separated by pain-free periods lasting at least 1 month.
    -CH attacks have started no more than 2 weeks (15 days, inclusive) prior to screening and, based on the patient’s previous medical history, it is expected that the patient’s CH attacks will continue for ≥6 weeks after the screening visit.
    d.The patient has a total body weight of ≥45 kg
    e.The patient is not using or using a maximum of 2 concomitant medications that are commonly prescribed as preventive treatments for CH , regardless of the indication for which the medication was prescribed. Patients must be on a stable dose and regimen for at least 2 weeks prior to screening and throughout the study.
    f.The patient has demonstrated compliance with the electronic headache diary during the run-in period by entry of headache data on 85% of days during the run-in period.
    g.The patient has at least 7 CH attacks during the run-in period.
    h.The patient is in good health in the opinion of the investigator as determined by a medical and psychiatric history; medical examination; 12 lead ECG; and serum chemistry, hematology, coagulation, and urinalysis.
    i.Women may be included only if they have a negative serum beta-human chorionic gonadotropin (β-HCG) test at screening, are sterile, or postmenopausal.
    j.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 (ie, starting at screening) and for 7.5 months after discontinuation of IMP.
    k.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 7.5 months after discontinuation of the IMP. Definitions of WOCBP, sterile, and postmenopausal women; male contraception; and highly effective and acceptable birth control methods
    l.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.Son capaces de entregar el consentimiento informado firmado tal y como se indica en el Anexo D donde se incluye conformidad con los requisitos y las restricciones enumerados en el documento de consentimiento informado (ICF) y en este protocolo.
    b.Son hombres o mujeres de 18 a 70 años de edad inclusive.
    c.Presentan antecedentes de CRE según los criterios de la ICHD-3 beta (Comité de Clasificación de las Cefaleas de la IHS 2013) durante ≥ 12 meses antes de la selección con:
    Crisis de dolor intenso y estrictamente unilateral en la región orbitaria, supraorbitaria, temporal o en cualquier combinación de estas regiones con una duración de 15 a 180 minutos y una frecuencia que oscila entre una vez al día en días alternos y 8 veces al día durante más del 50 % del tiempo en el que el trastorno está activo
    El dolor se asocia a, al menos, 1 de los síntomas o signos siguientes: Inyección conjuntival ipsilateral, lagrimeo, congestión nasal, rinorrea, sudoración frontal y facial, miosis y/o ptosis y/o edema parpebral y/o sensación de inquietud o agitación.
    Crisis de CR que se manifiestan en periodos de 7 días a 1 año, separadas por periodos sin dolor que duran al menos 1 mes.
    Inicio de las crisis de CR máximo 2 semanas (15 días, inclusive) antes de la selección y, según los antecedentes médicos del paciente, se espera que continúen durante ≥ 6 semanas después de la visita de selección.
    d.Peso total ≥ 45 kg
    e.Un máximo de 2 medicamentos concurrentes que se prescriben habitualmente como tratamiento profiláctico para la CR (Anexo H), independientemente de la indicación para la que ha sido prescrito el medicamento. No se debe modificar la dosis ni la pauta posológica del paciente durante al menos 2 semanas antes de la selección y hasta que finalice el estudio.
    f.Introducción de la información sobre sus cefaleas en el diario de cefalea electrónico el 85 % de los días del periodo de rodaje.
    g.Sufre al menos 7 crisis de CR durante el periodo de rodaje.
    h.Según el investigador y teniendo en cuenta los antecedentes clínicos y psiquiátricos del paciente, el reconocimiento médico, el ECG de 12 derivaciones así como la bioquímica sérica, la hematología, la coagulación y la analítica de orina, el paciente goza de buena salud.
    i.Las mujeres podrán participar únicamente si, en el momento de la selección, son estériles, posmenopáusicas o presentan un resultado negativo en la prueba de la gonadotropina coriónica humana (subunidad beta) en suero (β-HCG). Las definiciones de estéril y posmenopáusica se muestran en el Anexo E.
    j.Las mujeres en edad fértil con pareja potencialmente fértil (es decir, no sometido a vasectomía) deben emplear métodos de control de la natalidad durante todo el estudio (es decir, desde la selección) y los 7,5 meses posteriores a la interrupción del tratamiento con el PEI.
    k.Los hombres deben ser estériles o, si son potencialmente fértiles/pueden reproducirse (no estériles por causas naturales o quirúrgicas [p.ej.: vasectomía]) y sus parejas están en edad fértil, debe emplear tanto ellos como sus parejas, métodos de control de la natalidad válidos durante todo el estudio y los 7,5 meses siguientes a la interrupción del tratamiento con el PEI. Las definiciones de mujer en edad fértil, estéril y posmenopáusica así como de contracepción masculina y métodos de control de la natalidad muy eficaces y válidos (incluido ejemplos) se muestran en el Anexo E.
    l.Estar dispuesto y poder cumplir con las restricciones del estudio, permanecer en el centro médico durante el tiempo necesario en el periodo de estudio y volver para las evaluaciones de seguimiento tal y como se indica en el protocolo.
    E.4Principal exclusion criteria
    a.The patient has used short corticosteroid cycle to treat the current CH cycle.
    b.The patient reports using butalbital on more than 7 days during the 4 weeks prior to screening or using butalbital on more than 3 days during the screening/run-in period.
    c.The patient reports using opioids on more than 15 days during the 4 weeks prior to screening or using opioids on more than 4 days during the screening/run-in period.
    d.The patient has used an intervention/device (eg, scheduled nerve blocks) for headache during the 4 weeks prior to screening.
    e.The patient has clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, genitourinary, cardiac, neurologic, hepatic, or ocular disease at the discretion of the investigator.
    f.The patient has evidence or medical history of clinically significant psychiatric issues determined at the discretion of the investigator.
    g.The patient has a history of any suicide attempt in the past or current active suicidal ideation, as measured by the eC-SSRS.
    h.The patient has a history of clinically significant cardiovascular disease or vascular ischemia (such as myocardial, neurological [eg, 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
    i.The patient has known infection or history of human immunodeficiency virus, tuberculosis, or chronic hepatitis B or C infection.
    j.The patient has a past or current history of cancer in the past 5 years, except for appropriately treated non-melanoma skin carcinoma.
    k.The patient is pregnant or nursing.
    l.The patient has a history of hypersensitivity reactions to injected proteins, including monoclonal antibodies.
    m.The patient has participated in a clinical study of a new chemical entity or a prescription medicine within 2 months or 5 half-lives before administration of the first dose of the IMP, whichever is longer.
    n.The patient has participated in a clinical study of a monoclonal antibody, unless it is known that the patient received placebo during the study.
    o.The patient has a history of prior exposure to a monoclonal antibody targeting the CGRP pathway (AMG 334, ALD304, LY2951742, or fremanezumab).
    p.The patient has any finding in the baseline 12 lead ECG considered clinically significant in the judgment of the investigator.
    q.The patient has any finding that, in the 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.The patient has hepatic enzymes (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) >1.5 × the upper limit of normal (ULN) range after confirmation in a repeat test, or the patient has suspected hepatocellular damage that fulfills criteria for Hy’s law at screening.
    s.The patient has serum creatinine >1.5 × the ULN or evidence of clinically significant renal disease in the judgement of the investigator.
    t.The patient cannot participate or successfully complete the study, in the opinion of their healthcare provider or the 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 the study
    u.The patient is an employee of the sponsor/participating study center who is directly involved in the study or is the relative of such an employee.
    v.The patient has an implant for neurostimulation used in the treatment of CH.
    w.The patient is a member of a vulnerable population (eg, people kept in detention).
    x.The patient has a history of alcohol abuse prior to screening.
    a.Ha recibido ciclos cortos de corticoides para tratar el ciclo de CR actual.
    b.Ha tomado butalbital en más de 7 ocasiones durante las 4 semanas previas a la selección o en más de 3 durante el periodo de selección/de rodaje.
    c.Ha tomado opiáceos en más de 15 ocasiones durante las 4 semanas previas a la selección o en más de 4 durante el periodo de selección/de rodaje.
    d.Ha usado un dispositivo/intervención (p. ej: bloqueo nervioso programado) para la cefalea en las 4 semanas anteriores a la selección.
    e.Padece alguna enfermedad hemática, renal, endocrina, pulmonar, gastrointestinal, cardíaca, neurológica, hepática u ocular clínicamente significativa.
    f.Según el investigador presenta indicios o antecedentes médicos de problemas psiquiátricos clínicamente significativos.
    g.Tiene antecedentes de intento de suicidio o ideación suicida activa en la actualidad determinado por la eC-SSRS.
    h.Presenta antecedentes de enfermedad cardiovascular o isquemia vascular (como isquemia de miocardio, neurológica [p.ej.: isquemia cerebral] o periférica u otras afecciones isquémicas) o acontecimientos tromboembólicos (trombosis venosa o arterial o acontecimientos embólicos) tales como accidente cerebrovascular (a saber, accidente isquémico transitorio), trombosis venosa profunda o embolismo pulmonar.
    i.Sufre Infección conocida o ha tenido infección por el virus de la inmunodeficiencia humana, la tuberculosis o la hepatitis B o C.
    j.Padece o ha padecido cáncer en los últimos 5 años, salvo si se trata de un carcinoma de piel (no melanoma) tratado de forma adecuada.
    k.Mujeres embarazadas o que estén amamantando.
    l.Tiene antecedentes de reacciones de hipersensibilidad a proteínas inyectadas entre ellas anticuerpos monoclonales.
    m.Ha participado en un estudio clínico con un producto químico nuevo o un medicamento de receta en los 2 meses o 5 semividas (el periodo más largo) anteriores a la administración de la primera dosis de PEI.
    n.Ha participado en un estudio clínico con un anticuerpo monoclonal, a menos que el paciente recibiera placebo en dicho estudio.
    o.Ha sido expuesto previamente a un anticuerpo monoclonal contra la vía del CGRP (AMG 334, ALD304, LY2951742, o fremanezumab).
    p.Presenta al inicio del estudio un resultado del ECG de 12 derivaciones considerado, según el investigador, como clínicamente significativo.
    q.El investigador considera que presenta algún resultado alterado clínicamente significativo en las pruebas de bioquímica sérica, hematología, coagulación y en la analítica de orina (las pruebas con resultados alterados podrán repetirse para confirmar el resultado).
    r.Los valores de las enzimas hepáticas (alaninaaminotransferasa [ALT] y aspartatoaminotransferasa [AST]) en el periodo de selección y tras repetir la prueba para confirmar los resultados, son > 1,5 × límite superior de la normalidad (ULN) o se sospecha lesión hepatocelular que cumple los criterios de la ley de Hy.
    s.Presenta un valor de creatinina en suero > 1,5 × el ULN o indicios de enfermedad renal considerada, según el investigador, clínicamente significativa.
    t.Según el médico del paciente o el investigador, no puede participar en el estudio o finalizarlo por alguno de los siguientes motivos:
    incapacidad legal o psíquica o bien incapaz de cumplimentar el consentimiento informado por alguna razón
    estar en custodia por un motivo administrativo o legal, bajo tutela o admitido en una institución social o un sanatorio
    imposibilidad de contactar con el paciente en caso de emergencia padece otra afección que, en opinión del investigador, le haría incompatible con su inclusión en el estudio.
    u.es un empleado del centro de estudio promotor o participante directamente relacionado con el estudio o es pariente de este empleado.
    v.tiene un implante de neuroestimulación para el tratamiento de la CR.
    w.forma parte de una población vulnerable (p.ej.: está detenido).
    x.tiene antecedentes de abuso de alcohol previos al periodo de selección.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint of this study is the mean change from baseline (run-in period) in the weekly average number of cluster headache (CH) attacks during the 4-week period after administration of the first dose of the IMP, ie, based on week 0 to 4 data.
    El criterio principal de valoración de la eficacia de este estudio es el cambio medio respecto al inicio (periodo de rodaje) en el número medio de crisis de cefaleas en racimos (CR) semanales durante el periodo de 4 semanas tras la administración de la primera dosis del PEI, es decir, a partir de los datos obtenidos de la semana 0 a la 4.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 4
    Semana 4
    E.5.2Secondary end point(s)
    1.the proportion of patients with a ≥50% reduction from baseline (run-in period) in the weekly average number of CH attacks during the 4 week period after the first dose of the IMP, ie, based on week 0 to 4 data
    2.the mean change from baseline (run-in period) in the number of CH attacks during the 12 week period after administration of the first dose of the IMP, ie, based on week 0 to 12 data
    3.the mean change from baseline (run-in period) in the number of CH attacks during the 4 week period after administration of the third dose of the IMP, ie, based on week 8 to 12 data
    4.the mean change from baseline (run-in period) in the weekly average number of days with use of cluster-specific acute headache medications (triptans and ergot compounds) during the 12 week period after administration of the first dose of the IMP, ie, based on week 0 to 12 data
    5.the mean change from baseline (run-in period) in the weekly average number of days oxygen is used to treat ECH during the 12-week period after administration of the first dose of the IMP, ie, based on week 0 to 12 data
    6.assessment of patient’s perceived improvement, as measured by the Patient-Perceived Satisfactory Improvement (PPSI) at 1, 4, 8, and 12 weeks after administration of the first dose of the IMP relative to baseline (day 0)
    The secondary safety endpoints are as follows:
    1.occurrence of adverse events throughout the study
    2.clinical laboratory (serum chemistry, hematology, coagulation, and urinalysis) test results at each visit
    3.vital signs (systolic and diastolic blood pressure, oral temperature, and pulse rate) measurements at each visit. Note: Oxygen saturation will be measured in cases of suspected anaphylaxis and severe hypersensitivity. Respiratory rate will also be measured in these cases but not as a standard vital sign.
    4.12 lead electrocardiogram (ECG) findings at screening, baseline, and week 12
    5.use of concomitant medication during the study
    6.clinically significant changes in physical examinations, including body weight
    7.injection site reaction (ie, erythema, induration, and ecchymosis) and injection site pain assessments
    8.occurrence of hypersensitivity/anaphylaxis reactions
    9.suicidal ideation and behavior as measured by the electronic Columbia Suicide Severity Rating Scale (eC-SSRS)
    1.El criterio principal de valoración de la eficacia de este estudio es el cambio medio respecto al inicio (periodo de rodaje) en el número medio de crisis de cefaleas en racimos (CR) semanales durante el periodo de 4 semanas tras la administración de la primera dosis del PEI, es decir, a partir de los datos obtenidos de la semana 0 a la 4.
    2.el cambio medio del número de crisis de CR semanales desde el inicio del estudio (periodo de rodaje) y durante las 12 semanas siguientes a la administración de la primera dosis de PEI, es decir, datos obtenidos de la semana 0 a la semana 12.
    3.el cambio medio del número de crisis de CR semanales desde el inicio del estudio (periodo de rodaje) y durante las 4 semanas siguientes a la administración de la tercera dosis de PEI, es decir, datos obtenidos de la semana 8 a la semana 12.
    4.el cambio medio del número de días con administración de medicamentos específicos para la cefalea aguda en racimos (triptanes y ergotamínicos) desde el inicio del estudio (periodo de rodaje y durante las 12 semanas siguientes a la administración de la primera dosis de PEI, es decir, datos obtenidos de la semana 0 a la semana 12).
    5.el cambio medio del número promedio semanal de días en los que se administró oxígeno para tratar la CRE desde el inicio del estudio (periodo de rodaje) y durante las 12 semanas siguientes a la administración de la primera dosis de PEI, es decir, datos obtenidos de la semana 0 a la semana 12.
    6.evaluación de la mejoría percibida por los pacientes, determinado mediante la mejoría satisfactoria percibida por el paciente (PPSI) en las semanas 1, 4, 8 y 12 siguientes a la administración de la primera dosis de PEI en relación al inicio del estudio (día 0)
    Los criterios de seguridad secundarios son los siguientes:
    1.aparición de acontecimientos adversos durante el estudio
    2.pruebas de laboratorio (bioquímica sérica, hematología, coagulación y analítica de orina) en cada visita
    3.Toma de constantes vitales (presión arterial sistólica y diastólica, temperatura oral y frecuencia del pulso) en cada visita. Nota: En caso de sospecha de anafilaxia e hipersensibilidad extrema, se determinará la saturación de oxígeno. En estos casos, también se medirá la frecuencia respiratoria, pero no como una constante vital estándar.
    4.electrocardiograma (ECG) de 12 derivaciones en la selección, el inicio del estudio y la semana 12.
    5.administración de tratamientos concurrentes durante el estudio
    6.cambios de interés clínico en las exploraciones físicas tales como el peso
    7.reacción en la zona de inyección (es decir, eritema, induración y equimosis) y dolor en la zona de inyección
    8.aparición de reacciones de hipersensibilidad/anfilaxia
    9.ideación y comportamiento suicidas determinados por la escala Columbia electrónica de evaluación del riesgo de suicidio (eC-SSRS)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy:
    1. week 4,
    2. week 12
    3. week 8 to 12
    4-6. week 12
    Safety:
    1-9. Week 12
    Eficacia:
    1. semana 4,
    2. semana 12
    3. semanas 8 a 12
    4-6. semana 12
    Seguridad:
    1-9. semana 12
    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 Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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 No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Different dosing regimen of fremanezumab
    E.8.2.4Number of treatment arms in the trial3
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA35
    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
    Australia
    Canada
    Finland
    Germany
    Israel
    Italy
    Netherlands
    Poland
    Spain
    Sweden
    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 (ultima visita ultimo paciente)
    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 months2
    E.8.9.1In the Member State concerned days13
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months9
    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: 284
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 16
    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 state26
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 98
    F.4.2.2In the whole clinical trial 300
    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)
    After trial completion, patients may be offered to enter into a long-term safety study (TV48125-CNS-30058). A separate protocol will be issued for the long term safety study. Patients who do not enroll in the study for any reason may be offered the option to enter the study for the purpose of evaluating ADAs, fremanezumab concentrations, and safety (adverse events and concomitant medications) at approximately 7.5 months after administration of the last dose of the IMP.
    Tras el fin del estudio, se puede ofrecer la oportunidad de participar en un estudio de seguridad a largo plazo(TV48125-CNS-30058).Se elaborará otro protocolo para el estudio de seguridad a largo plazo.A los pacientes que no deseen participar en este estudio se les podrá ofrecer entrar en el estudio para evaluar las concentraciones de los AAF y fremanezumab y la seguridad (acontecimientos adversos y medicamentos concurrentes) unos 7,5 meses después de la administración de la última dosis de PEI.
    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 Decision2017-03-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-03-16
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2019-04-23
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