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    Summary
    EudraCT Number:2016-000778-40
    Sponsor's Protocol Code Number:BP39056
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2016-08-05
    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 number2016-000778-40
    A.3Full title of the trial
    A TWO PART SEAMLESS, OPEN-LABEL, MULTICENTER STUDY TO INVESTIGATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS AND EFFICACY OF RO7034067 IN INFANTS WITH TYPE1 SPINAL MUSCULAR ATROPHY
    ESTUDIO DE CONTINUIDAD EN DOS PARTES, ABIERTO, MULTICÉNTRICO, PARA INVESTIGAR LA SEGURIDAD, LA TOLERABILIDAD, LA FARMACOCINÉTICA, LA FARMACODINÁMICA Y LA EFICACIA DE RO7034067 EN LACTANTES CON ATROFIA MUSCULAR ESPINAL DE TIPO 1
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of RO7034067 in Infants with Type1 Spinal Muscular Atrophy
    Estudio para investigar la seguridad, la tolerabilidad, la farmacocinética, la farmacodinamia y la eficacia de RO7034067 en lactantes con atrofia muscular espinal tipo 1
    A.4.1Sponsor's protocol code numberBP39056
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/080/2018
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorF. Hoffmann-La Roche Ltd
    B.1.3.4CountrySwitzerland
    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 supportF. Hoffmann-La Roche Ltd
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationF.Hoffmann-La Roche Ltd
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4070
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number+34913257300
    B.5.5Fax number+34913248195
    B.5.6E-mailspain.start_up_unit@roche.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 nameRO7034067
    D.3.2Product code RO7034067/F12
    D.3.4Pharmaceutical form Powder for oral solution
    D.3.4.1Specific paediatric formulation Yes
    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 INNn/a
    D.3.9.2Current sponsor codeRO7034067/F12
    D.3.9.3Other descriptive nameRO7034067
    D.3.9.4EV Substance CodeSUB179686
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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 nameRO7034067
    D.3.2Product code RO7034067/F13
    D.3.4Pharmaceutical form Powder for oral solution
    D.3.4.1Specific paediatric formulation Yes
    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 INNn/a
    D.3.9.2Current sponsor codeRO7034067/F13
    D.3.9.3Other descriptive nameRO7034067
    D.3.9.4EV Substance CodeSUB179686
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Type 1 Spinal Muscular Atrophy (SMA)
    Atrofia muscular espinal Tipo 1 (AME)
    E.1.1.1Medical condition in easily understood language
    SMA is a muscular disease that affects child's muscular development leading to muscle weakness and progressive loss of movement. Type 1 children are usually diagnosed before 6 months of age.
    AME es una enfermedad muscular que afecta al desarrollo muscular de los niños y lleva a debilidad muscular y perdida progresiva del movimiento.
    Los niños tipo 1 son diagnosticados antes de 6 meses
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10041582
    E.1.2Term Spinal muscular atrophy
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Part 1
    •To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of RO7034067 in infants with Type 1 SMA and to select the dose for Part 2
    Part 2
    •To assess the efficacy of RO7034067 measured as the proportion of infants sitting without support after 12 months of treatment
    Parte 1
    •Evaluar la seguridad, la tolerabilidad, la farmacocinética y la farmacodinámica de RO7034067 en lactantes con AME de tipo 1, y seleccionar la dosis para la parte 2.
    Parte 2
    •Evaluar la eficacia de RO7034067 definida por la proporción de lactantes que pueden sentarse sin apoyo tras 12 meses de tratamiento
    E.2.2Secondary objectives of the trial
    To assess:
    •Safety and tolerability of RO7034067
    •Pharmacokinetics of RO7034067
    •Pharmacodynamic effects of RO7034067
    •Effect on motor development milestones
    •Effect on sitting without support and further motor development milestones
    •Impact of treatment with RO7034067 on time to event (death, permanent ventilation)
    •Change from baseline in the total raw score of the BSID-III gross motor scale
    •To assess the proportion of infants:
    •Who achieve a score of 40 or higher in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND)
    •Who achieve an increase of at least 4 points on their CHOP-INTEND score from baseline
    •Who achieve head control
    •Who achieve a reduction of at least 30 degrees in phase angle (respiratory inductance plethysmography)
    •Who are alive without permanent ventilation
    •Who do not require invasive or non-invasive respiratory support
    Evaluar:
    •Seguridad y tolerabilidad de RO7034067
    •Farmacocinética de RO7034067
    •Efectos farmacodinámicos de RO7034067
    •Efecto en los hitos del desarrollo motor
    •Efecto en la capacidad de sentarse sin apoyo y en otros hitos del desarrollo motor
    • El impacto del tratamiento con RO7034067 en el tiempo transcurrido hasta el acontecimiento (muerte, ventilación permanente).
    •El cambio desde el inicio en la puntuación total bruta de la escala de motricidad gruesa de las BSID-III
    •Evaluar la proporción de lactantes que:
    •Obtienen una puntuación de 40 o más en el Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND)
    •Alcanzan un aumento de al menos 4 puntos en su puntuación del CHOP-INTEND desde el inicio en la puntuación
    •Logran el control de la cabeza
    •Alcanzan una reducción de al menos 30 grados en ángulo de fase (pletismografía respiratoria)
    •Sobreviven sin ventilación permanente
    •No necesitan soporte respiratorio invasivo o no invasivo
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Males and females aged between 28 days (1 month) of life and 210 days (7 months) (inclusive) at enrollment
    - A legally authorized representative must be able to consent for the patient according to International Conference on Harmonisation and local regulations
    - Gestational age of 37 to 42 weeks
    - Confirmed diagnosis of 5q-autosomal recessive SMA, including:
    •Genetic confirmation of homozygous deletion or compound heterozygosity predictive of loss of function of the survival motor neuron 1 (SMN1) gene
    •Clinical history, signs or symptoms attributable to Type 1 SMA, i.e., hypotonia, absent deep tendon reflexes and/or tongue fasciculations with onset after the age of 28 days, but prior to the age of 3 months (inclusive), and inability to sit independently (without support) at the time of screening
    - Infant has two SMN2 gene copies, as confirmed by central testing
    - Body weight >= 3rd percentile for age, using appropriate country-specific guidelines (for the first infant only > 7 kg)
    - Receiving adequate nutrition and hydration (with or without gastrostomy) at the time of screening, in the opinion of the Investigator
    - Adequately recovered from any acute illness at the time of screening and considered well-enough to participate in the opinion of the Investigator
    -Niños y niñas de entre 28 días (1 mes) y 210 días (7 meses) (inclusive) de vida en el momento de la inclusión.
    -De acuerdo con las normas de la Conferencia Internacional de Armonización y la normativa local, un representante legalmente autorizado debe tener capacidad de otorgar el consentimiento por el paciente.
    -Edad gestacional de entre 37 y 42 semanas.
    -Diagnóstico confirmado de AME con cromosoma 5q autosómico recesivo, lo que abarca:
    •Confirmación genética de deleción homocigótica o heterocigosidad compuesta predictiva de la pérdida de la función del gen SMN1.
    •Historia clínica, signos o síntomas atribuibles a la AME de tipo 1, es decir, hipotonía, ausencia de reflejo tendinoso profundo (RTP) y/o fasciculaciones de la lengua que se inician después de los 28 días de vida, pero antes de la edad de 3 meses (inclusive), e incapacidad para sentarse solo (sin apoyo) en el momento de la selección.
    -El paciente tiene dos copias del gen SMN2, confirmado por las pruebas centralizadas.
    6) Peso corporal >=3er percentil para la edad, según las directrices específicas de cada país (solo para el primer lactante: > 7 kg).
    -Nutrición e hidratación adecuadas (con o sin gastrostomía) en el momento de la selección, según la opinión del investigador.
    -Recuperado adecuadamente de cualquier enfermedad aguda en el momento de la selección y considerado lo bastante sano como para participar, según la opinión del investigador.
    E.4Principal exclusion criteria
    - Concomitant or previous participation in any investigational drug or device study within 90 days prior to screening or 5 half-lives, whichever is longer
    - Concomitant or previous administration of a SMN2 targeting antisense oligonucleotide or SMN2 splicing modifier or gene therapy either in a clinical study or as part of medical care.
    - Any history of cell therapy
    - Hospitalization for pulmonary event within the last 2 months, or planned at the time of screening
    - Unstable gastrointestinal, renal, hepatic, endocrine or cardiovascular system diseases
    - Inadequate venous or capillary blood access for the study procedures
    - Patients requiring invasive ventilation or tracheostomy
    - Patients requiring awake non-invasive ventilation or with awake hypoxemia (arterial oxygen saturation < 95%) with or without ventilator support
    - Patients with a history of respiratory failure or severe pneumonia, and have not fully recovered their pulmonary function at the time of screening
    - Multiple or fixed contractures and/or hip subluxation or dislocation at birth
    - Presence of non-SMA related concurrent syndromes or diseases
    - Confirmed (2 consecutive measurements) systolic blood pressure or diastolic blood pressure outside the 95th percentile for age; resting heart rate < 70 bpm or > 170 bpm
    - Presence of clinically relevant electrocardiogram (ECG) abnormalities before study drug administration
    - History of malignancy if not considered cured
    - Any major illness within one month before the screening examination or any febrile illness within one week prior to screening and up to first dose administration
    - Taking any nutrients known to modulate cytochrome [CYP] 3A activity within 2 weeks prior to administration of study drugs
    - The infant (and the mother, if breastfeeding the infant):
    • Any inhibitor of CYP3A4 taken within 2 weeks (or within 5 times the elimination half life, whichever is longer) prior to dosing, including but not limited to ketoconazole, miconazole, itraconazole, fluconazole, erythromycin, clarithromycin, ranitidine, cimetidine
    • Any inducer of CYP3A4 taken within 4 weeks (or within 5 times the elimination half-life, whichever is longer) prior to dosing, including but not limited to rifampicin, rifabutin, glucocorticoids, carbamazepine, phenytoin, phenobarbital, St. John's wort
    • Any organic cation transporter-2 and multidrug and toxic compound extrusion substrates shall be avoided
    • Any known flavin containing monooxygenase (FMO) 1 or FMO3 inhibitors or substrates
    - Clinically significant abnormalities in laboratory test results
    - Ascertained or presumptive hypersensitivity to RO7034067 or the constituents of its formulation
    - Prior use (at any time in the patients’ lives) and/or, anticipated need for quinolones (chloroquine and hydroxychloroquine), thioridazine, hydroxychloroquine, vigabatrin, retigabine, or any other drug known to cause retinal toxicity during the study. Infants exposed to chloroquine, hydroxycholoroquine, thioridazine, vigabatrin, retigabine or drugs with known retinal toxicity given to mothers during pregnancy (and lactation) should not be enrolled.
    - Recent history (less than 6 months) of ophthalmic disease that would interfere with the conduct of the study as assessed by an ophthalmologist
    -Participación previa o concomitante en cualquier estudio con un fármaco o dispositivo experimental en un plazo de 90 días antes de la selección o 5 semividas, lo que sea más largo.
    -Administración previa o concomitante de un oligonucleótido en antisentido dirigido contra el SMN2, modificadores del procesado del SMN2 o una terapia génica en el marco de un ensayo clínico o de la atención médica.
    -Cualquier antecedente de terapia celular.
    -Hospitalización a causa de un acontecimiento pulmonar en los últimos 2 meses o que esté prevista en el momento de la selección.
    -Enfermedades gastrointestinales, renales, hepáticas, endocrinas o del sistema cardiovascular inestables.
    -Acceso sanguíneo venoso o capilar inadecuado para los procedimientos del estudio
    -Pacientes que precisen de ventilación invasiva o de una traqueotomía.
    -Pacientes que precisen de ventilación no invasiva mientras están despiertos o con hipoxemia mientras están despiertos (SaO2 < 95 %) con o sin soporte ventilador.
    -Pacientes con antecedentes de fallo respiratorio o neumonía grave, y que no hayan recuperado completamente la función pulmonar en el momento de la selección.
    -Contracturas múltiples o fijas y/o subluxación o dislocación de la cadera al nacer.
    -Presencia de síndromes o enfermedades concomitantes no relacionadas con la AME.
    -Tensión arterial sistólica (TAS) o tensión arterial diastólica (TAD) confirmadas (2 mediciones consecutivas) fuera del percentil 95 para la edad; ritmo cardiaco en reposo <70 lpm o >170
    -Presencia de anomalías en el electrocardiograma (ECG) significativas desde el punto de vista clínico antes de la administración del fármaco del estudio
    -Antecedentes de neoplasia maligna que no se considere curada.
    -Cualquier enfermedad importante un mes antes de las pruebas de la selección o cualquier enfermedad febril en el plazo de una semana antes de la selección y hasta la administración de la primera dosis.
    -Pacientes que hayan tomado nutrientes conocidos por modular la actividad del CYP3A en las 2 semanas previas a la administración de los fármacos del estudio.
    -El lactante (y la madre, si está en periodo de lactancia):
    •Cualquier inhibidor del CYP3A4 tomado en las 2 semanas previas a la administración (o en 5 veces la semivida de eliminación, lo que sea más largo) incluidos, entre otros: ketoconazol, miconazol, itraconazol, fluconazol, eritromicina, claritromicina, ranitidina,
    cimetidina
    • Cualquier inhibidor del CYP3A4 tomado en las 4 semanas previas a la administración (o en 5 veces la semivida de eliminación, lo que sea más largo) incluidos, entre otros: rifampicina, rifabutina, glucocorticoides, carbamazepina, fenitoína, fenobarbital, hierba de San Juan.
    • Se evitará cualquier sustrato de TCO-2 y MATE
    • Cualquier inhibidor o sustrato conocido de la FMO1 o la FMO3.
    -Anomalías significativas desde el punto de vista clínico en los resultados de pruebas analíticas
    -Hipersensibilidad conocida o presunta a RO7034067 o a los componentes de su formulación.
    -El uso previo (en cualquier momento de la vida de los pacientes) y/o la necesidad prevista de quinoloinas (cloroquina e hidroxicloroquina), tioridazina, vigabatrina, retigabina o cualquier otro fármaco con efectos conocidos por causar toxicidad retiniana durante el estudio impide la participación en este ensayo. No se debe incluir a los lactantes expuestos a cloroquina, hidroxicloroquina, tioridazina, vigabatrina, retigabina o fármacos con efectos conocidos por causar toxicidad retiniana administrados a las madres durante el embarazo (y la lactancia).
    -Antecedentes recientes (menos de 6 meses) de enfermedades oftálmicas que pudieran interferir con la realización del estudio, en función de la evaluación de un oftalmólogo.
    E.5 End points
    E.5.1Primary end point(s)
    Part 1 and 2: Safety
    1. Incidence and severity of adverse events (AE) and serious adverse events
    2. Incidence of treatment discontinuations due to AE
    3. Incidence of abnormal laboratory and ECG values
    4. Vital signs abnormalities
    5. Anthropometric and ophthalmological examination
    Part 1
    Pharmacokinetics
    6. Plasma concentrations of RO7034067, and its metabolite(s)

    Pharmacodynamic
    7. Assessment of SMN protein in blood
    8. Assessment of SMN messenger ribonucleic acid (mRNA) in blood
    Part 2: Efficacy
    9. Proportion of infants who are sitting without support at 12 months of treatment assessed by the Gross Motor Scale of the Bayley Scales of Infant and Toddler development – Third Edition (BSID-III)
    Parte 1 y 2: Seguridad
    1. Incidencia y severidad de los acontecimientos adversos (AE)y de los acontecimientos adversos graves.
    2. Incidencia de la discontinuación de los tratamientos debido a AE
    3. Incidencia de valores de laboratorio y ECG anormales
    4. Anormalidades de los signos vitales
    5. Exploración antropométrica y oftalmológica
    Parte 1
    Farmacocinética
    6. Concentraciones plasmáticas de RO7034067, y su(s) metabolito(s)
    Farmacodinamia
    7. Evaluación de la proteína SMN en sangre
    8. Evaluación del SMN acido ribonucleico mensajero (ARNm) en sangre
    Parte 2: Eficacia
    9. Proporción de lactantes que pueden sentarse sin apoyo tras 12 meses de tratamiento conforme la escala de motricidad gruesa de las Escalas Bayley de Desarrollo Infantil,tercera edición (BSID-III)
    E.5.1.1Timepoint(s) of evaluation of this end point
    1-4. Up to 2 years
    5. Screening (D [Day] -30 to D -2), D56, D119, D182, D245, D301, D364, D427, D490, D546, D609, D672, D728
    6. D1, D2, D7, D14, D28, D56, D84, D119, D182, D245, D301, D364, D427, D490, D546, D609, D672, D728
    7. D1, D14, D28, D119, D245, D364, D609, D728
    8. D1, D14, D28, D245, D364, D609, D728
    9. At Month 12
    1-4. Hasta un máximo de 2 años
    5. Screening (D [Dia -30 a D -2), D56, D119, D182, D245, D301, D364, D427, D490, D546, D609, D672, D728
    6. D1, D2, D7, D14, D28, D56, D84, D119, D182, D245, D301, D364, D427, D490, D546, D609, D672, D728
    7. D1, D14, D28, D119, D245, D364, D609, D728
    8. D1, D14, D28, D245, D364, D609, D728
    9. En el mes 12
    E.5.2Secondary end point(s)
    Part 2
    1. Plasma concentrations of RO7034067 and its metabolite (s)
    2. Assessment of SMN protein in blood
    3. Assessment of SMN mRNA in blood
    4. Change from baseline in the Total Raw Score of the BSID-III gross motor scale at Month 12 and 24
    5. Proportion of infants who achieve the attainment levels of the motor milestones assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 and 24
    6. Proportion of infants who achieve a score of 40 or higher in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) at Month 12
    7. Proportion of infants who achieve an increase of at least 4 points in their CHOP-INTEND score from baseline at Month 8 and Month 12
    8. Proportion of infants who achieve head control at Month 8, Month 12, and Month 24
    9. Proportion of infants who achieve a reduction of at least 30 degrees in their phase angle from baseline, as measured by respiratory inductance plethysmography, at Month 12
    10. Time to permanent ventilation (from enrollment)
    11. Proportion of infants who are alive at Month 12 and 24
    12. Proportion of infants who are alive without permanent ventilation at Month 12 and 24
    13. Proportion of infants who do not require invasive or non-invasive respiratory support at Month 12 and Month 24
    14. Ability to swallow and to feed orally at Month 12 and Month 24
    Parte 2
    1. Concentraciones plasmáticas de RO7034067 y su(s) metabolito(s)
    2. Evaluación de la proteína SMN en sangre
    3. Evaluación del SMN ARNm en sangre
    4. Investigar el cambio desde el inicio en la puntuación total bruta de la escala de motricidad gruesa de las BSID-III en el mes 12 y en el mes 24 de tratamiento.
    5. Proporcion de lactantes que alcanzan la consecución de hitos del desarrollo motor a los 12 y 24 meses conforme el módulo 2 del Examen neurológico infantil de Hammersmith (HINE).
    6. Proporción de lactantes que obtienen una puntuación de 40 o más en el Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) a los 12 meses de tratamiento.
    7. Proporción de lactantes que alcanzan un aumento de al menos 4 puntos en su puntuación del CHOP-INTEND desde el inicio en la puntuación a los 8 y 12 meses de tratamiento.
    8. Proporción de lactantes que logran el control de la cabeza a los 8, 12 y 24 meses de tratamiento
    9. Proporción de lactantes que alcanzan una reducción de al menos 30 grados en ángulo de fase a los 12 meses de tratamiento medida mediante pletismografía respiratoria.
    10. Tiempo a ventilación permanente (desde inclusión)
    11. Proporcion de lactantes que están vivos a los 12 y 24 meses
    12. Proporción de lactantes que están vivos sin ventilacion permanente a los 12 y 24 meses.
    13. Proporción de lactantes que no necesitan soporte respiratorio invasivo o no invasivo a los 12 y 24 meses de tratamiento.
    14. Habilidad para tragar y alimentarse oralmente en los meses 12 y 24
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. D1, D2, D14, D28, D56, D119, D182, D245, D301, D364, D427, D490, D546, D609, D672, D728
    2. D1, D28, D119, D245, D364, D609, D728
    3. D1, D28, D245, D364, D609, D728
    4. Baseline, Month 12 and 24
    5. Month 12 and 24
    6. Month 12
    7. Month 8 and 12
    8. Month 8, Month 12 and 24
    9. Baseline and Month 12
    10. Up to 2 years
    11-14. At Month 12 and 24
    1. D1, D2, D14, D28, D56, D119, D182, D245, D301, D364, D427, D490, D546, D609, D672, D728
    2. D1, D28, D119, D245, D364, D609, D728
    3. D1, D28, D245, D364, D609, D728
    4. Basal, Meses 12 y 24
    5. Meses 12 y 24
    6. Mes 12
    7. Meses 8 y 12
    8. Mes 8, Mes 12 y Mes 24
    9. Basal y Mes 12
    10. Hasta un máximo de 2 años
    11-14. En el Mes 12 y 24
    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 Yes
    E.6.13.1Other scope of the trial description
    genetic testing
    Análisis genético
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Diseño en 2 partes
    2 part design
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    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
    Belgium
    Brazil
    Canada
    China
    Croatia
    France
    Germany
    Italy
    Japan
    Lebanon
    Poland
    Russian Federation
    Saudi Arabia
    Serbia
    Spain
    Switzerland
    Turkey
    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
    The end of this study is defined as the date when the last patient last visit (LPLV) occurs.
    The study will continue until RO7034067 is commercially available in the infant’s country, or as per local regulation, or per the Sponsor’s decision to terminate RO7034067 development. However, the study will not exceed 4 years (or less as per country specific requirements) after the last infant is enrolled in the study.
    El final de este estudio se define como la fecha en que tenga lugar la última visita del último paciente (UVUP)
    El estudio continuará hasta que RO7034067 se comercialice en el país del lactante, o según la normativa local, o si el promotor decide finalizar el desarrollo de RO7034067. No obstante, el estudio no excederá los 4 años (o menos, según los requisitos específicos de cada país) después de la inclusión del último lactante en el estudio.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    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 years4
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 64
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 64
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    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 No
    F.3.3.2Women of child-bearing potential using contraception No
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    informed consent for study participation will be obtained from parents or legal guardian
    El consentimiento informado para la participación en el estudio se obtendrá de los padres o tutores legales
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 44
    F.4.2.2In the whole clinical trial 64
    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)
    Post-trial access to study drug (SD) to eligible patients is offered free of charge according to the Roche Global Policy. A patient will be eligible to receive SD after the end of study if all of these conditions are met:patient has a life-threatening or severe medical condition and requires continued SD treatment for his or her well-being/no appropriate alternative treatments available/patient and his or her doctor comply with and satisfy any legal or regulatory requirements that apply to them
    El acceso post-estudio al fármaco del ensayo (FE) en pacientes elegibles se ofrecerá gratis segun política global de Roche. Un paciente será elegible para recibir el FE después del final del estudio si todas estas condiciones se cumplen: El paciente tiene una enfermedad severa o amenazante para la vida que requiere tratamiento continuado con el FE para su bienestar/no hay tratamientos alternativos previos/paciente y su medico cumplen cualquier requerimiento legal o regulatorio que les aplique
    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 Decision2018-08-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-07-19
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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