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    Summary
    EudraCT Number:2017-002887-42
    Sponsor's Protocol Code Number:EORTC-1612-MG
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-01-14
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2017-002887-42
    A.3Full title of the trial
    Combination of targeted therapy (encorafenib and binimetinib) followed by combination of immunotherapy (ipilimumab and nivolumab) vs immediate combination of immunotherapy in patients with unresectable or metastatic melanoma with BRAF V600 mutation : an EORTC randomized phase II study (EBIN)
    Tratamiento combinado dirigido (encorafenib y binimetinib) seguido de inmunoterapia combinada (ipilimumab y nivolumab) frente a inmunoterapia combinada inmediata en pacientes con melanoma irresecable o metastásico con mutación BRAF V600: un estudio de EORTC aleatorizado en fase II (EBIN)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Combination of targeted therapy (encorafenib and binimetinib) followed by combination of immunotherapy (ipilimumab and nivolumab) vs immediate combination of immunotherapy in patients with unresectable or metastatic melanoma with BRAF V600 mutation : an EORTC randomized phase II study (EBIN)
    Tratamiento combinado dirigido (encorafenib y binimetinib) seguido de inmunoterapia combinada (ipilimumab y nivolumab) frente a inmunoterapia combinada inmediata en pacientes con melanoma irresecable o metastásico con mutación BRAF V600: un estudio de EORTC aleatorizado en fase II (EBIN)
    A.3.2Name or abbreviated title of the trial where available
    EBIN
    EBIN
    A.4.1Sponsor's protocol code numberEORTC-1612-MG
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03235245
    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 SponsorEuropean Organisation for Research and Treatment of Cancer
    B.1.3.4CountryBelgium
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportEuropean Organisation for the Research and Treatment of Cancer
    B.4.2CountryBelgium
    B.4.1Name of organisation providing supportBRISTOL-MYERS SQUIBB INTERNATIONAL CORPORATION
    B.4.2CountryBelgium
    B.4.1Name of organisation providing supportPierre Fabre Medicament
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEuropean Organisation for the Research and Treatment of Cancer
    B.5.2Functional name of contact pointClinical Operations Department
    B.5.3 Address:
    B.5.3.1Street Address83/11 Avenue E. Mounier
    B.5.3.2Town/ cityBrussels
    B.5.3.3Post code1200
    B.5.3.4CountryBelgium
    B.5.4Telephone number003227741013
    B.5.5Fax number003227727063
    B.5.6E-mailregulatory@eortc.org
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Opdivo
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namenivolumab
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    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 INNnivolumab
    D.3.9.2Current sponsor codeNIVOLUMAB
    D.3.9.3Other descriptive nameBMS936558
    D.3.9.4EV Substance CodeSUB32944
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 No
    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 RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Yervoy
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameipilimumab
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    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 INNIPILIMUMAB
    D.3.9.2Current sponsor codeIPILIMUMAB
    D.3.9.3Other descriptive nameBMS734016
    D.3.9.4EV Substance CodeSUB22577
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 No
    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: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.2Name of the Marketing Authorisation holderPierre Fabre Médicament
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameBinimetinib
    D.3.2Product code Binimetinib
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBINIMETINIB
    D.3.9.1CAS number 606143-89-9
    D.3.9.2Current sponsor codeBINIMETINIB
    D.3.9.4EV Substance CodeSUB179942
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.2Name of the Marketing Authorisation holderPierre Fabre Médicament
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameENCORAFENIB
    D.3.2Product code ENCORAFENIB
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNENCORAFENIB
    D.3.9.1CAS number 1269440-17-6
    D.3.9.2Current sponsor codeENCORAFENIB
    D.3.9.4EV Substance CodeSUB177218
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number75
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    BRAF V600 mutation–positive unresectable or metastatic melanoma.
    Melanoma metastásico irresecable positivo para la mutación BRAF V600
    E.1.1.1Medical condition in easily understood language
    Malignant melanoma
    Melanoma maligno
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10025650
    E.1.2Term Malignant melanoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to prospectively assess whether a sequential approach with an induction period of 12 weeks with encorafenib + binimetinib followed by an immunotherapy combination with nivolumab + ipilimumab improves Progression Free Survival (PFS) compared to an immunotherapy combination nivolumab + ipilimumab alone as first line treatment in patients with BRAF V600 mutation–positive unresectable or metastatic melanoma.
    El objetivo principal es evaluar de forma prospectiva si un enfoque secuencial con un periodo de inducción de 12 semanas con encorafenib + binimetinib seguido de inmunoterapia combinada con nivolumab + ipilimumab mejora la supervivencia sin progresión (SSP) en comparación con inmunoterapia combinada con nivolumab + ipilimumab únicamente como primera línea de tratamiento en pacientes con melanoma metastásico irresecable positivo para la mutación BRAF V600.
    E.2.2Secondary objectives of the trial
    • To prospectively assess whether a sequential approach with an induction period of 12 weeks with encorafenib + binimetinib followed by combination immunotherapy with nivolumab + ipilimumab improves Overall Survival (OS) as compared to combination immunotherapy nivolumab + ipilimumab alone.
    • To prospectively assess in both treatment groups:
    • Complete response (CR) rate, time to CR and duration of CR
    • Best overall response (CR+PR) rate (ORR), time to best response and duration of response
    • To prospectively assess adverse event (AE) profiles (AE, grade 3-4 AE rate and Serious Adverse Event) between patients receiving the sequential approach versus patients receiving combination immunotherapy alone.
    The exploratory objectives are:
    • To assess the iRECIST tumor response in both treatment groups.
    • To assess PFS2 in both treatment arms.
    • To assess response to second line by RECIST 1.1
    • To compare Quality of Life between the two arms.
    • TR
    • Evaluar de forma prospectiva si un enfoque secuencial con un periodo de inducción de 12 semanas con encorafenib + binimetinib seguido de inmunoterapia combinada con nivolumab + ipilimumab mejora la supervivencia general en comparación con inmunoterapia combinada con nivolumab + ipilimumab únicamente.
    • Evaluar de forma prospectiva en ambos grupos de tratamiento:
    • la tasa de respuesta completa, el tiempo hasta la RC y la duración de la RC;
    • la tasa de mejor respuesta objetiva global, el tiempo hasta la mejor respuesta y la duración de la respuesta.
    • Evaluar de forma prospectiva las características de los acontecimientos adversos entre los pacientes que reciben el enfoque secuencial frente a los pacientes que reciben únicamente la inmunoterapia combinada.
    Los objetivos exploratorios son:
    • Evaluar la respuesta tumoral iRECIST
    • Evaluar la SSP2
    • Evaluar la respuesta a la segunda línea de tratamiento según los criterios RECIST 1.1
    • Comparar la calidad de vida
    • TR
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Histologically or cytologically confirmed unresectable stage III/ IV cutaneous or mucosal melanoma
    • Presence of BRAF V600E or V600K mutation in tumor tissue prior to enrolment as per local assessment
    • Tumor tissue from an unresectable or metastatic site of disease must be provided for biomarker analyses. This can be an archived sample if obtained at maximum 3 months prior to randomization and if the patient did not receive treatment since then.
    • Measurable disease per RECIST 1.1 criteria by computed tomography (CT) or magnetic resonance imaging (MRI) of Chest/Abdomen/Pelvis and brain CT/MRI performed within 28 days prior to randomization
    • Patients ≥ 18 years of age
    • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
    • Patients must be able to swallow and retain oral tablets
    • Adequate organ function within 14 days prior to randomization:
    • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (≥ 1500 per mm3)
    • Lymphocyte count ≥ 1.0 x 109/L (≥ 1000 per mm3)
    • Platelet count ≥ 100 x 109/L (≥ 100,000 per mm3)
    • Hemoglobin ≥ 9.0 g/dL (≥ 5.59 mmol/l)
    • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) or direct bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 x ULN.
    • AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal (< 5x ULN in case of liver metastases)
    • Lipase < 2.0 x the ULN and no radiologic or clinical evidence of pancreatitis
    • Serum phosphorus, calcium, magnesium and potassium within normal ranges as per local lab values
    • Creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 60 mL/min for patient with creatinine levels > 1.5 x institutional laboratory value (according to Cockroft-Gault, Appendix D in protocol);
    • International Normalized Ratio (INR) or Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 x ULN
    Note: patients receiving anticoagulant therapy (have to be shifted to low molecular weight heparin (LMWH) before treatment start; as warfarin and related 4-hydroxycoumarin-containing molecules are not permitted) are eligible if their PT or INR or PTT is within the recommended range for the desired level of anticoagulation.
    • Patients with hyperthyroidism or hypothyroidism but that are stable on hormone replacement can be included.
    • Adequate cardiac function:
    • left ventricular ejection fraction (LVEF) ≥ 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram,
    • 12-lead ECG (in triplicate [2-5 minutes apart]). Single ECG should be obtained after the patient has been in a supine position for 5 minutes and recorded while the patient remains in that position on which QTcF must be <470 ms.
    • Women of child bearing potential (WOCBP) must have a negative serum (preferred) or urine pregnancy test within 72 hours prior to registration.
    Note: women of childbearing potential are defined as premenopausal females capable of becoming pregnant (i.e. females who have had evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons.
    • Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and after the study treatment:
    • for at least 5 months for a woman and 7 months for a man after the last study treatment (nivolumab and ipilimumab or nivolumab alone).
    • for a period of at least 2 months after last dose of encorafenib and binimetinib
    Note: A highly effective method of birth control is defined as a method which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly. Such methods include:
    • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
    • Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
    • Intrauterine device (IUD)
    • Intrauterine hormone-releasing system (IUS)
    • Bilateral tubal occlusion
    • Vasectomized partner
    • Sexual abstinence
    Note: for patient that will receive ENCO: there is a potential for ENCO to induce CYP3A4, which may reduce the effectiveness of hormonal contraception methods.
    • Female patients must not be breast feeding during the trial treatment and for a period of at least 5 months after treatment discontinuation.
    • Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
    • Before patient registration/randomization and before any related study activity, written informed consent must be given according to ICH/GCP, and national/local regulations
    • Melanoma cutáneo o mucoso de estadio III o IV irresecable confirmado histológica o citológicamente.
    • Presencia de mutación BRAF V600E o V600K en el tejido tumoral previa a la inscripción según la evaluación local.
    • Debe facilitarse tejido tumoral de una zona tumoral irresecable o metastásica para el análisis de biomarcadores. Este tejido puede ser una muestra de archivo si se obtiene, como máximo, 3 meses antes de la aleatorización y si el paciente no ha recibido tratamiento desde entonces.
    • Enfermedad medible según los criterios RECIST 1.1 mediante tomografía computarizada (TAC) o resonancia magnética (RM) de tórax/abdomen/pelvis y TAC/RM de cerebro realizadas en los 28 días previos a la aleatorización.
    • Pacientes de ≥18 años de edad.
    • Estado funcional (EF) 0 o 1 según el grupo oncológico cooperativo del este (Eastern Cooperative Oncology Group, ECOG).
    • Los pacientes deben ser capaces de tragar y retener los comprimidos orales.
    • Función orgánica adecuada en el plazo de 14 días previos a la aleatorización:
    • recuento absoluto de neutrófilos (RAN) ≥1,5 x 109/l (≥1500 por mm3);
    • recuento de linfocitos ≥1,0 x 109/l (≥1000 por mm3);
    • recuento de trombocitos ≥100 x 109/l (≥100 000 por mm3);
    • hemoglobina ≥9,0 g/dl (≥5,59 mmol/l);
    • bilirrubina total ≤1,5 x límite superior de la normalidad (LSN) institucional o bilirrubina directa ≤LSN para pacientes con niveles de bilirrubina total >1,5 x LSN;
    • AST (SGOT)/ALT (SGPT) ≤2,5 x límite superior de la normalidad institucional (<5 x LSN en caso de metástasis hepática);
    • lipasa <2,0 x LSN y sin evidencia radiológica o clínica de pancreatitis;
    • fósforo, calcio, magnesio y potasio séricos dentro de los rangos normales según los valores analíticos locales;
    • creatinina ≤1,5 x LSN o aclaramiento calculado de la creatinina ≥60 ml/min para pacientes con niveles de creatinina >1,5 veces el valor analítico institucional (de acuerdo con Cockroft-Gault, Apéndice D);
    • índice internacional normalizado (International Normalized Ratio, INR) o tiempo de protrombina (TP) y tiempo de tromboplastina parcial activado (TTPa) ≤1,5 x LSN.
    • Se puede incluir a pacientes con hipertiroidismo o hipotiroidismo, pero que se mantienen estables con un tratamiento de reposición hormonal.
    • Función cardíaca adecuada:
    • Las mujeres en edad fértil (MEF) deben obtener un resultado negativo en la test de embarazo en suero (preferiblemente) u orina en las 72 horas previas al registro en el ensayo.
    • Los pacientes en edad fértil/con capacidad reproductiva deben utilizar métodos anticonceptivos aceptables, de acuerdo con lo definido por el investigador, durante el periodo de tratamiento del estudio y después del tratamiento del estudio:
    • durante, al menos, 5 meses para las mujeres y 7 meses para los hombres después del último tratamiento del estudio (nivolumab e ipilimumab o nivolumab solo);
    • durante un periodo de, al menos, 2 meses después de la última dosis de encorafenib y binimetinib.
    Nota: Un método anticonceptivo altamente eficaz se define como aquel que tiene una baja tasa de fallo (es decir, inferior al 1 % anual) cuando se usa de manera sistemática y correcta. Dichos métodos incluyen:
    • anticonceptivo hormonal combinado (con estrógeno y progestágeno) asociado a una inhibición de la ovulación (oral, intravaginal o transdérmica);
    • anticonceptivo hormonal solo con progestágeno asociado a una inhibición de la ovulación (oral, inyectable, implantable);
    • dispositivo intrauterino (DIU);
    • sistema de liberación intrauterino (SLI);
    • ligadura de trompas;
    • pareja vasectomizada;
    • abstinencia sexual.
    • Las pacientes no deben estar en periodo de lactancia durante el tratamiento del ensayo y durante un periodo de, al menos, 5 meses después de la interrupción del tratamiento.
    • Los pacientes están dispuestos y son capaces de cumplir con el protocolo durante la duración del estudio, como someterse al tratamiento y realizar las visitas y los exámenes programados, incluido el seguimiento.
    • Antes del registro/la aleatorización de los pacientes y antes de cualquier actividad relacionada con el estudio, se debe otorgar el consentimiento informado por escrito conforme a las ICH/BPC y a los reglamentos nacionales/locales.
    E.4Principal exclusion criteria
    • Uveal melanoma
    • Any symptomatic brain or leptomeningeal disease. Subjects with brain metastases are eligible if these have been locally treated and there is no magnetic resonance imaging (MRI) evidence of progression 4 weeks after end of treatment. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration.
    • Any prior treatment for advanced disease including treatment with an anti-programmed death receptor-1 (PD-1), anti-programmed death-1 ligand-1 (PD-L1), anti-PD-L2, anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4) antibody, anti-LAG-3, anti-TIM-3, anti-IDO, etc or BRAF or MEK inhibitors.
    • History of hypersensitivity to study drugs or any excipient (refer to Investigator's brochures for binimetinib and encorafenib and SmPCs for ipilimumab and nivolumab).
    • Prior adjuvant melanoma therapy with IFN, anti-PD1, anti-PDL1 or anti-CTLA-4 or any other systemic treatment is permitted if completed at least 1 year prior to randomization and all related adverse events have returned to grade ≤ 1.
    • Concomitant administration of strong inducers and inhibitors of P-gp, glucuronidation, CYP3A4 (e.g. rifampicin, rifabutin, carbamazepine, phenytoin or St John’s Wort [hypericin])
    • Concomitant anticoagulation at therapeutic doses with oral anticoagulants (eg, warfarin)
    • Live vaccines within 30 days prior to the first dose of study therapy. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, H1N1 flu, rabies, BCG, and typhoid vaccine.
    • Current participation or treatment with other investigational agent or use of an investigational device within 4 weeks of the first dose of study treatment
    • Child-Pugh B/C and patients with history of acute or chronic pancreatitis
    • Known history or current evidence of active Hepatitis B (e.g., HBsAg reactive) or C (e.g., HCV RNA [qualitative] is detected)
    • History of Human Immunodeficiency Virus (HIV) (HIV-1/2 antibodies)
    • Chronic use of immunosuppressive agents and/or systemic corticosteroids or any use in the last 2 weeks prior to the first dose of study treatment
    • Corticosteroid use as premedication for IV contrast allergies/reactions is allowed
    • Conditions requiring systemic treatment with <10 mg daily prednisone equivalents or equivalent doses of any other corticosteroid are allowed
    • History of interstitial lung disease (ILD) OR pneumonitis (other than chronic obstructive pulmonary disease (COPD) exacerbation) that has required oral or IV steroids are allowed
    • Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed
    • Autoimmune paraneoplastic syndrome requiring immunosuppressive or dedicated treatment. A specific attention should be given in order to detect any minor myasthenia signs at enrolment; acetylcholine receptor antibodies will be systematically tested when symptoms are suggestive of a myasthenia
    • History of any other hematologic or primary solid tumor malignancy, unless in remission for at least 5 years. A patient with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible, for example cervical cancer in situ or pT1a incidental prostate cancer
    • Previous allogeneic tissue/solid organ transplant
    • Active infection requiring therapy
    • Major surgery or trauma within 12 weeks prior to first dose of treatment or presence of any non-healing wound. Complete wound healing from major surgery must have occurred one month before the first dose of study treatment.
    • Minor surgery (including uncomplicated tooth extractions) within 28 days before randomization with complete wound healing at least 10 days before randomization is permitted.
    • Any anticancer treatment within 4 weeks before randomization e.g. radiation, surgery, systemic therapy.
    • Patients with clinically relevant ongoing complications from prior anticancer therapies.
    • Severe or uncontrolled systemic disease or any concurrent condition which in the investigator's opinion makes it undesirable for the patient to participate in the study, or which would jeopardize compliance with the protocol
    • History or current evidence of retinal vein occlusion (RVO) or current risk factors to RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes); an ophthalmological assessment is mandatory within 28 days from the first dose of study treatment.
    • History of retinal degenerative disease....
    • Melanoma uveal.
    • Cualquier enfermedad cerebral o leptomeníngea sintomática. Los pacientes con metástasis cerebral son aptos si han sido tratados localmente y no existen indicios de progresión según una resonancia magnética 4 semanas después del final del tratamiento. Tampoco debe haber un requisito de dosis inmunosupresoras de corticosteroides sistémicos durante, al menos, 2 semanas antes de la administración del fármaco del estudio.
    • Cualquier tratamiento previo para la enfermedad avanzada, incluido el tratamiento con un anticuerpo antireceptor 1 de muerte programada, anticuerpo antiligando 1 de muerte programada, anticuerpo antiligando 2 de muerte programada, anticuerpo anti antígeno-4 asociado al linfocito T citotóxico, anti-LAG-3, anti-TIM-3, anti-IDO, etc. o inhibidores de BRAF o MEK.
    • Antecedente de hipersensibilidad a fármacos del estudio o a cualquier excipiente
    • Se permite el tratamiento adyuvante previo para el melanoma con IFN, anti-PD1, anti-PDL1 o anti-CTLA-4, o cualquier otro tratamiento sistémico, si se completa al menos 1 año antes de la aleatorización y todos los acontecimientos adversos relacionados han regresado a grado ≤1.
    • Administración concomitante de inductores e inhibidores potentes de P-gp, glucuronidación, CYP3A4
    • Anticoagulación concomitante a dosis terapéuticas con anticoagulantes orales
    • Vacunas atenuadas en los 30 días previos a la primera dosis del tratamiento del estudio.
    • Actualmente participando o en tratamiento con otro fármaco en investigación, o uso de un dispositivo de investigación en las 4 semanas previas a la primera dosis del tratamiento del estudio.
    • Clasificación B/C según Child-Pugh y pacientes con antecedentes de pancreatitis aguda o crónica.
    • Antecedentes conocidos o indicios actuales de hepatitis B o C
    • Antecedente de virus de la inmunodeficiencia humana
    • Uso crónico de inmunosupresores o corticosteroides sistémicos o cualquier uso en las 2 semanas previas a la primera dosis del tratamiento del estudio.
    • Enfermedad autoinmune activa que haya requerido tratamiento sistémico en los últimos 2 años.
    • Síndrome paraneoplásico autoinmunitario que requiere tratamiento inmunosupresor o dedicado.
    • Antecedentes de cualquier otra neoplasia maligna hematológica o de tumor sólido primario, a menos que haya estado en remisión desde, al menos, 5 años. Los pacientes con antecedentes de cáncer de piel no melanoma completamente resecado o carcinoma localizado tratado con éxito son aptos
    • Trasplante previo de tejido alogénico/de órganos sólidos.
    • Infección activa que requiere tratamiento.
    • Ausencia de cirugía mayor o de traumatismo en las 12 semanas anteriores a la primera dosis del tratamiento o presencia de cualquier herida que no cicatrice. La cicatrización completa de la herida de una cirugía mayor debe haberse producido un mes antes de la primera dosis del tratamiento del estudio.
    • Se permite la cirugía menor en los 28 días previos a la aleatorización con cicatrización completa de las heridas al menos 10 días antes de la aleatorización.
    • Cualquier tratamiento antineoplásico en las 4 semanas previas a la aleatorización
    • Pacientes con complicaciones clínicamente importantes en curso debidas a tratamientos antineoplásicos previos.
    • Enfermedad sistémica grave o no controlada, o cualquier afección concurrente que, en opinión del investigador, hiciera que no fuera deseable la participación del paciente en el estudio, o que pudiera poner en riesgo el cumplimiento del protocolo.
    • Antecedentes o indicios actuales de oclusión venosa retiniana (OVR) o factores de riesgo actuales de OVR; se requiere una evaluación oftalmológica en los 28 días previos a la primera dosis del tratamiento del estudio.
    • Antecedentes de enfermedad retiniana degenerativa.
    • Disfunción o enfermedad gastrointestinal que pudiera alterar de manera significativa la absorción de encorafenib o binimetinib
    • Pacientes con alteraciones neuromusculares asociadas a CK > LSN
    • Pacientes que estén planificando embarcarse en una nueva pauta de ejercicio agotador después de la primera dosis del tratamiento del estudio.
    • Disfunción cardiovascular o enfermedades cardiovasculares clínicamente significativas
    • Hipertensión no controlada, definida como elevación persistente de tensión arterial sistólica ≥150 mmHg o tensión arterial diastólica ≥100 mmHg, a pesar del tratamiento actual.
    • Antecedentes de enfermedad intestinal inflamatoria crónica o enfermedad de Crohn que requiera intervención médica ≤12 meses antes del inicio del tratamiento del estudio.
    • Antecedentes de acontecimientos tromboembólicos o cerebrovasculares ≤6 meses antes del inicio del tratamiento del estudio
    • Cualquier afección psicológica o situación familiar, sociológica o geográfica que pudiera potencialmente dificultar el cumplimiento del protocolo del estudio y el calendario de seguimiento
    E.5 End points
    E.5.1Primary end point(s)
    -> Criteria for evaluation:

    EFFICACY
    Main efficay endpoint will be:
    Progression-free survival (PFS): defined as the time from the date of randomization until the first date of progression, or until date of death (whatever the cause), whichever occurs first. For patients who remain alive and whose disease has not progressed, PFS will be censored on the date of last visit/contact when a disease assessment was performed. PFS will be based on the disease assessment or date of death provided by the local investigator
    Secondary efficay endpoints will be:
    • Overall survival (OS): defined as the time from the date of randomization to the date of death, whatever the cause. The follow-up of patients still alive will be censored at the moment of last visit/contact
    • CR rate, time to CR and duration of CR
    • Best overall objective response (CR+PR) rate (ORR), time to best objective reponse (OR) and duration of OR


    SAFETY
    Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4).

    -> Statistical methods:
    All the main analyses of the efficacy endpoints (PFS and OS) will be performed on the ITT population using the ITT principle: patients will be considered in the treatment group as indicated at randomization, regardless the “treatment” duration, cause of going off-protocol treatment, possible switch to another treatment before the 1st progression, etc.
    The Kaplan-Meier technique will be used to obtain estimates of the survival-type distributions (PFS, time to CR, time to best response, PFS2 and OS from randomization, duration of CR and of response). In addition, based on the Kaplan-Meier curves, estimates at given time-points will be provided (e.g. 9-, 12- and 18-month PFS rates), along with their standard errors, computed using the Greenwood formula. Medians - if reached - will be presented with a 95% confidence interval (CI) based on the non-parametric method of Brookmeyer and Crowley.
    The comparison of the PFS between the two treatment groups will be done using the log-rank test stratified by stage/LDH, at a 1-sided alpha level of 5% (2-sided alpha level of 10%).
    The HR of arm B:arm A, and its 2-sided 90% confidence interval, will be estimated using a Cox proportional hazards (PH) model (using Efron’s tie-handling method), stratified by stage/LDH as indicated at randomization, with treatment as the single covariate.
    For PFS analysis, in case a category of the stage/LDH variable contains less than 10% of the total number of events (e.g. 134 PFS events), patients in such a category will be poolled together with the one of an adjacent category, allowing to perform a meaningful stratified treatment comparison.
    In each treatment arm, the rates of CR and of ORR (CR+PR) will be summarized with their corresponding 2-sided 95% CI. As one does not expect that the incidences of CR rate to be very high in both groups, and this phase II study the sample size is relatively low, no statistical inference will be done. Idem for the ORR rates and the irRECIST rates.
    At the time of PFS final analysis, PFS2 and OS analyses will be performed, but they will be descriptive only; no formal comparisons will be done.
    El criterio de valoración principal de la eficacia será:
    La supervivencia sin progresión (SSP): definida como el tiempo desde el momento de la aleatorización hasta la primera fecha de progresión o hasta la fecha de la muerte (cualquiera que sea la causa), lo que ocurra primero. Para pacientes que sigan vivos y cuya enfermedad no haya progresado, la SSP se censurará en el momento de la última visita/el último contacto cuando se realice una evaluación de la enfermedad. La SSP se basará en la evaluación de la enfermedad o la fecha de la muerte facilitada por el investigador local.
    Seguridad
    Los grados de toxicidad son acordes a la versión 4.0 de los Criterios de Terminología Común para los Acontecimientos Adversos del Instituto Nacional del Cáncer (National Cancer Institute Common Terminology Criteria of Adverse Events, NCI-CTCAE v4).
    Métodos estadísticos
    Todos los análisis principales de los criterios de valoración de la eficacia (SSP y SG) se realizarán en la población por intención de tratar (Intention to Treat, ITT) utilizando el principio por ITT: se considerará a los pacientes en el grupo de tratamiento según se indique en la aleatorización, independientemente de la duración del “tratamiento”, la causa del tratamiento en curso fuera del protocolo, el posible cambio a otro tratamiento antes de la 1.ª progresión, etc.
    La técnica de Kaplan-Meier se utilizará para obtener estimaciones de las distribuciones del tipo de supervivencia (SSP, tiempo hasta RC, tiempo hasta la mejor respuesta, SSP2 y SG desde la aleatorización, duración de la RC y de la respuesta). Además, basándose en las curvas de Kaplan-Meier, se proporcionarán las estimaciones en determinados puntos temporales (p. ej., tasas de SSP a los 9 meses, 12 meses y 18 meses), junto con sus errores estándares, calculados mediante la fórmula de Greenwood. Las medianas, si se alcanzan, se presentarán con un intervalo de confianza (IC) del 95 % basándose en el método no paramétrico de Brookmeyer y Crowley.
    La comparación de la SSP entre los dos grupos de tratamiento se hará utilizando la prueba de rangos logarítmicos estratificados por estadio/LDH (véase 8.1.2), a un nivel α unilateral del 5 % (nivel α bilateral del 10 %).
    El CRI del grupo B:grupo A, y su intervalo de confianza del 90 % bilateral, se calcularán utilizando un modelo de riesgos proporcionales de Cox (proportional hazards, PH) (utilizando el método de Efron para el tratamiento de sucesos simultáneos), estratificado por estadio/LDH (véase 8.1.2) según se indique en la aleatorización, con el tratamiento como la única covariable.
    Para el análisis de la SSP, en caso de que una categoría de la variable de estadio/LDH contenga menos del 10 % del número total de acontecimientos (p. ej., 134 acontecimientos de SSP), se agrupará a los pacientes de esta categoría junto a los de una categoría adyacente, lo que permite realizar una comparación estratificada de tratamientos significativa.
    En cada grupo de tratamiento, las tasas de RC y TRO (RC+RP) se resumirán con el IC bilateral del 95 % correspondiente. Dado que no se espera que las incidencias de tasas de RC sean muy altas en ambos grupos, y el tamaño muestral de este estudio en fase II es relativamente bajo, no se realizará ninguna inferencia estadística. Lo mismo ocurre para las tasas de TRO y las tasas de irRECIST.
    En el momento del análisis final de la SSP, se realizarán los análisis de SSP2 y SG, pero solo serán descriptivos; no se realizarán comparaciones formales.
    E.5.1.1Timepoint(s) of evaluation of this end point
    PFS is defined as the time from the date of randomization until the first date of progression, or until date of death (whatever the cause), whichever occurs first. For patients who remain alive and whose disease has not progressed, PFS will be censored on the date of last visit/contact when a disease assessment was performed. PFS will be based on the disease assessment or date of death provided by the local investigator

    Accrual: 40 pts/0-<6 months and 160 pts/year thereafter; Rate of lost to follow-up: 2.5%/year
    134 PFS events expected to be reached after 4.1 years (49 months)
    La supervivencia sin progresión (SSP): definida como el tiempo desde el momento de la aleatorización hasta la primera fecha de progresión o hasta la fecha de la muerte (cualquiera que sea la causa), lo que ocurra primero. Para pacientes que sigan vivos y cuya enfermedad no haya progresado, la SSP se censurará en el momento de la última visita/el último contacto cuando se realice una evaluación de la enfermedad. La SSP se basará en la evaluación de la enfermedad o la fecha de la muerte facilitada por el investigador local.

    La inclusión estimada para este estudio se espera que sea de 40 pac./0-<6 meses y 160 pacientes/año en adelante.
    Tasa de pérdidas de seguimiento: 2,5% / año.
    Se esperan 134 eventos de SSP después de 4.1 años (49 meses)
    E.5.2Secondary end point(s)
    Secondary efficay endpoints will be:
     Overall survival (OS)
     CR rate, time to CR and duration of CR
     Best overall objective response (CR+PR) rate (ORR), time to best objective reponse (OR) and duration of OR

    Exploratory endpoints:
    • iRECIST tumor response
    • PFS2
    • Response to second line by RECIST 1.1
    • Quality of life
    • Health-related quality of life (HRQoL), by means of the 30-item EORTC QLQ-C30 version 3 at baseline, week 12, 24, 36 and 60
    • Translational research projects to explore the biology of melanoma and in parallel assessing the prognostic and/or predictive value of potential biomarkers
    Los criterios de valoración secundarios de la eficacia serán:
    • La supervivencia general (SG): definida como el tiempo desde el momento de la aleatorización hasta la fecha de la muerte, cualquiera que sea la causa. El seguimiento de los pacientes aún con vida se censurará en el momento de la última visita/el último contacto.
    • La tasa de RC, el tiempo hasta la RC y la duración de la RC.
    • La tasa de mejor respuesta objetiva global (RC+RP) (TRO), tiempo hasta la mejor respuesta objetiva (RO) y duración de la RO.
    Los objetivos exploratorios son:
    • Evaluar la respuesta tumoral iRECIST en ambos grupos de tratamiento.
    • Evaluar la SSP2 en ambos grupos de tratamiento.
    • Evaluar la respuesta a la segunda línea de tratamiento según los criterios RECIST 1.1
    • Comparar la calidad de vida entre los dos grupos.
    • Recopilar material biológico para proyectos de investigación traslacional con el fin de explorar la biología del melanoma y, en paralelo, evaluar el valor pronóstico o predictivo de posibles biomarcadores.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Overall survival (OS) is defined as the time from the date of randomization to the date of death, whatever the cause. The follow-up of patients still alive will be censored at the moment of last visit/contact.

    All patients will have their BEST OVERALL IMMUNE RESPONSE (iBOR) from the start of study treatment until confirmed progression according to iRECIST or the start of further anticancer therapy or maximum 1y after treatment starts whatever comes first.

    Each patient will be followed until death or for approximately 5y following enrollment in order to document the long-term outcome (e.g. PFS and OS).

    Under the same assumptions of accrual period (Accrual: 40 pts/0-<6 months and 160 pts/year thereafter; Rate of lost to follow-up: 2.5%/year) OS endpoint reached after 7y
    La supervivencia general (SG) se define como el tiempo desde la fecha de la aleatorización hasta la fecha de la muerte, sea cual sea la causa. El seguimiento de los pacientes que todavía están vivos se censurará en el momento de la última visita / contacto.

    Todos los pacientes tendrán su MEJOR RESPUESTA INMUNE GENERAL (iBOR) desde el inicio del tratamiento del estudio hasta la progresión confirmada según iRECIST o el inicio de una nueva terapia contra el cáncer o un máximo de 1 año después de que comience el tratamiento, lo que ocurra primero.

    Cada paciente será seguido hasta la muerte o aproximadamente 5 años después de la registración para documentar el resultado a largo plazo (por ejemplo, SSP y SG).

    La tasa de mejor respuesta objetiva global se alcanzará después de los 7 años.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA57
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    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
    End of study occurs when all of the following criteria have been satisfied:
    1. 5 months after all patients have stopped protocol treatment
    2. The trial is mature for the 2 final analyses of the efficacy endpoints as defined in the protocol: one for PFS and one for OS
    3. The database has been fully cleaned and frozen for these 2 final analyses
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months3
    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: 200
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 70
    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 state16
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 270
    F.4.2.2In the whole clinical trial 270
    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)
    according to the discretion of the treating clinician
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-03-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-03-07
    P. End of Trial
    P.End of Trial StatusOngoing
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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