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    Summary
    EudraCT Number:2021-000639-30
    Sponsor's Protocol Code Number:AB20009
    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:2021-09-20
    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 number2021-000639-30
    A.3Full title of the trial
    A 96-Weeks, Prospective, Multicenter, Randomised, Double-Blind, Placebo-Controlled, Phase 3 Study to Compare Efficacy and Safety of Masitinib Dose Titration to 4.5 mg/kg/day versus Placebo in the Treatment of Patients with Primary Progressive or Secondary Progressive Multiple Sclerosis Without Relapse.
    Estudio de Fase III, prospectivo, multicéntrico, randomizado, doble ciego, controlado con placebo, de 96 semanas para comparar la eficacia y seguridad del ajuste de dosis de masitinib a 4,5 mg/kg/día frente a placebo en el tratamiento de pacientes con esclerosis múltiple primaria progresiva o secundaria progresiva sin recidivas.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase 3 study to compare efficacy and safety of masitinib with placebo in the patients with primary progressive or secondary progressive multiple sclerosis without relapse.
    Estudio de Fase III para comparar la eficacia y seguridad de masitinib con placebo en el tratamiento de pacientes con esclerosis múltiple primaria progresiva o secundaria progresiva sin recidivas.
    A.4.1Sponsor's protocol code numberAB20009
    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 SponsorAB Science
    B.1.3.4CountryFrance
    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 supportAB Science
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAlpha Bioresearch S.L.
    B.5.2Functional name of contact pointAlicia Pereira
    B.5.3 Address:
    B.5.3.1Street AddressC/ López de Hoyos 155, 3 6-7
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28002
    B.5.3.4CountrySpain
    B.5.4Telephone number0034917452520
    B.5.5Fax number0034917450653
    B.5.6E-mailregulatory@alphabioresearch.com
    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 nameMasitinib
    D.3.2Product code AB1010
    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 INNMasitinib mesilate
    D.3.9.1CAS number 790299-79-5
    D.3.9.2Current sponsor codeAB1010
    D.3.9.4EV Substance CodeSUB32266
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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: 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 nameMasitinib
    D.3.2Product code AB1010
    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 INNMasitinib mesilate
    D.3.9.1CAS number 790299-79-5
    D.3.9.4EV Substance CodeSUB32266
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with primary progressive or secondary progressive multiple sclerosis without relapse
    Pacientes con esclerosis múltiple primaria progresiva o secundaria progresiva sin recaída
    E.1.1.1Medical condition in easily understood language
    Multiple sclerosis
    Esclerosis múltiple
    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 21.1
    E.1.2Level PT
    E.1.2Classification code 10063400
    E.1.2Term Secondary progressive multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10063401
    E.1.2Term Primary progressive multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    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 evaluate whether masitinib treatment will show a significant delay on three-month confirmed disease progression versus placebo in the study patients.
    El objetivo principal del estudio es evaluar si el tratamiento con masitinib mostrará un retraso significativo en la progresión de la enfermedad confirmada a los tres meses frente al placebo en los pacientes del estudio.
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are to evaluate the efficacy of masitinib compared with placebo on a range of clinical parameters of multiple sclerosis. The secondary objectives also include the assessment of safety and tolerability of masitinib as compared to placebo in terms of adverse events, vital signs, physical examination, ECG, and clinical laboratory tests.
    Los objetivos secundarios del estudio son evaluar la eficacia de masitinib en comparación con el placebo en una serie de parámetros clínicos de la esclerosis múltiple. Los objetivos secundarios también incluyen la evaluación de la seguridad y la tolerabilidad de masitinib en comparación con el placebo en términos de eventos adversos, signos vitales, examen físico, ECG y pruebas de laboratorio clínico.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    A patient must fulfil all of the following inclusion criteria to be eligible to participate in the study:
    1. Male or female patients aged between 18 and 65 years at baseline (both inclusive)
    2. Weight >45 kg and BMI between 18 and 35 kg/m2 at screening or at baseline
    3. Patients with either primary progressive or secondary progressive multiple sclerosis with onset of symptoms at least five years before inclusion and with no relapse diagnosed according to the 2017 revised McDonald’s criteria at least two years before inclusion
    4. Patients with Expanded Disability Status Scale (EDSS) score between 3.0 to 6.0 (both inclusive) at screening and baseline
    5. Patients with an EDSS score progression ≥1 point with no improvement during 2 years before inclusion
    6. Absence of T1 Gadolinium-enhancing brain lesions at baseline as measured by MRI
    7. Patients able to understand, and willing to follow the safety procedures mentioned on the patient card in case of signs or symptoms of severe neutropenia or severe cutaneous toxicity
    8. Contraception:
    - Female patients of childbearing potential (entering the study after a menstrual period and who has a negative pregnancy test), who agrees to use a highly effective method of contraception and an effective method of contraception by her male partner during the study and for 3 months and a half after the last treatment intake
    - Male patients with a female partner of childbearing potential who agrees to use a highly effective method of contraception and an effective method of contraception by his female partner during the study and for 3 months and 2 weeks after the last treatment intake OR who agrees to use an effective method of contraception and a highly effective method of contraception by his female partner during the study and for 3 months and 2 weeks after the last treatment intake
    Highly effective and effective methods of contraception are detailed in the appendix 14.1 of the protocol.
    9. Patient able to understand, and willing to sign, and date the written informed consent form prior to any protocol-specific procedures. If patients are duly capable of study consent but are unable to sign by themselves due to aggravation of disease condition, written informed consent can be obtained from a legally authorized representative who can sign on behalf of the patients after confirming the patients' agreement to study participation
    10. Patient able and willing to comply with study protocol and to come on-site as per protocol visits schedule
    Los pacientes deben cumplir todos los criterios de inclusión siguientes para poder participar en el estudio:
    1. Hombres y mujeres, con edades comprendidas entre 18 y 65 años (ambas incluidas) en la visita basal.
    2. Peso >45 kg, IMC entre 18 kg/m2 y 35 kg/m2 en las visitas de selección o basal.
    3. Pacientes con esclerosis múltiple primaria progresiva o bien secundaria progresiva, con inicio de síntomas al menos cinco años antes de la inclusión y sin recidiva diagnosticada según los criterios revisados de McDonald’s de 2017 al menos dos años antes de la inclusión.
    4. Pacientes con una puntuación entre 3,0 y 6,0 (ambas incluidas) en la Escala del Estado de Incapacidad Ampliada (Expanded Disability Status Scale, EDSS) en las visitas de selección y basal.
    5. Pacientes con una progresión en la puntuación de la EDSS ≥1, sin mejoría en los 2 años previos a la inclusión.
    6. Ausencia de lesiones cerebrales potenciadas en T1 con gadolinio en la visita basal según RM.
    7. Pacientes capaces de entender y dispuestos a seguir los procedimientos de seguridad mencionados en la tarjeta del paciente en caso de observar signos o síntomas de neutropenia severa o toxicidad cutánea severa.
    8. Anticoncepción:
    Las pacientes mujeres en edad fértil (que participen en el estudio una vez pasado el periodo menstrual y con una prueba de embarazo negativa) que accedan a utilizar un método anticonceptivo de alta eficacia y cuyas parejas de sexo masculino acepten utilizar otro método anticonceptivo eficaz durante el estudio y en los 3 meses y medio posteriores a la última toma del tratamiento.
    Los pacientes varones con una pareja de sexo femenino en edad fértil que accedan a utilizar un método anticonceptivo de alta eficacia y cuyas parejas de sexo femenino acepten utilizar otro método anticonceptivo eficaz durante el estudio y en los 3 meses y medio posteriores a la última toma del tratamiento O que accedan a utilizar un método anticonceptivo eficaz y cuyas parejas de sexo femenino acepten utilizar otro método anticonceptivo de alta eficacia durante el estudio y en los 3 meses y medio posteriores a la última toma del tratamiento.
    Los métodos anticonceptivos eficaces y de alta eficacia se detallan en el Apéndice 14.1 del Protocolo.
    9. Pacientes capaces de entender, firmar y fechar el documento de consentimiento informado antes de que se lleve a cabo cualquier procedimiento específico del protocolo. Si los pacientes están debidamente capacitados para consentir, pero no pueden firmar ellos solos a causa del empeoramiento de la enfermedad, se podrá obtener el consentimiento informado de un representante legalmente autorizado, quien firmará en nombre del paciente tras confirmar su acuerdo a participar en el estudio.
    10. Pacientes capaces y dispuestos a cumplir el protocolo del estudio y a acudir al centro según el programa de visitas del protocolo.
    E.4Principal exclusion criteria
    1. Patients suffering from a disease other than MS that would better explain the patient’s neurological clinical signs and symptoms and/or MRI lesions
    2. Inability to complete MRI (contraindications for MRI) and/or any known allergy or hypersensitivity or any contra-indication to gadolinium macrocyclic
    3. Patients with hypersensitivity to masitinib or its excipients
    4. Patients with history (or family history) of severe skin toxicities or reactions
    5. Patients with history of severe bone marrow disorders such as agranulocytosis or aplasia, or with abnormal laboratory results from local laboratory assessments at screening and baseline defined as:
    - Neutropenia with ANC <1.5 × 109/L
    - Anemia with Hgb <LLN or red blood cell count below the LLN
    - Thrombocytopenia with platelet counts <150 × 109/L
    - Lymphocyets <1.0 × 109/L
    6. Patients with history of hepatic disorders, with a known liver disease or recent alcohol abuse, or with abnormal laboratory results from local laboratory assessments defined as:
    - Hepatic transaminase levels >2 ULN at baseline, or
    - Total bilirubin level >1.5 ULN at baseline, or
    - Both hepatic transaminase levels and total bilirubin level outside of the normal ranges at screening and baseline, or
    - Albuminemia <1 × LLN at screening and baseline
    7. Patients with pre-existing severe renal impairment, or with abnormal laboratory results from local laboratory assessments at screening:
    - Creatinine clearance <60 mL/min (Cockcroft and Gault formula) or
    - Proteinuria >30 mg/dL (1+) on dipstick; in case of the proteinuria ≥1+ on the dipstick, 24 hours proteinuria must be >1.5 g/24 hours
    8. Patients with current or history of severe cardiovascular disease:
    - Myocardial infarction
    - Unstable angina pectoris
    - Coronary revascularization procedure
    - Congestive heart failure of NYHA Class III or IV
    - Stroke, including a transient ischemic attack
    - Second degree or third-degree atrioventricular block not successfully treated with a pacemaker
    - Bi-fascicular block
    - QTc Fridericia interval > 450 milliseconds for males and > 470 milliseconds for females
    - Drug induced heart failure or ischemic heart disease
    - Radiotherapy induced cardiomyopathy
    - Family history of unexpected death of cardiovascular origin
    - Edema of cardiac origin and left ventricular ejaculation fraction ≤50%
    9. Patients, with two or more of the risk factors listed below assessed by a cardiologist as Very High Risk (calculated SCORE* ≥10%.) or High Risk (calculated SCORE* ≥5% and <10%) according to the Systematic Coronary Risk Estimation (SCORE*):
    - Hypertension (uncontrolled)
    - Diabetes
    - Kidney disease
    - Current tabagism (≥ 10 Pack-year: equivalent to 1 pack of 20 cigarettes for 10 years with the formula N (number of packs of 20 cigarettes smoked daily) × T (number years smoking)) Patients who stopped smoking 6 months prior to the evaluation, are not concerned.
    - Hypercholesterolemia,
    - COPD
    * This assessment is done according to the Systematic Coronary Risk Estimation (SCORE) using the country specific free full version of HeartScore®, the interactive tool for predicting and managing the risk of heart attack and stroke in Europe, available at https://www.heartscore.org/en_GB/access
    If the country specific version is not available, EU one should be used.
    10. Patients with active severe infection such as tuberculosis, viral hepatitis, human immunodeficiency virus infection, syphilis or COVID-19 (confirmed by positive RT-PCR and/or other applicable methods)
    11. Patient treated concomitantly with known substrates of P-gp and BCRP with narrow therapeutic index.
    12. Patients requiring medications, which are prohibited in the current protocol, including corticosteroids use other than as defined by the protocol, chemotherapies, immunomodulators or immunosuppressors, investigational drugs, drugs known to be at high risk of Stevens-Johnson syndrome or for Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome
    13. Any medical condition that, in the opinion of the Investigator, might interfere with the patients’ participation in the trial, poses any added risk for the patients, or confounds the assessment of the patients
    14. Patients under psychiatric, patients protected by law under guardianship or curatorship, patients in emergency situations, prisoners and patients without national health insurance
    15. Patients who had major surgery within 2 weeks prior to screening visit
    16. Pregnant, or nursing female patients
    17. Patients with a diagnosis of cancer or evidence of continued disease within five years before screening
    18. Previous participation in an earlier study with masitinib
    19. Patients treated with other disease modifying treatments in the time frames and conditions mentioned under previous treatment wash out period.
    1. Pacientes con una enfermedad distinta a la EM que pueda explicar mejor los síntomas y signos clínicos neurológicos y/o las lesiones en la RM.
    2. Incapacidad para completar una RM (contraindicaciones para una RM) y/o cualquier alergia o hipersensibilidad conocidas o cualquier contraindicación al gadolinio macrocíclico.
    3. Pacientes con hipersensibilidad a masitinib o a sus excipientes.
    4. Pacientes con antecedentes (o antecedentes familiares) de toxicidades o reacciones cutáneas severas.
    5. Pacientes con antecedentes de trastornos medulares graves como agranulocitosis o aplasia, o con unos resultados analíticos anómalos evaluados en un laboratorio local en las visitas de selección y basal definidos como:
    - Neutropenia con RAN <1,5 × 109/l
    - Anemia con Hgb < LIN (límite inferior de normalidad) o recuento de eritrocitos inferior al LIN.
    - Trombocitopenia con recuento de trombocitos <150 × 109/l
    - Linfocitos < 1,0 × 109/l
    6. Pacientes con antecedentes de trastornos hepáticos, con una hepatopatía conocida o alcoholismo reciente, o con unos resultados analíticos anómalos evaluados en un laboratorio local definidos como:
    - niveles de transaminasas hepáticas >2 LSN (límite superior de normalidad) en la visita basal, o
    - nivel de bilirrubina total >1,5 LSN en la visita basal, o
    - niveles tanto de transaminasas hepáticas o bilirrubina total fuera de los límites de la normalidad en las visitas de selección y basal, o
    - albuminemia <1 × LIN en las visitas de selección y basal.
    7. Pacientes con antecedentes de trastornos renales severos preexistentes o con unos resultados analíticos anómalos evaluados en un laboratorio local en las visitas de selección:
    - aclaramiento de creatinina <60ml/min (fórmula de Cockcroft y Gault) o
    - proteinuria >30 mg/dl (1+) en tira reactiva; en caso de proteinuria ≥1+ en tira reactiva, la proteinuria de 24 horas debe ser >1,5 g/24 horas.
    8. Pacientes con antecedentes o presencia de enfermedad cardiovascular severa:
    - infarto de miocardio
    - angina de pecho inestable
    - procedimiento de revascularización coronaria
    - insuficiencia cardíaca congestiva de clase III o IV según NYHA
    - ictus, incluido accidente isquémico transitorio
    - bloqueo auriculoventricular de segundo o tercer grado tratado sin éxito con un marcapasos
    - bloqueo bifascicular
    - intervalo QTc por la fórmula de Fridericia >450 milisegundos para varones y >470 milisegundos para mujeres
    - insuficiencia cardiaca o cardiopatía isquémica de origen medicamentoso
    - miocardiopatía causada por radioterapia
    - antecedentes familiares de muerte súbita de origen cardiovascular
    - edema de origen cardiaco y una fracción de eyección ventricular izquierda ≤50 %
    9. Pacientes que tienen dos o más de los factores de riesgo que aparecen mencionados más abajo que, con criterios cardiológicos, son de Riesgo Muy Alto (estimación SCORE* ≥10 %) o Riesgo Alto (estimación SCORE ≥5 % y <10 %), según la Estimación de riesgo coronario sistémico (Systematic Coronary Risk Estimation, SCORE):
    - hipertensión (no controlada)
    - diabetes
    - nefropatía
    - tabaquismo activo (≥10 cajetilla-año: equivalente a una cajetilla de 20 cigarrillos durante 10 años con la fórmula N, número de cajetillas de 20 cigarrillos fumados diariamente) × T (número de años de tabaquismo). No afecta a los pacientes que hayan dejado de fumar 6 meses antes de la evaluación.
    - hipercolesterolemia
    - EPOC
    * Esta evaluación se realiza según la Systematic Coronary Risk Estimation (SCORE) con la versión íntegra específica gratuita de cada país de la HeartScore®, el instrumento interactivo para predecir y gestionar el riego de infarto e ictus en Europa, disponible en https://www.heartscore.org/en_GB/access
    Si no se dispone de una versión específica del país, deberá utilizarse una versión de la UE.
    10. Pacientes con una infección activa severa como tuberculosis, hepatitis vírica, infección por HIV, sífilis o COVID-19 (confirmada mediante PCR positivo y/u otros métodos aplicables).
    11. Paciente tratado de forma concomitante con sustratos conocidos de la P-gp y la BCRP con un índice terapéutico estrecho.
    12. Los pacientes que requieren medicamentos que están prohibidos en el protocolo actual, incluido el uso de corticoesteroides distintos de los definidos por el protocolo, quimioterapias, inmunomoduladores o inmunosupresores, medicamentos en fase de investigación, medicamentos conocidos por presentar un elevado riesgo de Síndrome de Stevens-Johnson o de la reacción farmacológica con eosinofilia y síndrome de síntomas sistémicos (DRESS).
    13. Cualquier enfermedad que, a criterio del Investigador, pueda afectar a la participación de los pacientes en el ensayo, presente algún riesgo añadido para los pacientes o pueda crear confusión al evaluar a los pacientes.
    14. Pacientes en tratamiento psiquiátrico, protegidos legalmente mediante tutela o curatela, pacientes en situaciones de urgencia, reclusos o pacientes sin Seguridad Social.
    ...
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is to assess the efficacy of masitinib 3.0 mg/kg/day with a dose escalation to 4.5 mg/kg/day after four weeks on the time to confirmed (12-weeks CDP) EDSS progression. Progression is defined as 1-point worsening when EDSS score ≤5.5, or 0.5-point worsening if baseline score >5.5.
    CDP: Confirmed Disease Progress
    El tiempo hasta la progresión según la Escala Expandida del Estado de Discapacidad (EDSS) confirmada (12 semanas de PCD [Progreso confirmado de la discapacidad]) La progresión de la EDSS se define como el empeoramiento de 1 punto cuando la puntuación basal de la EDSS es ≤5,5 o el empeoramiento de 0,5 punto si la puntuación basal es >5,5 desde la randomización hasta la semana 96.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 96
    Semana 96
    E.5.2Secondary end point(s)
    The secondary endpoints of the study include the following:
    Expanded Disability Status Scale (EDSS):
    • Time to confirmed (24-weeks CDP) EDSS progression. Progression is defined as 1-point worsening when EDSS score ≤5.5, or 0.5 if baseline score >5.5)
    • Expanded Disability Status Scale (EDSS): Absolute and ordinal change from baseline considering all measurements up to Week 96
    • Time to EDSS score of 7.0

    Clinical Global Assessment Tools:
    • Timed 25-foot walk (T25-FW) from baseline up to Week 96 and 12 weeks confirmed worsening using 20% threshold
    • Nine-hole peg test (9-HPT), right and left hands sides (finger dexterity) from baseline up to Week 96 and 12 weeks confirmed worsening using 20% threshold
    • The Symbol Digit Modalities Test (SDMT) from baseline up to Week 96 and 12 weeks confirmed worsening using 4-point threshold

    Brain MRI Assessments:
    • Brain Volume and Lesions will be measured and assessed at Baseline, Week 48 and Week 96, or early termination (only if patient discontinues after Week 48 and more than 24 weeks have elapsed since last MRI) for the following endpoints: Brain atrophy - Percent brain volume change (PBVC) from baseline at Week 96 or early termination
    • New/newly enlarged T2 lesion count (compared with baseline MRI scan) at Week 96 or early termination

    Quality of Life assessment:
    • Quality of life assessment: Multiple Sclerosis Quality of Life (MSQOL)-54 instrument from baseline up to Week 96
    • Modified Fatigue Impact Scale (MFIS) from baseline up to Week 96
    • Hamilton Depression Rating Scale (HAM-D) from baseline up to Week 96
    • Disability Impact Profile (DIP) from baseline up to Week 96

    Relapses:
    • Occurrence of new or worsening neurological symptoms attributable to MS
    • Symptoms persisting for >24 hours
    • Symptoms not attributable to confounding clinical factors (e.g., fever, infection, injury, adverse reactions to medications)
    • Symptoms immediately preceded by a stable or improving neurological state for at least 30 days
    • Ssymptoms accompanied by objective neurological worsening consistent with an increase of at least half a step on the EDSS scale

    Biomarker(s):
    • Comparison of serum Neurofilament Light Chain (NfL) and Glial Fibrillary Acidic Protein (GFAP) levels at Baseline and Week 96 or early termination (only if patient discontinues after Week 48 and more than 24 weeks have elapsed since last test)
    These biomarkers are to be tested in a subgroup of 200 patients of pre-selected sites

    Elevated blood concentrations of Comparison of serum Neurofilament Light Chain (NfL) were found to correlate with an increase in the number of relapses, disability worsening, MRI disease activity and brain volume loss in Multiple Sclerosis (MS). Glial Fibrilliary Acidic Protein (GFAP) is the major intermediate cytoskeletal protein of astrocytes and that of axons may be released into the cerebrospinal fluid (CSF) during pathological processes in the central nervous system (CNS). GFAP, is a marker for astrogliosis and a potential biomarker for MS progression.
    - El tiempo hasta la progresión de la EDSS confirmada (24 semanas de PCD). La progresión de la EDSS se define como el empeoramiento de 1 punto cuando la puntuación basal de la EDSS es ≤5,5 o el empeoramiento de 0,5 punto si la puntuación basal es >5,5 desde la randomización hasta la semana 96.
    - El cambio absoluto en la EDSS desde el valor basal teniendo en cuenta todas las mediciones desde la visita basal hasta la semana 96.
    - El cambio ordinal en la EDSS desde el valor basal teniendo en cuenta todas las mediciones desde la visita basal hasta la semana 96.
    - El tiempo hasta la puntuación de la EDSS de 7,0.
    • La prueba cronometrada de marcha de 8 metros (T25-FW) desde la visita basal hasta la semana 96 y 12 semanas de empeoramiento confirmado con un umbral del 20 %.
    • La prueba del tablero con 9 orificios (9-HPT), tanto en el lado izquierdo como en el derecho (destreza manual), desde la visita basal hasta la semana 96 y 12 semanas de empeoramiento confirmado con un umbral del 20 %.
    - El test de símbolos y dígitos (SDMT) desde la visita basal hasta la semana 96 y 12 semanas de empeoramiento confirmado con un umbral de 4 puntos.
    - Evaluación de la calidad de vida: Cuestionario de calidad de vida específico de esclerosis múltiple MSQOL-54 desde la visita basal hasta la semana 96.
    - Escala modificada de impacto del cansancio (MFIS) desde la visita basal hasta la semana 96.
    - Escala de evaluación de la depresión de Hamilton (HAM-D) desde la visita basal hasta la semana 96.
    - Escala de impacto de la discapacidad (DIP) desde la visita basal hasta la semana 96.
    - Número de recidivas desde la visita basal hasta la semana 96.
    - Uso de corticoesteroides desde la visita basal hasta la semana 96.
    - Evaluaciones cerebrales mediante RM:
    - Atrofia cerebral - Porcentaje de cambio del volumen cerebral (PCVC) desde la visita basal hasta la semana 96 o el final anticipado (solo si el paciente interrumpe su participación tras la semana 48 y han pasado más de 24 semanas desde la última RM).
    - Número de lesiones nuevas en secuencias potenciadas en T2 (en comparación con la RM basal) en la semana 96 o en el final anticipado (solo si el paciente interrumpe su participación tras la semana 48 y han pasado más de 24 semanas desde la última RM).
    - Comparación de los niveles séricos de la cadena ligera de neurofilamentos (NfL) y la proteína ácida fibrilar glial (GFAP) en la visita basal y la semana 96 o en el final anticipado (solo si el paciente interrumpe su participación tras la semana 48 y han pasado más de 24 semanas desde las últimas pruebas).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 96
    Semana 96
    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) 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 No
    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 concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA75
    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
    Canada
    Israel
    Russian Federation
    South Africa
    Ukraine
    United States
    Bulgaria
    Finland
    France
    Germany
    Hungary
    Italy
    Poland
    Portugal
    Spain
    Sweden
    United Kingdom
    Greece
    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
    The end of study is defined as the date of the last visit of the last patient undergoing the trial
    El final del estudio se define como la fecha de la última visita del último paciente sometido al ensayo
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    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: 800
    F.1.3Elderly (>=65 years) No
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2021-09-20. Yes
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 720
    F.4.2.2In the whole clinical trial 800
    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)
    None
    Ninguno
    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 Decision2022-01-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-12-27
    P. End of Trial
    P.End of Trial StatusOngoing
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