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    Summary
    EudraCT Number:2019-001862-13
    Sponsor's Protocol Code Number:AB19001
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Temporarily Halted
    Date on which this record was first entered in the EudraCT database:2020-11-06
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2019-001862-13
    A.3Full title of the trial
    A prospective, multicenter, randomised, double-blind, placebo-controlled, parallel groups, phase 3 study to compare the efficacy and safety of masitinib in combination with Riluzole versus placebo in combination with Riluzole in the treatment of patients suffering from Amyotrophic Lateral Sclerosis (ALS)
    Studio prospettico, multicentrico, randomizzato, in doppio cieco, controllato verso placebo, a gruppi paralleli, di fase 3, per confrontare l’efficacia e la sicurezza di masitinib in combinazione con riluzolo versus placebo in combinazione con riluzolo nel trattamento di pazienti affetti da Sclerosi Laterale Amiotrofica (SLA)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Evaluation of masitinib in Amyotrophic Lateral Sclerosis (ALS)
    Valutazione di masitinib nella Sclerosi Laterale Amiotrofica (SLA)
    A.3.2Name or abbreviated title of the trial where available
    non applicable
    non applicable
    A.4.1Sponsor's protocol code numberAB19001
    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 organisationAB Science
    B.5.2Functional name of contact pointAlain Moussy
    B.5.3 Address:
    B.5.3.1Street Address3 Avenue George V
    B.5.3.2Town/ cityParis
    B.5.3.3Post code75008
    B.5.3.4CountryFrance
    B.5.4Telephone number0033147202311
    B.5.5Fax number0033147202411
    B.5.6E-maila.moussy@ab-science.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 mesilate
    D.3.2Product code [AB1010]
    D.3.4Pharmaceutical form 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.3.9.3Other descriptive name4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-thiazolyl]amino]phenyl]-benzamide, methane sulphonic acid salt. AB1010base; AB 1003
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 mesilate
    D.3.2Product code [AB1010]
    D.3.4Pharmaceutical form 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.3.9.3Other descriptive name4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-thiazolyl]amino]phenyl]-benzamide, methane sulphonic acid salt. AB1010base; AB 1003
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 placeboTablet
    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 placeboTablet
    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 suffering from Amyotrophic Lateral Sclerosis (ALS)
    Pazienti affetti da Sclerosi Laterale Amiotrofica (SMA)
    E.1.1.1Medical condition in easily understood language
    Amyotrophic Lateral Sclerosis (ALS)
    Sclerosi Laterale Amiotrofica (SMA)
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to demonstrate statistically significant improvement from baseline in ALSFRS-R after 48-week treatment of two doses of masitinib versus matching placebo in patients diagnosed with ALS treated with Riluzole
    L'obiettivo primario è dimostrare un miglioramento statisticamente significativo rispetto al basale di ALSFRS-R dopo un trattamento di 48 settimane di due dosi di masitinib rispetto al placebo corrispondente nei pazienti con diagnosi di SLA trattati con Riluzolo
    E.2.2Secondary objectives of the trial
    Secondary objectives are to assess the efficacy and safety of two doses of masitinib versus matching placebo in the treatment of patients diagnosed with ALS treated with Riluzole
    L' obiettivo secondario è valutare l'efficacia e la sicurezza di due dosi di masitinib rispetto al placebo corrispondente nel trattamento dei pazienti con diagnosi di SLA trattati con Riluzolo
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives

    Pharmacogenomics
    Version: Version 6.0 (main study protocol)
    Date: 09/03/2020
    Title: Pharmacogenomic Study (in case of Severe Neutropenia or Severe Skin Toxicity)
    Objectives: In case a patient experiences either severe neutropenia or severe skin toxicity, and if the patient gave his/her consent, a blood sample can be collected for the genomic study aimed to better understand why the patients are presenting those adverse events

    Other types of substudies
    Specify title, date and version of each substudy with relative objectives: Pharmacodynamic/Biomarker(s) Study: included in the main study protocol version 6.0 dated 9 March 2020; The following CSF and serum biomarkers known to be associated with the evolution of the disease and potentially modulated by masitinib treatment will be assessed before and during study treatment:
    - Lumbar puncture at baseline prior to the first dose, at week 24 and on the last day prior to the last dose (W48 or final visit) to assess CSF levels of phosphorylated neurofilament heavy chain (pNfH), neurofilament light chain (NfL), chitinase 1 (CHIT1), Chitinase-3-like protein 1 (CHI3L1), Chitinase-3-like protein 2 (CHI3L2) in addition to glucose, protein, albumin and cell counts.
    - Serum assessment of Albumin, C-reactive protein, Creatine kinase, NfL, pNfH, interleukin-1 beta, interleukin-6, interleukin-8, interleukin-12p70, tumor necrosis factor-alpha, chemokine ligand 2 (CCL2), interferon-gamma at baseline prior to the first dose, at week 24 and on the last day prior to the last dose (week 48 or final visit).

    Pharmacokinetic Study: included in the main study protocol version 6.0 dated 9 March 2020; From plasma concentrations versus time profiles, the following pharmacokinetic parameters will be assessed for masitinib/Riluzole:
    - Maximal Plasmatic Concentration (Cmax)
    - Area Under the Curve (AUC)
    - Clearance / Bioavailability factor (Cl/F)
    - Elimination half-life (t½).

    Farmacogenomica
    Versione: Version 6.0 (main study protocol)
    Data: 09/03/2020
    Titolo: Pharmacogenomic Study (in case of Severe Neutropenia or Severe Skin Toxicity)
    Obiettivi: Nel caso in cui un paziente manifesti neutropenia grave o grave tossicità cutanea e se il paziente ha dato il proprio consenso, potrà essere raccolto un campione di sangue per lo studio genomico volto a comprendere meglio perché i pazienti presentano tali eventi avversi

    Altre tipologie di sottostudi
    specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Pharmacodynamic/Biomarker(s) Study: incluso nel protocollo di studio principale versione 6.0 del 9 marzo 2020; I seguenti biomarcatori del CSF e sierici noti per essere associati all'evoluzione della malattia e potenzialmente modulati dal trattamento con masitinib saranno valutati prima e durante il trattamento in studio:
    - Puntura lombare al basale prima della prima dose, alla settimana 24 e l'ultimo giorno prima dell'ultima dose (W48 o visita finale) per valutare i livelli di CSF della catena pesante del neurofilamento fosforilato (pNfH), catena leggera del neurofilamento (NfL), chitinasi 1 (CHIT1), proteina 1 simile a Chitinase-3 (CHI3L1), proteina 2 simile a Chitinase-3 (CHI3L2) oltre a glucosio, proteine, albumina e conta cellululare.
    - Valutazione sierica di albumina, proteina C-reattiva, creatina chinasi, NfL, pNfH, interleuchina-1 beta, interleuchina-6, interleuchina-8, interleuchina-12p70, fattore alfa di necrosi tumorale, ligando di chemochine 2 (CCL2), interferone gamma al basale prima della prima dose, alla settimana 24 e l'ultimo giorno prima dell'ultima dose (settimana 48 o visita finale).

    Pharmacokinetic Study: incluso nel protocollo di studio principale versione 6.0 del 9 marzo 2020; dalle concentrazioni plasmatiche rispetto ai profili temporali, saranno valutati i seguenti parametri farmacocinetici per masitinib / Riluzolo:
    - Massima concentrazione plasmatica (Cmax)
    - Area sotto la curva (AUC)
    - Fattore di clearance / biodisponibilità (Cl / F)
    - Emivita di eliminazione (t½).
    E.3Principal inclusion criteria
    1. Patient, male or female, diagnosed with laboratory supported probable, clinically probable or definite ALS according to the World Federation of Neurology Revised El Escorial criteria
    2. Patient with a familial or sporadic ALS
    3. Patient aged between 18 and 75 years old inclusive at screening
    4. Patient treated with a stable dose of Riluzole (100 mg/day) for at least 12 weeks prior to the baseline visit
    5. Patient with an ALS disease duration from diagnosis no longer than 24 months at screening
    6. Patient with an ALSFRS-R total score progression between onset of the disease and screening of > 0.3 and <1.1 point/month
    7. Patient with an ALSFRS-R total score decrease equal or greater than 1 point between screening and baseline
    8. Patient with an ALSFRS-R total score of at least 26 at screening following rules below:
    - at least 3 on item #3 and
    - at least 2 on each of the other 11 items (i.e. item #1, #2, #4, #5a or #5b, #6, #7, #8, #9, #10, #11 and #12)
    9. Patient with an ALSFRS-R total score of at least 25 at randomization following rules below:
    - at least 3 on item #3 and
    - at least 2 on each of the other 11 items (i.e. item #1, #2, #4, #5a or #5b, #6, #7, #8, #9, #10, #11 and #12)
    10. Contraception:
    - Female patient 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 patient 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 a half 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 a half after the last treatment intake
    Highly effective and effective methods of contraception are detailed in appendix 15.1 of the protocol
    11. 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
    12. Patient able and willing to comply with study protocol and to come on-site as per protocol visits schedule
    13. Patient 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
    1. Paziente di sesso maschile o femminile con diagnosi di sclerosi laterale amiotrofica definita, clinicamente probabile o probabile con supporto di laboratorio secondo i criteri di El Escorial rivisti della World Federation of Neurology
    2. Paziente con SLA familiare o sporadica
    3. Paziente di età compresa tra 18 e 75 anni allo screening
    4. Paziente trattato con una dose stabile di Riluzolo (100 mg / die) per almeno 12 settimane prima della visita basale
    5. Paziente con una durata della malattia ALS dalla diagnosi non più di 24 mesi allo screening
    6. Paziente con una progressione del punteggio totale ALSFRS-R tra l'insorgenza della malattia e lo screening di> 0,3 e <1,1 punti / mese
    7.Paziente con una diminuzione del punteggio totale ALSFRS-R uguale o maggiore di 1 punto tra lo screening e il basale
    8. Paziente con un punteggio totale ALSFRS-R di almeno 26 allo screening che segue le seguenti regole:
    - almeno 3 sull'item # 3 e
    - almeno 2 su ciascuno degli altri 11 elementi (ovvero item # 1, # 2, # 4, # 5a o # 5b, # 6, # 7, # 8, # 9, # 10, # 11 e # 12)
    9. Paziente con un punteggio totale ALSFRS-R di almeno 25 alla randomizzazione secondo le seguenti regole:
    - almeno 3 sull'item # 3 e
    - almeno 2 su ciascuno degli altri 11 elementi (ovvero item # 1, # 2, # 4, # 5a o # 5b, # 6, # 7, # 8, # 9, # 10, # 11 e # 12)
    10. Contraccezione:
    - Donna in età fertile (che entra nello studio dopo un ciclo mestruale e che ha un test di gravidanza negativo), che accetta di utilizzare un metodo contraccettivo altamente efficace e un metodo contraccettivo efficace da parte del suo partner uomo durante lo studio e per 3 mesi e mezzo dopo l'ultima assunzione del trattamento
    - Uomo con una partner donna in età fertile che accetta di utilizzare un metodo contraccettivo altamente efficace e un metodo contraccettivo efficace da parte della sua partner durante lo studio e per 3 mesi e mezzo dopo l'ultima assunzione del trattamento OPPURE che accetta di utilizzare un metodo contraccettivo efficace e un metodo contraccettivo altamente efficace da parte della sua compagna durante lo studio e per 3 mesi e mezzo dopo l'ultima assunzione del trattamento
    I metodi contraccettivi altamente efficaci ed efficaci sono dettagliati nell'appendice 15.1 del protocollo
    11. Paziente in grado di comprendere e disposto a firmare e datare il modulo di consenso informato scritto prima di qualsiasi procedura specifica del protocollo. Se i pazienti sono debitamente in grado di fornire il consenso allo studio ma non sono in grado di firmare da soli a causa dell'aggravamento delle condizioni della malattia, il consenso informato scritto può essere ottenuto da un rappresentante legalmente autorizzato che può firmare per conto dei pazienti dopo aver confermato l'accordo del paziente per la partecipazione allo studio
    12. Paziente in grado e disposto a rispettare il protocollo di studio e a recarsi nel centro sperimentale secondo il programma delle visite del protocollo
    13. Paziente in grado di comprendere e disposto a seguire le procedure di sicurezza indicate sulla scheda del paziente in caso di segni o sintomi di neutropenia grave o tossicità cutanea grave
    E.4Principal exclusion criteria
    1. Patient with dementia or significant neurological, psychiatric, systemic or organic disease, uncontrolled or that may interfere with the conduct of the trial or its results
    2. Patient with hypersensitivity to masitinib excipients
    3. Patient with an FVC < 60% predicted normal value for gender, height, and age at screening
    4. Patient with a weight < 41 kg and a BMI < 21 or > 30 kg/m² at screening and at baseline
    5. Pregnant, or nursing female patient
    6. Patient with history (or family history) of severe skin toxicities or reactions
    7. Patients treated by drugs known to be at high risk for Stevens-Johnson Syndrome or for Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome
    8. Patient 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 :
    - Neutropenia with ANC < 1.5x109/L
    - Anemia with Hgb < LLN and red blood cell count below the LLN
    - Thrombocytopenia with platelets counts < 150 x 109/L
    9. Patient 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 x LLN at screening and baseline
    10. Patient with pre-existing severe renal impairment, or with abnormal laboratory results from local laboratory assessments at screening and baseline :
    - Creatinine clearance < 60 mL/min (Cockcroft and Gault formula)
    - Proteinuria > 30 mg/dL (1+) on dipstick; in case of the proteinuria equal or greater than 1+ on the dipstick, 24 hours proteinuria must be > 1.5g/24 hours
    11. Patient with active severe infection such as herpes, tuberculosis, viral hepatitis, human immunodeficiency virus infection
    12. Patient with autoimmune conditions such as systemic lupus erythematosus
    13. Patient with a diagnosis of cancer or evidence of continued disease within five years before screening
    14. Patient with severe cardiac conditions:
    - Patient with recent history of severe cardiovascular conditions including acute myocardial infarction, unstable angina pectoris, coronary revascularization procedure, congestive heart failure of NYHA Class III or IV, stroke, including a transient ischemic attack
    - Patient with cardiac conduction abnormalities at study entry including a QTc Fredericia interval >450 milliseconds for males and >470 milliseconds for females, a second- or third-degree atrioventricular block not successfully treated with a pacemaker
    - Patient presenting with edema of cardiac origin and left ventricular ejection fraction = 50%
    15. Patient with risk factors for sudden unexpected death of cardiovascular origin
    16. Patient who has been exposed to an investigational treatment within 3 months prior to screening
    17. Patient who has been exposed to Edaravone within at least 30 days prior to screening
    18. Patient treated concomitantly with drugs known to interact with cytochrome P450 (CYP450) isoenzymes (2C9, 2D6 and 3A4)
    1. Paziente con demenza o significativa malattia neurologica, psichiatrica, sistemica o organica, incontrollata o che può interferire con lo svolgimento della sperimentazione o i suoi risultati
    2. Paziente con ipersensibilità agli eccipienti di masitinib
    3. Il paziente con una FVC <60% del valore normale previsto per sesso, altezza ed età allo screening
    4. Paziente con un peso <41 kg e un BMI <21 o> 30 kg / m² allo screening e al basale
    5. Paziente in gravidanza o in allattamento
    6. Paziente con anamnesi (o storia familiare) di gravi tossicità o reazioni cutanee
    7. Pazienti trattati con farmaci noti per essere ad alto rischio per la sindrome di Stevens-Johnson o per la reazione da farmaco con eosinofilia e sintomi sistemici (DRESS)
    8. Paziente con anamnesi di gravi patologie del midollo osseo come agranulocitosi o aplasia o con risultati di laboratorio anomali dalle valutazioni di laboratorio locali allo screening e al basale:
    - Neutropenia con ANC <1,5x109 / L
    - Anemia con Hgb <LLN e conta dei globuli rossi al di sotto della LLN
    - Trombocitopenia con conta piastrinica <150 x 109 / L
    9. Paziente con anamnesi di patologie epatiche, con malattia epatica nota o recente abuso di alcol, o con risultati di laboratorio anormali dalle valutazioni di laboratorio locali definite come:
    - Livelli di transaminasi epatica> 2 ULN al basale, o
    - Livello di bilirubina totale> 1,5 ULN al basale, o
    - Livelli di transaminasi epatica e livello di bilirubina totale al di fuori dei normali intervalli allo screening e al basale, oppure
    - Albuminemia <1 x LLN allo screening e al basale
    10. Paziente con insufficienza renale grave preesistente o con risultati di laboratorio anormali dalle valutazioni di laboratorio locali allo screening e al basale:
    - Clearance della creatinina <60 mL / min (formula Cockcroft e Gault)
    - Proteinuria> 30 mg / dL (1+) su astina di livello; in caso di proteinuria uguale o maggiore a 1+ sull'astina di livello, la proteinuria 24 ore deve essere> 1,5 g / 24 ore
    11. Paziente con infezione grave attiva come herpes, tubercolosi, epatite virale, infezione da virus dell'immunodeficienza umana
    12. Paziente con condizioni autoimmuni come il lupus eritematoso sistemico
    13. Paziente con diagnosi di cancro o evidenza di malattia continuata entro cinque anni prima dello screening
    14. Paziente con gravi condizioni cardiache:
    - Paziente con storia recente di gravi condizioni cardiovascolari tra cui infarto miocardico acuto, angina pectoris instabile, procedura di rivascolarizzazione coronarica, insufficienza cardiaca congestizia di classe NYHA III o IV, ictus, incluso un attacco ischemico transitorio
    - Paziente con anomalie della conduzione cardiaca all'ingresso nello studio incluso un intervallo QTc di Fredericia> 450 millisecondi per gli uomini e> 470 millisecondi per le donne, un blocco atrioventricolare di secondo o terzo grado non trattato con successo con un pacemaker
    - Paziente che presenta edema di origine cardiaca e frazione di eiezione ventricolare sinistra = 50%
    15. Paziente con fattori di rischio per morte improvvisa inaspettata di origine cardiovascolare
    16. Paziente che è stato esposto a un trattamento sperimentale entro 3 mesi prima dello screening
    17. Paziente che è stato esposto a Edaravone almeno 30 giorni prima dello screening
    18. Paziente trattato in concomitanza con farmaci noti per interagire con gli isoenzimi del citocromo P450 (CYP450) (2C9, 2D6 e 3A4)
    E.5 End points
    E.5.1Primary end point(s)
    Absolute Change from baseline to week 48 in Amyotrophic Lateral Sclerosis functional rating scale (ALSFRS)-Revised total score
    Cambiamento assoluto rispetto al basale del punteggio totale ALSFRS-R alla settimana 48
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 48
    Settimana 48
    E.5.2Secondary end point(s)
    - Progression free survival (PFS) defined as the time from randomization to progression (decline of more than 9 points in ALSFRS-R score from baseline) or death
    - Amyotrophic Lateral Sclerosis Assessment Questionnaire 40 (ALSAQ-40) change
    - Forced Vital Capacity (FVC) change
    - Upper- and lower-limb muscle strength using hand-held dynamometry (HHD)
    - Clinician-rated Clinical Global Impression (CGI)
    - Combined Assessment of Function and Survival (CAFS)
    - Overall Survival (OS)
    - Event free survival (EFS) defined as the time from randomization to the first occurrence of either death or tracheostomy

    Safety Analysis:
    - Adverse events
    - Vital signs, physical examination, ECGs
    - Clinical laboratory tests (haematology, biochemistry, urinalysis and urinary cytology)
    - Sopravvivenza libera da progressione (Progression free survival, PFS) definita come tempo trascorso
    dalla randomizzazione alla progressione (declino di oltre 9 punti del punteggio di ALSFRS-R dal
    basale) o morte
    - Cambiamento nel Amyotrophic Lateral Sclerosis Assessment Questionnaire 40 (ALSAQ-40)
    - Cambiamento nella capacità vitale forzata (Forced Vital Capacity, FVC)
    - Forza muscolare degli arti superiori e inferiori misurata con dinamometro a mano (hand-held dynamometry, HHD)
    - Impressione clinica globale valutata dal medico (Clinical Global Impression, CGI)
    - Valutazione combinata di funzione e sopravvivenza (Combined Assessment of Function and Survival, CAFS)
    - Sopravvivenza globale (Overall Survival, OS)
    - Sopravvivenza priva di eventi (Event free survival, EFS) definita come il tempo trascorso tra la randomizzazione e il decesso o la tracheostomia.

    Analisi della safety:
    - Eventi avversi
    - Parametri vitali, esame fisico, ECG
    - Test clinici di laboratorio (ematologici, biochimici, analisi delle urine e citologia urinaria).
    E.5.2.1Timepoint(s) of evaluation of this end point
    At week 48 or event occurrence (death, progression, tracheostomy) depending on secondary endpoint
    Alla settimana 48 o occorrenza dell'evento (morte, progressione, tracheostomia) a seconda dell'endpoint secondario
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA29
    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
    Argentina
    Austria
    Belgium
    Canada
    Denmark
    France
    Germany
    Ireland
    Israel
    Italy
    Netherlands
    Poland
    Portugal
    Russian Federation
    Slovenia
    Spain
    Sweden
    Ukraine
    United Kingdom
    United States
    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
    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: 450
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 45
    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 state70
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 350
    F.4.2.2In the whole clinical trial 495
    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)
    Patients will be monitored and treated according to local clinical practice.
    I pazienti saranno seguiti e trattati in accordo alla pratica clinica locale.
    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 Decision2021-02-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-12-14
    P. End of Trial
    P.End of Trial StatusTemporarily Halted
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