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    Summary
    EudraCT Number:2016-003171-21
    Sponsor's Protocol Code Number:TV48125-CNS-30057
    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 number2016-003171-21
    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 Chronic Cluster Headache
    Estudio multicéntrico, aleatorizado, de doble enmascaramiento, con doble simulación, controlado por placebo y de grupos paralelos que compara la eficacia y la seguridad de 2 pautas posológicas (intravenosa/subcutánea y subcutánea) de TEV-48125 frente a placebo para la prevención de la cefalea en racimos crónica
    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 chronic cluster headache
    Un ensayo clínico que investiga la eficacia y seguridad del producto en investigación TEV-48125 desarrollado para prevenir la cefalea crónica en racimos.
    A.4.1Sponsor's protocol code numberTV48125-CNS-30057
    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
    Chronic Cluster headache (CCH)
    Cefalea en racimos crónica (CRC )
    E.1.1.1Medical condition in easily understood language
    Chronic Cluster headache (CCH)
    Cefalea en racimos crónica (CRC)
    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 CCH in adult patients.
    El objetivo principal de este estudio es demostrar la eficacia de fremanezumabTEV 48125 en la prevención de CRC 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 CCH in adult patients.
    2. to evaluate the safety of fremanezumab in adult patients with CCH.
    Objetivos secundarios de este estudio son:
    1.demostrar en mayor medida la eficacia de fremanezumab en la prevención de CRC en pacientes adultos.
    2. evaluar la seguridad de fremanezumab en pacientes adultos con CRC.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    a.Patients are capable of giving signed informed consent 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 history of CCH 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, rhinorrhea, forehead and facial sweating, miosis and/or ptosis and/or eyelid edema, and/or sense of restlessness or agitation.
    - CH attacks occurring for more than 1 year without remission, or with remission periods lasting less than 1 month.
    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 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 10 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.
    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. Los pacientes tienen capacidad para proporcionar el consentimiento informado firmado como se describe en el Apéndice D, que incluye el cumplimiento de los requisitos y las restricciones enumerados en el formulario de consentimiento informado (FCI) y en este protocolo.
    b. El paciente, hombre o mujer, tiene entre 18 y 70 años de edad, ambos inclusive.
    c. El paciente tiene antecedentes de CRC según los criterios de ICHD-3 beta (Headache Classification Committee de la IHS 2013) durante ≥12 meses antes de la selección, que incluyen lo siguiente:
    – episodios de dolor intenso, estrictamente unilateral, orbital, supraorbital, temporal o en cualquier combinación de estas zonas, de 15 a 180 minutos de duración, que se producen entre una vez al día en días alternos y 8 veces al día durante más de la mitad del tiempo cuando el trastorno está activo.
    – Dolor asociado a, al menos, uno de los siguientes síntomas o signos: inyección conjuntival homolateral, lagrimeo, congestión nasal, rinorrea, sudoración en la frente y en la cara, miosis y/o ptosis y/o edema de párpado, y/o sensación de inquietud o agitación.
    – episodios de CR que se produzcan durante más de 1 año sin remisión o con periodos de remisión que duren menos de 1 mes.
    d. El paciente tiene un peso corporal total ≥45 kg.
    e. El paciente no está usando o, como máximo, está usando 2 medicaciones concomitantes que se prescriban habitualmente como tratamientos preventivos de la CR (Apéndice H), independientemente de la indicación para la que se prescribiera la medicación. El paciente debe mantener una dosis y una pauta posológica estables durante al menos las 2 semanas anteriores a la selección y a lo largo del estudio.
    f. El paciente ha demostrado utilizar según lo estipulado el diario electrónico de cefaleas durante el periodo de preinclusión, con la introducción de datos sobre cefaleas el 85% de los días durante este periodo.
    g. El paciente tiene al menos 10 episodios de CR durante el periodo de preinclusión.
    h. En opinión del investigador, el paciente se encuentra en un buen estado de salud, determinado por el historial médico y psiquiátrico; un examen médico; un ECG de 12 derivaciones; así como las pruebas analíticas de bioquímica sérica, hematología, coagulación y análisis de orina.
    i. Las mujeres podrán ser incluidas en el estudio únicamente si tienen una prueba de gonadotropina coriónica humana beta (β-HCG) negativa en suero en el momento de la selección o si son estériles o posmenopáusicas. Las definiciones de estéril y posmenopáusica se pueden encontrar en el Apéndice E.
    j. Las mujeres con capacidad de procrear (MCCDP) cuyas parejas masculinas sean potencialmente fértiles (es decir, sin vasectomía) deben usar métodos de control de la natalidad muy eficaces durante todo el estudio (a partir de la selección) y durante los 7,5 meses posteriores a la interrupción del tratamiento con el MEI.
    k. Los hombres deberán ser estériles o, si son potencialmente fértiles/tienen capacidad reproductiva (no se han sometido a esterilización quirúrgica [p. ej., vasectomía] ni son estériles de forma congénita) y tienen parejas del sexo femenino con capacidad de procrear, deben usar, junto con sus parejas, métodos de control de la natalidad aceptables durante todo el estudio y durante los 7,5 meses posteriores a la interrupción del MEI. Las definiciones de MCCDP, mujeres estériles y posmenopáusicas, contracepción masculina y métodos de control de la natalidad aceptables y muy eficaces, incluidos ejemplos, se pueden encontrar en el Apéndice E.
    l. El paciente debe estar dispuesto y ser capaz de cumplir con las restricciones del estudio, permanecer en la clínica el tiempo necesario durante el periodo del estudio y volver a la clínica para las evaluaciones de seguimiento, tal como se indica en este 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 10 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 15 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. El paciente ha utilizado un ciclo de corticoesteroides corto para el tratamiento del ciclo de CR actual.
    b. El paciente afirma haber utilizado butalbital en más de 7 días durante las 4 semanas anteriores a la selección o haber utilizado butalbital en más de 10 días durante el periodo de selección/preinclusión.
    c. El paciente afirma haber utilizado opioides en más de 15 días durante las 4 semanas anteriores a la selección o haber utilizado opioides en más de 15 días durante el periodo de selección/preinclusión.
    d. El paciente ha utilizado una intervención o un dispositivo (por ejemplo, bloqueos de nervios programados) para la cefalea durante las 4 semanas anteriores a la selección.
    e. El paciente tiene una enfermedad hematológica, renal, endocrina, pulmonar, gastrointestinal, genitourinaria, cardiaca, neurológica, hepática u ocular, según el criterio del investigador.
    f. El paciente presenta evidencias o tiene antecedentes médicos de problemas psiquiátricos clínicamente significativos, según el criterio del investigador.
    g. El paciente tiene antecedentes de intento de suicidio o ideación suicida activa, según determina el eC-SSRS.
    h. El paciente tiene antecedentes de enfermedad cardiovascular clínicamente significativa o isquemia vascular (tal como isquemia miocárdica, neurológica [p. ej., isquemia cerebral], isquemia periférica de extremidades u otro acontecimiento isquémico) o acontecimientos tromboembólicos (acontecimientos trombóticos o embólicos arteriales o venosos), tales como accidente cerebrovascular (incluidos episodios isquémicos transitorios), trombosis venosa profunda o embolia pulmonar.
    i. El paciente tiene infección confirmada o antecedentes de infección por el virus de inmunodeficiencia humana (VIH), tuberculosis o hepatitis crónica por infección por el virus de la hepatitis B o C.
    j. El paciente tiene antecedentes de cáncer en los últimos 5 años o cáncer activo, excepto carcinoma cutáneo no melanómico tratado adecuadamente.
    k. La paciente está embarazada o en periodo de lactancia.
    l. El paciente tiene antecedentes de reacciones de hipersensibilidad a proteínas inyectadas, incluidos anticuerpos monoclonales.
    m. El paciente ha participado en un estudio clínico de un nuevo compuesto químico o un medicamento con receta en los 2 meses o 5 semividas anteriores a la administración de la primera dosis del MEI, lo que sea mayor.
    n. El paciente ha participado en un estudio clínico de un anticuerpo monoclonal, a menos que se confirme que el paciente recibió placebo durante el estudio.
    o. El paciente tiene antecedentes de exposición previa a un anticuerpo monoclonal cuya diana sea la ruta de CGRP (AMG 334, ALD304, LY2951742 o fremanezumab).
    p. El paciente tiene algún hallazgo en el ECG de 12 derivaciones realizado al inicio del estudio que se considera relevante desde un punto de vista clínico, a juicio del investigador.
    q. El paciente tiene cualquier hallazgo que, a juicio del investigador, constituye una anomalía de relevancia clínica, incluidos los resultados de los análisis de bioquímica sérica, hematología, coagulación y orina (los análisis con anomalías se pueden repetir para fines de confirmación).
    r. El paciente tiene un nivel de enzimas hepáticas (alanina aminotransferasa [ALT] y aspartato aminotransferasa [AST]) >1,5 × el límite superior de la normalidad (LSN) tras confirmación en una repetición de la prueba o sospecha de lesión hepatocelular que cumpla los criterios de la ley de Hy en la selección.
    s. El paciente tiene un nivel de creatinina en suero >1,5 × el LSN o signos de enfermedad renal clínicamente significativa, a juicio del investigador.
    t. El paciente no puede participar o completar correctamente el estudio, en opinión de su médico o del investigador, por cualquiera de las razones siguientes:
    – mental o legalmente incapacitado o incapaz de dar su consentimiento por cualquier motivo
    – en custodia debido a una decisión legal o administrativa, bajo tutela o ingresado en un sanatorio o una institución social
    – imposibilidad de contactar con él en caso de emergencia
    – padece cualquier otra afección que, en opinión del investigador, lo haría inadecuado para su inclusión en el estudio
    u. El paciente es un empleado del promotor o del centro participante en el estudio que está implicado directamente en el estudio o es familiar de tal empleado.
    v. El paciente tiene un implante para neuroestimulación para el tratamiento de CR.
    w. El paciente es miembro de una población vulnerable (p. ej., personas detenidas).
    x. El paciente tiene antecedentes de abuso del alcohol antes de la 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 monthly average number of cluster headache (CH) attacks during the 12-week period after administration of the first dose of the IMP, ie, based on week 0 to 12 data.
    El criterio principal de valoración de eficacia del estudio es el cambio medio desde el inicio del estudio (periodo de preinclusión) en el número medio de crisis de cefaleas en racimos (CR) mensuales durante las 12 semanas siguientes a la administración de la primera dosis del PEI, es decir, a partir de los datos obtenidos de la semana 0 a la semana 12.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 12
    Semana 12
    E.5.2Secondary end point(s)
    The secondary efficacy endpoints to further demonstrate efficacy are:
    1.the proportion of patients with a ≥50% reduction from baseline (run-in period) in the monthly average number of CH attacks over the 12-week period after the administration of the first dose of the IMP, ie, based on week 0 to 12 data
    2. mean change from baseline (run-in period) in the number of CH attacks during the 4 week period after administration of the first dose of the IMP, ie, based on week 0 to 4 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 CCH 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)
    Los criterios de valoración secundarios de eficacia para demostrar en mayor medida la eficacia son los siguientes:
    1-La proporción de pacientes con una reducción ≥50 % respecto al valor de referencia (periodo de preinclusión) en el número medio semanal de crisis de CR durante el periodo de 12 semanas tras la administración de la primera dosis del PEI, es decir, a partir de los datos obtenidos de la semana 0 a la 12.
    2-Promedio de cambio respecto al valor de referencia (periodo de preinclusión) en el número de episodios de CR durante el periodo de 4 semanas tras la administración de la primera dosis del MEI, es decir, sobre la base de los datos de las semanas 0 a 4.
    3-Promedio de cambio respecto al valor de referencia (periodo de preinclusión) en el número de episodios de CR durante el periodo de 4 semanas tras la administración de la tercera dosis del MEI, es decir, sobre la base de los datos de las semanas 8 a 12.
    4-Promedio de cambio respecto al valor de referencia (periodo de preinclusión) en el número medio semanal de días en los que se utilizan medicamentos específicos para la cefalea aguda en racimos (compuestos de cornezuelo y triptanos) durante el periodo de 12 semanas tras la administración de la primera dosis del MEI, es decir, sobre la base de los datos de las semanas 0 a 12.
    5-Promedio de cambio respecto al valor de referencia (periodo de preinclusión) en el número medio semanal de días en los que se utiliza oxígeno para tratar la CRC durante el periodo de 12 semanas tras la administración de la primera dosis del MEI, es decir, sobre la base de los datos de las semanas 0 a 12.
    6-Evaluación de la mejora percibida por el paciente, respecto al valor de referencia (día 0), medida mediante la escala PPSI (Patient-Perceived Satisfactory Improvement, Mejora satisfactoria percibida por el paciente) en las semanas 1, 4, 8 y 12 tras la administración de la primera dosis de MEI.
    Los criterios de valoración secundarios de seguridad son los siguientes:
    1-Aparición de acontecimientos adversos durante el estudio.
    2-Resultados de las pruebas de laboratorio clínicas (análisis de bioquímica sérica, hematología, coagulación y orina) en cada visita.
    3-Medición de las constantes vitales (presión arterial sistólica y diastólica, temperatura oral y frecuencia del pulso) en cada visita. Nota: Se medirá la saturación de oxígeno en aquellos casos en los que se sospeche anafilaxia e hipersensibilidad intensa. En estos casos, también se medirá la frecuencia respiratoria, pero no como constante vital estándar.
    4-Resultados de electrocardiograma (ECG) de 12 derivaciones en la selección, al inicio del estudio y en la semana 12.
    5-Uso de medicamentos concurrentes durante el estudio.
    6-Cambios de transcendencia clínica en las exploraciones físicas, incluida la variación del peso corporal.
    7-Reacción en la zona de inyección (eritema, induración y equimosis) y exploraciones del dolor en la zona de inyección.
    8-Incidencia de reacciones de anafilaxia e hipersensibilidad.
    9-Evaluación de la ideación y del comportamiento suicidas utilizando la Escala Columbia para evaluar el riesgo de suicidio en formato electrónico (eC-SSRS).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy:
    1. week 12,
    2. week 4
    3. week 8 to 12
    4-6. week 12
    Safety:
    1-9. Week 12
    Eficacia:
    1. Semana 12
    2. Semana 4
    3. Semana 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
    Administración de diferentes regímenes de dosis de fremanezumab
    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
    Última visita del último paciente.
    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: 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 completar el ensayo, se puede ofrecer a los pacientes la posibilidad de entrar en un estudio a largo plazo (TV48125-CNS-30058) que tendrá un protocolo específico. A los pacientes que no participen en el estudio por cualquier motivo se les puede ofrecer la posibilidad de participar en el estudio para evaluar ADAs, concentraciónes de fremanezumab y seguridad (acontecimientos adversos y medicaciones concomitantes) aproximadamente 7.5 meses después de la administración de la última dosis
    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
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