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    Summary
    EudraCT Number:2014-005413-23
    Sponsor's Protocol Code Number:CY4031
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-12-10
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2014-005413-23
    A.3Full title of the trial
    A Phase 3, Multi-National, Double-Blind, Randomized, Placebo-Controlled, Stratified, Parallel Group, Study to Evaluate the Safety, Tolerability and Efficacy of Tirasemtiv in Patients with Amyotrophic Lateral Sclerosis (ALS)
    Estudio de Fase 3, multinacional, en doble ciego, aleatorizado, controlado con placebo, estratificado y de grupos paralelos, para evaluar la seguridad, la tolerabilidad y la eficacia de tirasemtiv en pacientes con esclerosis lateral amiotrófica (ELA)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year (VITALITY-ALS)
    Investigación ventilatoria de Tirasemtiv y evaluación de los índices longitudinales tras tratamiento durante un año (VITALITY-ALS)
    A.4.1Sponsor's protocol code numberCY4031
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02496767
    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 SponsorCytokinetics, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportCytokinetics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCytokinetics, Inc.
    B.5.2Functional name of contact pointMedical Affairs
    B.5.3 Address:
    B.5.3.1Street Address280 East Grand Avenue
    B.5.3.2Town/ citySouth San Francisco, California
    B.5.3.3Post code94080
    B.5.3.4CountryUnited States
    B.5.4Telephone number+349139134432929
    B.5.6E-mailmedicalaffairs@cytokinetics.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/12/970
    D.3 Description of the IMP
    D.3.1Product nameTirasemtiv
    D.3.2Product code CK-2017357
    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 INNTirasemtiv
    D.3.9.1CAS number 1005491-05-3
    D.3.9.2Current sponsor codeCK-2017357
    D.3.9.3Other descriptive name6-ethynyl-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one
    D.3.9.4EV Substance CodeSUB93455
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number125
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Amyotrophic Lateral Sclerosis (ALS)
    Esclerosis Lateral Amiotrófica (ELA)
    E.1.1.1Medical condition in easily understood language
    Amyotrophic lateral sclerosis, or ALS, is a disease of the nerve cells in the brain and spinal cord that control voluntary muscle movement.
    La esclerosis lateral amiotrófica, o ELA, es una enfermedad de las células nerviosas del cerebro y la médula espinal que controlan el movimiento de los músculos voluntarios.
    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 18.1
    E.1.2Level PT
    E.1.2Classification code 10002026
    E.1.2Term Amyotrophic lateral sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    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 assess the effect of tirasemtiv versus placebo on respiratory function in patients with ALS.
    El objetivo principal es evaluar el efecto del tirasemtiv frente al placebo sobre la función respiratoria en pacientes con ELA.
    E.2.2Secondary objectives of the trial
    Secondary objectives include:
    - Evaluation of alternative methods to assess the effect of tirasemtiv versus placebo on percent predicted SVC in patients with ALS
    - Assessment of the effect of tirasemtiv versus placebo on other clinical measures related to the progressive decline in respiratory function in patients with ALS
    - Assessment of the effect of tirasemtiv versus placebo on measures of skeletal muscle function in patients with ALS
    Los objetivos secundarios son:
    -Evaluación de métodos alternativos para valorar el efecto del tirasemtiv frente al placebo sobre el porcentaje de SVC predicha en pacientes con ELA
    -Evaluación del efecto del tirasemtiv frente al placebo sobre otras medidas clínicas relacionadas con el deterioro progresivo de la función respiratoria pacientes con ELA
    -Evaluación del efecto del tirasemtiv frente al placebo sobre medidas de la función muscular esquelética en pacientes con ELA
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Biomarker Sample Collection
    Biomarkers are objective measures or indicators of normal biological processes, pathological processes or pharmacological responses to a therapeutic intervention. Biomarker development may be useful in developing markers to identify disease subtypes, to guide therapy, or predict disease severity. Where authorized by the applicable IRB/EC/REB approved informed consent, blood samples for biomarker development will be collected at the time points below:
    - Day 1
    - Week 8
    - Week 16
    - Week 24
    - Week 32
    - Week 40
    - Week 48
    Plasma samples will be stored for future biomarker analyses and will NOT be used for pharmacogenomic testing.
    Recogida de muestras para biomarcadores
    Los biomarcadores son medidas objetivas o indicadores de procesos biológicos normales, procesos patológicos o respuestas farmacológicas a una intervención terapéutica. El desarrollo de biomarcadores puede ser útil en para identificar subtipos de enfermedad, orientar el tratamiento o pronosticar la severidad de la enfermedad. Si se autoriza en el consentimiento informado aprobado por el comité de ética (CEIC/IRB/REB) pertinente, se recogerán muestras de sangre para desarrollo de biomarcadores en los puntos de tiempo siguientes:
    -Día 1
    -Semana 8
    -Semana 16
    -Semana 24
    -Semana 32
    -Semana 40
    -Semana 48
    Se conservarán muestras de plasma para futuros análisis de biomarcadores y NO se utilizarán en exámenes farmacogenómicos.
    E.3Principal inclusion criteria
    1. Able to comprehend and willing to sign an Informed Consent Form (ICF)
    2. Male or female 18 years of age or older
    3. A diagnosis of familial or sporadic ALS (defined as meeting the possible, laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS according to the World Federation of Neurology El Escorial criteria) </= 24 months prior to screening
    4. Upright SVC >/=70 % of predicted for age, height and sex
    5. Able to swallow tablets without crushing, and in the opinion of the Investigator, is expected to continue to be able to do so during the trial
    6. A caregiver if one is needed
    7. Clinical laboratory findings within the normal range or, if outside the normal range, deemed not clinically significant by the Investigator
    8. Male patients must agree for the duration of the study and 10 weeks after the end of the study to use a condom during sexual intercourse with female partners who are of reproductive potential and to have female partners use an additional effective means of contraception (e.g., diaphragm plus spermicide, or oral contraceptives) or the male patient must agree to abstain from sexual intercourse during and for 10 weeks after the end of the study
    9. Female patients must be post-menopausal (>/= 1 year) or sterilized, or, if of childbearing potential, not be breastfeeding, have a negative pregnancy test, have no intention to become pregnant during the course of the study, and use contraceptive drugs or devices as detailed in item 8 for the duration of the study and for 10 weeks after the end of the study
    10. Patients must be either on a stable dose of riluzole 50 mg twice daily for at least 30 days prior to screening or have not taken riluzole for at least 30 days prior to screening and are willing not to begin riluzole use until they complete study drug dosing
    1. Capacidad de comprender y voluntad de firmar el documento de consentimiento informado (DCI).
    2. Hombre o mujer a partir de los 18 años.
    3. Diagnóstico de ELA familiar o esporádica (definida como el cumplimiento de los criterios de El Escorial de diagnóstico de ELA posible, probable respaldada por los resultados analíticos, probable o demostrada de acuerdo con la Federación Mundial de Neurología) </=24 meses antes de la selección.
    4. SVC con el paciente erguido >/=70% del valor predicho según la edad, altura y sexo.
    5. Capacidad para ingerir los comprimidos sin machacarlos y que, en opinión del Investigador, vaya a continuar así durante el ensayo.
    6. Existencia de un cuidador, si es preciso.
    7. Resultados de los análisis clínicos dentro del intervalo de la normalidad o, de no ser así, que el Investigador no los considere de importancia clínica.
    8. Los varones deben comprometerse a utilizar preservativos en las relaciones sexuales con mujeres potencialmente fértiles y hacer que estas utilicen un método anticonceptivo eficaz adicional (por ejemplo, diafragma más espermicida o anticonceptivos orales), o bien abstenerse de mantener relaciones sexuales, durante todo el estudio y las 10 semanas siguientes a su término.
    9. Las mujeres deben ser posmenopáusicas (>/=1 año) o haber sido esterilizadas, o, si son potencialmente fértiles, no deben dar lactancia natural y deben presentar una prueba de embarazo negativa, no tener intención de quedarse embarazadas durante el estudio y utilizar fármacos o dispositivos anticonceptivos, tal como se detalla en el punto 8, durante todo el estudio y las 10 semanas siguientes a su término.
    10. Los pacientes deben estar recibiendo una dosis estable de riluzol, de 50 mg dos veces al día, desde como mínimo 30 días antes de la selección o no haber tomado riluzol desde al menos 30 días antes de la selección y estar dispuestos a no comenzar a utilizar riluzol hasta que finalicen el tratamiento con el fármaco del estudio.
    E.4Principal exclusion criteria
    1. At the time of screening, any use of non-invasive positive pressure ventilation (NIPPV, e.g. continuous positive airway pressure [CPAP] or bi-level positive airway pressure [BiPAP]) for any portion of the day, or mechanical ventilation via tracheostomy, or on any form of oxygen supplementation
    2. Patients with a diaphragm pacing system (DPS) at study entry or who anticipate DPS placement during the course of the study
    3. BMI of 20.0 kg/m2 or lower
    4. Unwilling or unable to discontinue tizanidine and theophylline-containing medications during study participation
    5. Serum chloride outside the normal reference range
    6. Neurological impairment due to a condition other than ALS, including history of transient ischemic attack within the past year
    7. Presence at screening of any medically significant cardiac, pulmonary, GI, musculoskeletal, or psychiatric illness that might interfere with the patient´s ability to comply with study procedures or that might confound the interpretation of clinical safety or efficacy data, including, but not limited to:
    a. Poorly controlled hypertension
    b. NYHA Class II or greater congestive heart failure
    c. Chronic obstructive pulmonary disease or asthma requiring daily use bronchodilator medications
    d. GI disorder that might impair absorption of study drug
    e. History of significant liver disease defined by bilirubin > 2 times the upper limit of normal (ULN) or ALT or AST > 3 times the ULN on repeat testing
    f. Poorly controlled diabetes mellitus
    g. History of vertigo within three months of study entry
    h. History of syncope without an explainable or treated cause
    i. History of untreated intracranial aneurysm or poorly controlled seizure disorder
    j. Amputation of a limb
    k. Cognitive impairment, related to ALS or otherwise, sufficient to impair the patient´s ability to give informed consent and to understand and/or comply with study procedures
    l. Cancer with metastatic potential (other than basal cell carcinoma, carcinoma in situ of the cervix, or squamous cell carcinoma of the skin excised with clean margins) diagnosed and treated within the last two years
    m. Any other condition, impairment or social circumstance that, in the opinion of the Investigator, would render the patient not suitable to participate in the study
    n. Patient judged to be actively suicidal or a suicide risk by the Investigator
    8. Has taken any investigational study drug within 30 days or five half-lives of the prior agent, whichever is greater, prior to dosing
    9. Prior participation in any form of stem cell therapy for the treatment of ALS
    10. Previously received tirasemtiv in any previous clinical trial
    1. Uso en el momento de la selección de ventilación no invasiva con presión positiva (por ejemplo, presión positiva continua en las vías respiratorias o presión positiva de dos niveles en las vías respiratorias) durante cualquier parte del día, o ventilación mecánica por traqueostomía o todo tipo de administración de oxígeno.
    2. Pacientes con sistema de electroestimulación diafragmática a la entrada en el estudio o cuya colocación esté prevista a lo largo del estudio.
    3. Índice de masa corporal igual o inferior a 20,0 kg/m2.
    4. Paciente que no desea o no puede suspender los medicamentos con tizanidina y teofilina durante su participación en el estudio.
    5. Cloruro sérico fuera del intervalo de la normalidad.
    6. Afectación neurológica por un trastorno distinto de la ELA, lo que incluye los antecedentes de accidente isquémico transitorio el último año.
    7. Presencia en la selección de cualquier enfermedad médicamente importante de tipo cardiovascular, respiratorio, digestivo, locomotor o psiquiátrico, que pudiera alterar la capacidad del paciente para cumplir los procedimientos del estudio o que pudiera representar un factor de confusión en la interpretación de los datos clínicos de seguridad o eficacia, como, entre otros procesos:
    a. Hipertensión arterial mal controlada
    b. Insuficiencia cardiaca congestiva de clase II o superior de la NYHA
    c. Enfermedad pulmonar obstructiva crónica o asma que precise broncodilatadores a diario
    d. Trastorno del tubo digestivo que pudiera alterar la absorción del fármaco del estudio
    e. Antecedentes de hepatopatía importante, definida por: bilirrubina >2 veces el límite superior de la normalidad o ALT o AST >3 veces el límite superior de la normalidad en un análisis repetido
    f. Diabetes mellitus mal controlada
    g. Antecedentes de vértigo en un plazo de tres meses respecto a la entrada en el estudio
    h. Antecedentes de síncope sin causa explicable o no tratado
    i. Antecedentes de aneurisma intracraneal no tratado o trastorno epiléptico mal controlado
    j. Amputación de un miembro
    k. Alteración cognitiva, relacionada o no con la ELA, suficiente para alterar la capacidad del paciente para dar su consentimiento informado y entender o cumplir los procedimientos del estudio

    l. Cáncer con riesgo de metástasis (distinto del carcinoma basocelular, el carcinoma in situ de cuello uterino o el carcinoma cutáneo espinocelular resecado con bordes limpios) diagnosticado y tratado en los últimos dos años
    m. Cualquier otro trastorno, afección o circunstancia social que, en opinión del Investigador, hiciera que el paciente no fuera adecuado para participar en el estudio
    n. Conducta suicida o riesgo de suicidio a juicio del Investigador
    8. Tratamiento con cualquier fármaco en investigación en el plazo de 30 días o cinco semividas del producto anterior, eligiéndose el más prolongado, antes de la administración del fármaco del estudio.
    9. Cualquier tipo de tratamiento previo con células madre para la ELA.
    10. Tratamiento previo con tirasemtiv en cualquier ensayo clínico anterior.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the change from baseline to Week 24 of the double-blind, placebo-controlled phase in percent predicted SVC.
    El criterio principal de valoración es el cambio entre el momento basal y la Semana 24 de la fase en doble ciego controlada con placebo en el porcentaje de SVC predicha.
    E.5.1.1Timepoint(s) of evaluation of this end point
    week 24
    Semana 24
    E.5.2Secondary end point(s)
    1. "Time to Event" analyses including:
    a. Time to the first occurrence of a decline in SVC to </= 50% predicted or the onset of respiratory insufficiency (defined as tracheostomy or the use of non-invasive ventilation for </= 22 hours per day for >/= 10 consecutive days) or death during the first 24 weeks and during all 48 weeks of double-blind, placebo-controlled treatment
    b. Time to the first occurrence of a decline from baseline in percent predicted SVC >/= 10 percentage points or the onset of respiratory insufficiency or death during the first 24 weeks of double-blind, placebo-controlled treatment
    c. Time to the first occurrence of a decline from baseline in percent predicted SVC >/= 20 percentage points or the onset of respiratory insufficiency or death during the 48 weeks of double-blind, placebo-controlled treatment
    d. Time to the first occurrence of a decline in the respiratory components of the ALSFRS-R (i.e., items 10, 11, and 12) or death during the first 24 weeks and during all 48 weeks of double-blind, placebo-controlled treatment
    e. Time to the first occurrence of a decline in either of the ALSFRS-R items 11 or 12 or death during the first 24 weeks and during all 48 weeks of double-blind, placebo-controlled treatment
    f. Time to the first occurrence of the first use of mechanical ventilatory assistance or death during the first 24 weeks and during all 48 weeks of double-blind, placebo-controlled treatment
    In addition, each of the first three composite endpoints listed above will be analyzed with "first use of mechanical ventilatory assistance" in place of "respiratory insufficiency".

    2. "Responder analyses" including:
    a. Proportion of patients with no decline from baseline in percent predicted SVC, free from respiratory insufficiency and alive during the first 24 weeks and during all 48 weeks of double-blind, placebo-controlled treatment
    b. Proportion of patients with a decline from baseline </= 6 percentage points in percent predicted SVC, free from respiratory insufficiency and alive during the first 24 weeks and during all 48 weeks of double-blind, placebo-controlled treatment
    c. Proportion of patients with a decline from baseline </= 10 percentage points in percent predicted SVC, free from respiratory insufficiency and alive during the first 24 weeks and during all 48 weeks of double-blind, placebo-controlled treatment
    d. Proportion of patients with a decline from baseline </= 20 percentage points in percent predicted SVC, free from respiratory insufficiency and alive during the first 24 weeks and during all 48 weeks of double-blind, placebo-controlled treatment

    3. Change from baseline to 24 weeks of double-blind, placebo-controlled treatment in the following measures:
    a. ALSFRS-R total score
    b. ALSFRS-R score of the three respiratory subdomains of the ALSFRS-R (i.e., items 10, 11, and 12)
    c. Muscle strength as determined by the mega-score of:
    - Elbow flexion (bilateral)
    - Wrist extension (bilateral)
    - Knee extension (bilateral)
    - Ankle dorsiflexion (bilateral)
    - Handgrip strength (bilateral)
    d. SNIP

    4. Slopes of the changes from baseline in percent predicted SVC, ALSFRS-R, mega-score of muscle strength, and SNIP:
    a. From baseline to 24 weeks of the randomized, double-blind, placebo-controlled phase
    b. From baseline to 48 weeks of the randomized, double-blind, placebo-controlled phase
    c. From the end of 24 weeks of the randomized, double-blind, placebo-controlled phase to the end of the double-blind, randomized, placebo-controlled phase at 48 weeks

    5. Changes in percent predicted SVC, ALSFRS-R total score, ALSFRS-R score of the three respiratory subdomains of the ALSFRS-R (i.e., items 10, 11, and 12), muscle strength mega-score, and SNIP from baseline to the end of Week 48 of the double-blind, placebo-controlled phase.

    6. Change in percent predicted SVC from baseline to the end of Week 12 of the double-blind, placebo-controlled phase.
    1. Análisis de tipo «tiempo hasta el acontecimiento»:
    a. Tiempo hasta la primera presentación de un deterioro en la SVC hasta >/=50% del valor predicho o la aparición de insuficiencia respiratoria (definida como traqueostomía o uso de ventilación no invasiva durante >/=22 horas al día >/=10 días consecutivos) o la muerte durante las primeras 24 semanas y durante la totalidad de las 48 semanas de tratamiento en doble ciego controlado con placebo.
    b. Tiempo hasta la primera presentación de un deterioro respecto al basal en el porcentaje de SVC predicha >/=10 puntos porcentuales o la aparición de insuficiencia respiratoria o la muerte durante las primeras 24 semanas de tratamiento en doble ciego controlado con placebo.
    c. Tiempo hasta la primera presentación de un deterioro respecto al basal en el porcentaje de SVC predicha >/=20 puntos porcentuales o la aparición de insuficiencia respiratoria o la muerte durante las 48 semanas de tratamiento en doble ciego controlado con placebo.
    d. Tiempo hasta la primera presentación de deterioro en los componentes respiratorios de la ALSFRS-R (es decir, elementos 10, 11 y 12) o la muerte durante las primeras 24 semanas y durante la totalidad de las 48 semanas de tratamiento en doble ciego controlado con placebo.
    e. Tiempo hasta la primera presentación de deterioro en los elementos 11 o 12 de la ALSFRS-R o la muerte durante las primeras 24 semanas y durante la totalidad de las 48 semanas de tratamiento en doble ciego controlado con placebo.
    f. Tiempo hasta el primer uso de soporte ventilatorio mecánico o la muerte durante las primeras 24 semanas y durante la totalidad de las 48 semanas de tratamiento en doble ciego controlado con placebo.
    Además, cada uno de los tres primeros criterios de valoración compuestos que se han enumerado se analizarán con «primer uso de soporte ventilatorio mecánico» en lugar de «insuficiencia respiratoria».
    2. Análisis de «pacientes con respuesta»:
    a. Porcentaje de pacientes sin deterioro respecto al basal en el porcentaje de SVC predicha, sin insuficiencia respiratoria y con vida durante las primeras 24 semanas y durante la totalidad de las 48 semanas de tratamiento en doble ciego controlado con placebo.
    b. Porcentaje de pacientes con un deterioro respecto al basal </=6 puntos porcentuales en el porcentaje de SVC predicha, sin insuficiencia respiratoria y con vida durante las primeras 24 semanas y durante la totalidad de las 48 semanas de tratamiento en doble ciego controlado con placebo.
    c. Porcentaje de pacientes con un deterioro respecto al basal </=10 puntos porcentuales en el porcentaje de SVC predicha, sin insuficiencia respiratoria y con vida durante las primeras 24 semanas y durante la totalidad de las 48 semanas de tratamiento en doble ciego controlado con placebo.
    d. Porcentaje de pacientes con un deterioro respecto al basal </=20 puntos porcentuales en el porcentaje de SVC predicha, sin insuficiencia respiratoria y con vida durante las primeras 24 semanas y durante la totalidad de las 48 semanas de tratamiento en doble ciego controlado con placebo.
    3. Cambio respecto al basal a las 24 semanas y a las 48 semanas de tratamiento en doble ciego controlado con placebo en las siguientes medidas:
    a. Puntuación total de la ALSFRS-R
    b. Puntuación de los tres subdominios respiratorios de la ALSFRS-R (es decir, elementos 10, 11 y 12)
    c. Fuerza muscular en su determinación mediante la megapuntuación de:
    -Flexión del codo (bilateral)
    -Extensión de la muñeca (bilateral)
    -Extensión de la rodilla (bilateral)
    -Dorsiflexión del tobillo (bilateral)
    -Fuerza agarre de la mano (bilateral)
    d. SNIP
    4. Pendientes de los cambios respecto al basal en el porcentaje de SVC predicha, la ALSFRS-R, la megapuntuación de la fuerza muscular y la SNIP:
    a. Entre el basal y 24 semanas de la fase aleatorizada, en doble ciego y controlada con placebo.
    b. Entre el basal y 48 semanas de la fase aleatorizada, en doble ciego y controlada con placebo.
    c. Entre transcurridas 24 semanas de la fase aleatorizada, en doble ciego y controlada con placebo y el final de la fase en doble ciego, aleatorizada y controlada con placebo a las 48 semanas.
    5. Cambio en el porcentaje de SVC predicha, la puntuación total de la ALSFRS-R, la puntuación de los tres subdominios respiratorios de la ALSFRS-R (es decir, elementos 10, 11 y 12), la megapuntuación de la fuerza muscular y la SNIP entre el basal y el fin de la Semana 48 de la fase en doble ciego controlada con placebo.
    6. Cambio del porcentaje de SVC predicha entre el basal y el fin de la Semana 12 de la fase en doble ciego controlada con placebo.
    E.5.2.1Timepoint(s) of evaluation of this end point
    week 12, week 24, week 48
    semana 12, semana 24, semana 48
    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 Yes
    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 trial4
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA19
    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
    France
    Germany
    Ireland
    Netherlands
    Spain
    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
    Último Paciente Última Visita
    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 months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months9
    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: 320
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 125
    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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 145
    F.4.2.2In the whole clinical trial 445
    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
    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 Decision2016-02-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-01-28
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-09-27
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