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    Summary
    EudraCT Number:2017-002441-30
    Sponsor's Protocol Code Number:TV48125-CNS-30068
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-11-04
    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 ConcernedItaly - Italian Medicines Agency
    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
    Studio multicentrico, randomizzato, in doppio cieco, a gruppi paralleli, controllato con placebo, con un periodo in aperto per valutare l¿efficacia e la sicurezza di fremanezumab per il trattamento profilattico dell¿emicrania in pazienti con risposta inadeguata a precedenti trattamenti preventivi
    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
    Studio per valutare se fremanezumab sia efficace nel prevenire l¿emicrania in pazienti che non hanno risposto a precedenti trattamenti preventivi dell¿emicrania
    A.3.2Name or abbreviated title of the trial where available
    A Study to Test if Fremanezumab is Effective in Preventing Migraine in Patients Who Did Not Respond
    Uno studio per testare se Fremanezumab ¿ afficace nella prevenzione dell'emicrania in pazienti che n
    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 number00
    B.5.5Fax number00
    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
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNfremanezumab
    D.3.9.1CAS number 1655501-53-3
    D.3.9.2Current sponsor codeTEV-48125
    D.3.9.4EV Substance CodeSUB181665
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    episodic and chronic migraine
    emicrania cronica ed episodica
    E.1.1.1Medical condition in easily understood language
    episodic and chronic migraine
    emicrania cronica ed episodica
    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
    L¿obiettivo primario dello studio ¿ dimostrare l¿efficacia di fremanezumab somministrato mediante iniezioni sottocutanee (sc) mensili e trimestrali a pazienti adulti affetti da emicrania con risposta inadeguata a 2-4 classi di precedenti trattamenti preventivi rispetto al 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.
    L¿obiettivo secondario dello studio ¿ valutare ulteriormente l¿efficacia di fremanezumab somministrato mediante iniezioni sc mensili e trimestrali a pazienti adulti affetti da emicrania con risposta inadeguata a 2-4 classi di precedenti trattamenti preventivi rispetto al placebo. Un ulteriore obiettivo secondario dello studio ¿ valutare la sicurezza e la tollerabilit¿ di fremanezumab somministrato mediante iniezioni sc mensili e trimestrali a pazienti adulti affetti da emicrania con risposta inadeguata a 2-4 classi di precedenti trattamenti preventivi rispetto al 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 (ß-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. Il paziente è in grado di fornire il consenso informato firmato.
    b. Paziente di sesso maschile e femminile di età compresa tra 18 e 70 anni, inclusi.
    c. Il paziente presenta una diagnosi di emicrania con esordio a = 50 anni di età.
    d. Il paziente è in buona salute secondo il parere degli sperimentatori, in base a quanto determinato dall’anamnesi medica, dall’esame obiettivo, dagli esami di laboratorio e dall’ECG. e. Peso corporeo =45 kg e indice di massa corporea (IMC) entro l’intervallo da 17,5 a 34,9 kg/m2 (inclusi).
    f. Il paziente presenta un’anamnesi di emicrania (secondo i criteri ICHD-3 [IHS 2013]) o il giudizio clinico suggerisce una diagnosi di emicrania (non meglio rappresentata da un’altra diagnosi secondo i criteri ICHD-3) da = 12 mesi precedenti lo screening.
    g. Il paziente soddisfa i seguenti criteri per CM o EM nelle informazioni basali raccolte in maniera prospettica durante il periodo di run-in di 28 giorni: Per i pazienti con CM:
    - Mal di testa manifestato per = 15 giorni
    - Conformità a uno qualsiasi dei seguenti criteri per = 8 giorni:
    ¿ Criteri diagnostici C e D dell’ICHD-3 per 1.1 Emicrania senza aura
    ¿ Criteri B e C dell’ICHD-3 per 1.2 Emicrania con aura
    ¿ Probabile emicrania (un sottotipo di emicrania in cui manca soltanto 1 criterio di emicrania)
    ¿ Il paziente ha utilizzato un triptano o un derivato dell’ergot per trattare un mal di testa accertato Per i pazienti con EM:
    - Mal di testa manifestato per = 6 ma < 15 giorni
    - Conformità a uno qualsiasi dei seguenti criteri per = 4 giorni:
    ¿ Criteri diagnostici C e D dell’ICHD-3 per 1.1 Emicrania senza aura
    ¿ Criteri B e C dell’ICHD-3 per 1.2 Emicrania con aura
    ¿ Probabile emicrania (un sottotipo di emicrania in cui manca soltanto 1 criterio di emicrania)
    ¿ Il paziente ha utilizzato un triptano o un derivato dell’ergot per trattare un mal di testa accertato h. Al momento dello screening, il paziente deve presentare una risposta inadeguata documentata a 2-4 classi di precedenti farmaci preventivi dell’emicrania (come definito nell’ Appendice H ) negli ultimi 10 anni (nella scheda clinica o in base alla conferma del medico curante; si veda l’ Appendice I per la documentazione accettabile del precedente fallimento della terapia). La risposta inadeguata ai precedenti farmaci preventivi dell’emicrania (incluso l’acido valproico) è definita come: nessun miglioramento clinicamente significativo in base al giudizio del medico curante dopo almeno 3 mesi di terapia a una dose stabile considerata appropriata per la prevenzione dell’emicrania secondo le linee guida nazionali accettate o il momento in cui è stato necessario interrompere il trattamento a causa di eventi avversi che lo hanno reso intollerabile da parte del paziente, oppure il farmaco (come definito nell’Appendice H) è controindicato o non adatto al trattamento profilattico dell’emicrania per il paziente. Il periodo di 3 mesi non si applica se il farmaco è intollerabile o controindicato. Qualora onabotulinum tossina A sia stato il precedente farmaco preventivo, devono essere state eseguite almeno 2 serie di iniezioni e devono essere trascorsi almeno 3 mesi dall’ultima serie di iniezioni prima della visita di screening. i. Il paziente acconsente a non iniziare alcun farmaco preventivo per l’emicrania (come definito nell’Appendice H) durante il periodo di run-in, il periodo di trattamento in doppio cieco e il periodo in aperto. Alla visita di screening, devono essere trascorse almeno 5 emivite di questi farmaci da quando il paziente ha assunto un qualsiasi farmaco preventivo per l’emicrania, come definito nell’Appendice H. j. Altri farmaci su prescrizione non riportati nell’Appendice H devono essere stati assunti a dosi stabili per almeno 2 mesi alla visita di screening, senza alcuna previsione di apportare modifiche durante il periodo di trattamento in doppio cieco dello studio. k. Il paziente ha dimostrato conformità al diario elettronico del mal di testa durante il periodo di run-in inserendo dati concernenti il mal di testa nel corso di almeno 24 giorni cumulativi durante il periodo di run-in (conformità al diario di circa l’85%). l. Le donne possono essere incluse soltanto se risultano negative al test sierico della beta-gonadotropina corionica umana (ß-HCG) allo screening, se sono sterili o in post-menopausa. Le definizioni di sterilità e post-menopausa sono riportate nell’Appendice E. m. Le donne in età fertile (WOCBP) i cui compagni sono potenzialmente fertili (ovvero, non vasectomizzati) devono adottare metodi contraccettivi altamente efficaci per la durata dello studio e per il periodo di follow-up (ovvero, a partire dallo screening) e per 6,0 mesi dopo l’interruzione dell’IMP
    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. Al momento della visita di screening, il paziente sta ricevendo un qualsiasi farmaco preventivo per l’emicrania, indipendentemente dall’indicazione medica (come definito nell’Appendice H) per più di 5 giorni e prevede di continuare ad assumere questo farmaco.
    b. Il paziente ha ricevuto onabotulinum tossina A per l’emicrania o per qualsiasi motivo medico o cosmetico che richieda iniezioni nella testa, nel viso o nel collo durante i 3 mesi precedenti la visita di screening.
    c. Il paziente fa uso di farmaci contenenti oppiacei (inclusa codeina) o barbiturici (inclusi butalbital/aspirina/caffeina [Fiorinal®, Actavis plc], butalbital/paracetamolo/caffeina [Fioricet®, Cardinal Health], o qualsiasi altra combinazione contenente butalbital) per più di 4 giorni durante il periodo di run-in per il trattamento dell’emicrania o per qualsiasi altro motivo. d. Il paziente ha fatto uso di un intervento/dispositivo (per es. blocchi nervosi programmati e stimolazione magnetica transcranica) per l’emicrania durante i 2 mesi precedenti lo screening.
    e. Il paziente fa uso di triptani/ergot come terapie preventive per l’emicrania.
    f. Il paziente fa uso di farmaci antinfiammatori non steroidei (FANS) come terapia preventiva per l’emicrania pressoché su base giornaliera per altre indicazioni. Nota: sono consentite basse dosi di aspirina (per es. 81 mg) per la prevenzione di malattie cardiovascolari. g. Il paziente soffre di cefalee non remittenti, definite come cefalee manifestate per oltre l’80% del tempo di veglia e meno di 4 giorni senza mal di testa al mese. Il mal di testa giornaliero è accettabile se il paziente manifesta mal di testa per =80% del tempo di veglia per la maggior parte dei giorni. h. Il paziente presenta una malattia ematologica, cardiaca, renale, endocrina, polmonare, gastrointestinale, genito-urinaria, neurologica, epatica od oculare clinicamente significativa che, secondo l’opinione dello sperimentatore, potrebbe pregiudicare o compromettere la capacità del paziente di partecipare a questo studio.
    i. Evidenza o anamnesi medica di disturbi psichiatrici clinicamente significativi che, secondo il parere dello sperimentatore, potrebbero pregiudicare o compromettere la capacità del paziente di partecipare a questo studio, tra cui depressione maggiore, disturbo di panico o disturbo d’ansia generalizzato, eventuale tentativo di suicidio in passato o ideazione suicidaria con uno specifico piano negli ultimi due anni precedenti lo screening o attuale ideazione suicidaria misurata mediante l’eC-SSRS. j. Anamnesi oppure malattia cardiovascolare o ischemia vascolare clinicamente significativa (come ischemia miocardica, neurologica [per es. ischemia cerebrale], periferica delle estremità o altro evento ischemico) o eventi tromboembolici (eventi trombotici o embolici arteriosi o venosi), come incidente cerebrovascolare (inclusi attacchi ischemici transitori), trombosi venosa profonda o embolia polmonare.
    k. Anamnesi di infezione da virus dell’immunodeficienza umana, tubercolosi o epatite B o C cronica. l. Anamnesi pregressa o attuale di tumore, escluso il carcinoma cutaneo non melanoma adeguatamente trattato negli ultimi 5 anni.
    m. Pazienti di sesso femminile in gravidanza o allattamento o pazienti di sesso femminile che prevedono di rimanere incinte durante lo studio. n. Partecipazione a uno studio clinico di una nuova entità chimica o un farmaco su prescrizione nei 2 mesi precedenti lo screening (o 3 mesi in caso di farmaci biologici se l’emivita di questi ultimi non è nota) o 5 emivite, a seconda di quale periodo sia più lungo, o attuale partecipazione a un altro studio di un IMP (o un dispositivo medico).
    o. Qualsiasi precedente esposizione a un anticorpo monoclonale che agisce sul pathway di CGRP (quali AMG 334, ALD304, LY2951742, o fremanezumab). p. Qualsiasi riscontro nell’ECG a 12 derivazioni al basale considerato clinicamente significativo a giudizio dello sperimentatore.
    q. Qualsiasi riscontro che, a giudizio dello sperimentatore, rappresenti un’anomalia clinicamente significativa, inclusi i valori degli esami di ematochimica, ematologia, coagulazione e dell’analisi delle urine (esami con risultati anomali possono essere ripetuti per essere confermati). r. Enzimi epatici (alanina aminotransferasi, aspartato aminotransferasi e fosfatasi alcalina) > 1,5 volte l’intervallo del limite superiore della norma (ULN) dopo conferma in un test ripetuto o sospetta lesione epatocellulare che soddisfa i criteri per la legge di Hy allo screening.
    s. Creatinina sierica > 1,5 volte l’ULN, proteinuria clinicamente significativa o evidenza di malattia renale allo screening.
    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
    L’endpoint primario di efficacia è la variazione media rispetto al basale (periodo di run-in di 28 giorni) nel numero medio mensile di giorni con emicrania durante il periodo di 12 settimane dopo la 1a dose di 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.
    le valutazioni finali dello studio saranno effettuate alla visita 8 (fine di fine trattamento (EOT)), circa 4 settimane dopo la somministrazione dell'ultima dose di 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
    ¿ percentuale di pazienti che raggiunge una riduzione di almeno il 50% nel numero medio mensile
    di giorni con emicrania durante il periodo di 12 settimane dopo la 1a dose di fremanezumab
    ¿ variazione media rispetto al basale (periodo di run-in di 28 giorni) nel numero medio mensile di giorni con mal di testa di gravit¿
    almeno moderata durante il periodo di 12 settimane dopo la 1a dose di fremanezumab ¿ variazione media rispetto al basale
    (periodo di run-in di 28 giorni) nel numero medio mensile di giorni con emicrania durante il periodo di 4 settimane dopo la 1a dose
    di fremanezumab¿ percentuale di pazienti che raggiunge una riduzione di almeno il 50% nel numero medio mensile di giorni con
    emicrania durante il periodo di 4 settimane dopo la 1a dose di fremanezumab
    ¿ variazione media rispetto al basale (periodo di run-in di 28 giorni) nel numero medio mensile di giorni di utilizzo di qualsiasi
    farmaco per episodi di mal di testa acuto durante il periodo di 12 settimane dopo la 1a dose di fremanezumab ¿ variazione media
    rispetto al basale (periodo di run-in di 28 giorni) nel numero di giorni con mal di testa di gravit¿ almeno moderata durante il
    periodo di 4 settimane dopo la 1a dose di fremanezumab ¿ comparsa di eventi avversi durante tutto lo studio
    ¿ risultati degli esami clinici di laboratorio (ematochimica, ematologia, coagulazione e analisi delle urine) a punti temporali
    specificati
    ¿ misurazioni dei segni vitali (pressione arteriosa sistolica e diastolica, temperatura orale e frequenza del polso) ad ogni visita.
    Nota: in caso di anafilassi sospetta e ipersensibilit¿ grave, saranno misurate anche la saturazione di ossigeno e la frequenza
    respiratoria
    ¿ Risultati dell¿ECG a 12 derivazioni a specifici punti temporali
    ¿ uso di farmaci concomitanti per eventi avversi durante lo studio ¿ numero (%) di pazienti che non hanno completato lo studio a
    causa di eventi avversi
    ¿ variazioni clinicamente significative negli esami obiettivi, incluso il peso corporeo
    ¿ insorgenza di reazioni gravi di ipersensibilit¿/anafilassi
    ¿ ideazioni e comportamenti suicidari misurati mediante la scala eC-SSRS
    E.5.2.1Timepoint(s) of evaluation of this end point
    Final study assessments will be performed at visit 8 (end-of-treatment
    [EOT] visit), approximately 4 weeks after administration of last dose of
    fremanezumab.
    le valutazioni finali dello studio saranno effettuate alla visita 8 (visita di fine
    trattamento (EOT)), circa 4 settimane dopo la somministrazione dell'ultima dose di 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
    12 settimane trattamento in doppio cieco, controllato con placebo seguite da 12 settimane in aperto
    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 concerned7
    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 Information not present in EudraCT
    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
    Czechia
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 764
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state33
    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.
    Alla fine del periodo di trattamento di 24 settimane si prevede che i pazienti ritornino alle cure dei loro medici curanti. Nessun trattamento ¿ pianificato dallo sponsor dopo il completamento del periodo di trattamento di 24 settimane e dello studio.I pazienti dovrebbero essere trattati con la cura standard dopo ritiro dallo studio o completamento del periodo di trattamento, come appropriato.
    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 Decision2017-12-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-12-13
    P. End of Trial
    P.End of Trial StatusCompleted
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