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    Summary
    EudraCT Number:2021-003417-19
    Sponsor's Protocol Code Number:BN42644
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2023-01-10
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2021-003417-19
    A.3Full title of the trial
    A TWO-PART, SEAMLESS, MULTI-CENTER, RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND STUDY TO INVESTIGATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS AND EFFICACY OF RO7204239 IN COMBINATION WITH RISDIPLAM (RO7034067) IN AMBULANT PATIENTS WITH SPINAL MUSCULAR ATROPHY
    ESTUDIO MULTICENTRO DE CONTINUACIÓN EN DOS PARTES, ALEATORIZADO, CONTROLADO CON PLACEBO, DOBLE CIEGO PARA INVESTIGAR LA SEGURIDAD, TOLERABILIDAD, FARMACOCINÉTICA, FARMACODINÁMICA Y EFICACIA DE RO7204239 EN COMBINACIÓN CON RISDIPLAM (RO7034067) EN PACIENTES AMBULANTES CON ATROFIA MUSCULAR ESPINAL
    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 RO7204239 in Combination with Risdiplam (RO7034067) in Ambulant Patients with Spinal Muscular Atrophy
    Un Estudio para Investigar la Seguridad, Tolerabilidad, Farmacocinética, Farmacodinámica y Eficacia de RO7204239 en Combinación con Risdiplam (RO7034067) en Pacientes Ambulatorios con Atrofia Muscular Espinal
    A.4.1Sponsor's protocol code numberBN42644
    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 SponsorRoche Farma S. A. U. que realiza el ensayo en España y que actúa como representante F. 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+34913248196
    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 nameN/A
    D.3.2Product code RO7204239/F01-01
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNN/A
    D.3.9.1CAS number N/A
    D.3.9.2Current sponsor codeRO7204239
    D.3.9.3Other descriptive nameGYM329
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number80
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    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 Yes
    D.2.1.1.1Trade name Evrysdi
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH, Germany
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/19/2145
    D.3 Description of the IMP
    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 INNRisdiplam
    D.3.9.2Current sponsor codeRO7034067
    D.3.9.4EV Substance CodeSUB193759
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Spinal Muscular Atrophy (SMA)
    Atrofia Muscular Espinal (AME)
    E.1.1.1Medical condition in easily understood language
    SMA is a group of hereditary diseases that destroys nerve cells in the spinal cord that control essential skeletal muscle activity such as speaking, walking, breathing, and swallowing.
    La AME es un grupo de enfermedades hereditarias que destruye las células nerviosas de la médula espinal que controlan la actividad esencial del músculo esquelético (hablar, caminar, respirar y tragar)
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10051203
    E.1.2Term Spinal muscular atrophy congenital
    E.1.2System Organ Class 100000004850
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10041583
    E.1.2Term Spinal muscular atrophy, unspecified
    E.1.2System Organ Class 100000004850
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10079413
    E.1.2Term Spinal muscular atrophy type I
    E.1.2System Organ Class 100000004850
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10079415
    E.1.2Term Spinal muscular atrophy type III
    E.1.2System Organ Class 100000004850
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10079416
    E.1.2Term Spinal muscular atrophy type II
    E.1.2System Organ Class 100000004850
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10079417
    E.1.2Term Spinal muscular atrophy infantile onset
    E.1.2System Organ Class 100000004850
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10079418
    E.1.2Term Spinal muscular atrophy later onset
    E.1.2System Organ Class 100000004850
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10079419
    E.1.2Term Spinal muscular atrophy pre-symptomatic
    E.1.2System Organ Class 100000004850
    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
    • Evaluation of the safety of RO7204239 in combination with risdiplam compared with placebo in combination with risdiplam
    • Evaluation of pharmacokinetic (PK) parameters for RO7204239 when administered in combination with risdiplam
    • Evaluation of PK parameters for risdiplam when administered in combination with RO7204239
    • Evaluation of the immune response to RO7204239 in combination with risdiplam
    • Evaluation of the pharmacodynamic (PD) effects of RO7204239 in combination with risdiplam compared with placebo in combination with risdiplam
    • Evaluation of RO7204239 PK/PD effects
    Part 2
    • Evaluation of the efficacy of RO7204239 in combination with risdiplam compared with placebo in combination with risdiplam
    Parte 1:
    •Evaluación de la seguridad de RO7204239 combinado con risdiplam en comparación con placebo combinado con risdiplam
    •Evaluación de parámetros FC de RO7204239 al administrarlo en combinación con risdiplam
    •Evaluación de parámetros FC de risdiplam al administrarlo en combinación con RO7204239
    •Evaluación de la respuesta inmunitaria a RO7204239 en combinación con risdiplam
    •Evaluación de los efectos FD de RO7204239 combinado con risdiplam en comparación con placebo combinado con risdiplam
    •Evaluación de los efectos FC/FD de RO7204239
    Parte 2:
    •Evaluación de la eficacia y FD de RO7204239 combinado con risdiplam en comparación con placebo combinado con risdiplam
    E.2.2Secondary objectives of the trial
    Part 2
    • Evaluation of the efficacy and PD of RO7204239 in combination with risdiplam compared with placebo in combination with risdiplam
    • Evaluation of the safety of RO7204239 in combination with risdiplam compared with placebo in combination with risdiplam
    • Evaluation of PK parameters for RO7204239 when administered in combination with risdiplam
    • Evaluation of PK parameters for risdiplam when administered in combination with RO7204239
    • Evaluation of immune response to RO7204239 in combination with risdiplam
    Parte 2:
    •Evaluación de la eficacia y FD de RO7204239 combinado con risdiplam en comparación con placebo combinado con risdiplam
    •Evaluación de la seguridad de RO7204239 combinado con risdiplam en comparación con placebo combinado con risdiplam
    •Evaluación de parámetros FC de RO7204239 al administrarlo en combinación con risdiplam
    •Evaluación de parámetros FC de risdiplam al administrarlo en combinación con RO7204239
    •Evaluación de la respuesta inmunitaria a RO7204239 en combinación con risdiplam
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Participants who are 2 to 10 years of age inclusive at screening
    • Participants who have a confirmed genetic diagnosis of 5q-autosomal recessive SMA
    • Symptomatic SMA disease, as per investigator’s clinical judgement
    • Participants who are ambulant, where ambulant is defined as able to walk/run unassisted (i.e., without the use of assistive devices such as canes, walking sticks, crutches, walkers, person/hand held assistance, braces, orthoses, over the malleoli insoles or any other type of support) 10 meters in <= 30 seconds as measured by the Timed 10-Meter Walk/Run Test [10MWRT]) at screening
    • Participants who have received previous SMA disease-modifying therapies may be included provided that
    o Onasemnogene abeparvovec was received at least 90 days prior to screening. Participants should be tapered off steroids prior to receiving risdiplam. In addition, participants should have normal levels of liver function tests, coagulation parameters, platelets, and troponin-I at 90 days after administration of onasemnogene abeparvovec or at least 1 month after tapering off corticosteroids, whichever comes later
    o Nusinersen last dose was received at least 90 days prior to screening
    o Risdiplam is switched to the investigational medicinal product (IMP) provided by the site
    • Participants who have a legally authorized representative able to consent for the participant
    • Participants who are able and willing to comply with the study protocol and to complete all study procedures, measurements, and visits
    • Negative pregnancy test at screening for females of childbearing potential
    • Females of childbearing potential or who may reach childbearing potential during the study: must agree to remain abstinent (refrain from heterosexual intercourse) or use contraception during the treatment period and for both 17 months after the final dose of RO7204239 and 28 days after the final dose of risdiplam
    • For males who are expected to reach sexual maturity during the study: participants must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agree to refrain from donating sperm during the treatment period and for 28 days after the final dose of risdiplam and 4 months after the final dose of RO7204239
    •Edad de entre 2 y 10 años, ambos inclusive, en el período de selección.
    •Diagnóstico genético confirmado de AME autosómica recesiva 5q.
    •Atrofia muscular espinal sintomática, según el criterio clínico del investigador.
    •Capacidad ambulante, entendiéndose como tal la capacidad de caminar/correr sin ayuda (es decir, sin el uso de dispositivos de ayuda como bastones, muletas, andadores, ayuda de otra persona o de la mano, suspensores, aparatos ortopédicos, ortesis supramaleolares o cualquier otro tipo de apoyo) 10 metros en no más de 30 segundos, según la prueba cronometrada de caminar/correr 10 metros [10MWRT]), en el período de selección.
    •Podrán participar pacientes que hayan recibido terapias modificadoras de la enfermedad para la AME previas, siempre que:
    oSe haya recibido onasemnogén abeparvovec al menos 90 días antes de la selección. Antes de recibir risdiplam, los participantes deberán reducir gradualmente los corticoides hasta suspenderlos. Además, deberán presentar valores normales de pruebas de función hepática, parámetros de coagulación, plaquetas y troponina I 90 días después de la administración de onasemnogén abeparvovec o al menos un mes después de la reducción gradual de los corticoides, lo que ocurra más tarde.
    oSe haya recibido la última dosis de nusinersén al menos 90 días antes de la selección.
    oSe sustituya el risdiplam por el medicamento en investigación suministrado por el centro.
    •Disponibilidad de un representante legal capaz de otorgar su consentimiento en nombre del participante
    •Capacidad y disposición a cumplir el protocolo del estudio y a completar todos los procedimientos, determinaciones y visitas del estudio.
    •Prueba de embarazo negativa en el período de selección en las mujeres con capacidad de procrear.
    •Las mujeres con capacidad de procrear o que puedan alcanzar dicha capacidad durante el estudio deberán comprometerse a practicar abstinencia sexual (abstenerse de mantener relaciones heterosexuales) o a utilizar métodos anticonceptivos durante el período de tratamiento y 17 meses después de la dosis final de RO7204239 y 28 días después de la dosis final de risdiplam
    •Varones que se espera que alcancen la madurez sexual durante el estudio: deberán comprometerse a practicar abstinencia sexual (abstenerse de mantener relaciones heterosexuales) o a utilizar métodos anticonceptivos, y aceptan abstenerse de donar esperma durante el período de tratamiento y durante los 28 días posteriores a la dosis final de risdiplam y los 4 meses posteriores a la dosis final de RO7204239
    E.4Principal exclusion criteria
    • Participants with concomitant or previous participation in any investigational drug or device study within 90 days prior to screening, or 5 half-lives of the drug, whichever is longer, with the exception of those who have completed a risdiplam study, or participated in a nusinersen or onasemnogene abeparvovec study
    • Participants who are receiving or have received previous administration of anti-myostatin therapies
    • For Part 1 participants aged 5-10 years only: Participants who have contraindications for magnetic resonance imaging (MRI) scans, difficulties maintaining a prolonged supine position, or any other clinical history or examination finding that would pose a potential hazard in combination with MRI
    • Participants with any history of cell therapy
    • Participants who have been hospitalized for a pulmonary event within the last 2 months or planned hospitalization at the time of screening
    • Participants who have had surgery for scoliosis or hip fixation in the 6 months preceding screening or planned within the next 9 months (Part 1) or 21 months (Part 2)
    • Participants who have unstable gastrointestinal, renal, hepatic, endocrine, or cardiovascular system diseases considered to be clinically significant
    • Participants who have clinically significant electrocardiography (ECG) abnormalities at screening
    • Participants with clinically significant abnormal findings at echocardiography at screening from average of triplicate measurement or cardiovascular disease indicating a safety risk for participants
    • Participants who have had any major illness within 1 month before screening
    • Participants who have received any MATE1/2K substrates within 2 weeks before screening
    • Participants with hereditary fructose intolerance
    • Participants who have used any of the following medications within 90 days prior to screening: riluzole, valproic acid, hydroxyurea, sodium phenylbutyrate, butyrate derivatives, creatine, carnitine, growth hormone, anabolic steroids, probenecid, acetyl cholinesterase inhibitors, agents that could potentially increase or decrease muscle strength, and agents with known or presumed histone deacetylase (HDAC) inhibitory effect
    • For Part 2 only: Participants who have recently initiated treatment (within <6 months prior to screening) with oral salbutamol or another β2-adrenergic agonist taken orally is not allowed
    • Participants who have clinically significant abnormalities in laboratory test results
    • Participants who have ascertained or presumptive hypersensitivity to RO7204239 or risdiplam, or to the constituents of their formulations
    • Participants with concomitant disease or a condition that could interfere with, or treatment of which might interfere with, the conduct of the study, or that would pose an unacceptable risk to the participant in this study
    • Participants who have a history of any malignancy
    • Participants who have any clinically relevant history of anaphylactic reaction requiring inotropic support
    • Participants who have any abnormal skin conditions, pigmentation or lesions in the area intended for subcutaneous (SC) injection (abdomen) and that would prevent visualization of potential injection site reactions to RO7204239
    • Participants with immobilization, surgical procedures, fracture, or trauma to the upper or lower limbs within 90 days prior to screening
    • Female participants who are pregnant or breastfeeding, or intending to become pregnant during the study or within either 17 months after the final dose of RO7204239 or 28 days after the final dose of risdiplam
    •Participación simultánea o previa en cualquier estudio de un fármaco o dispositivo en investigación en los 90 días previos a la selección, o el equivalente a 5 semividas del fármaco, lo que suponga más tiempo, con la excepción de los que hayan completado un estudio de risdiplam o hayan participado en un estudio de nusinersén o de onasemnogén abeparvovec.
    •Recepción activa o administración previa de terapias antimiostatina.
    •Exclusivamente para los participantes de 5-10 años en la parte 1: Presencia de contraindicaciones de la RM, dificultades para mantener una posición prolongada en decúbito supino o cualquier otro antecedente clínico o dato de la exploración que suponga un posible riesgo en combinación con la RM.
    •Antecedentes de terapia celular.
    •Hospitalización por un episodio pulmonar en los dos últimos meses u hospitalización prevista en el momento de la selección.
    •Práctica de una intervención quirúrgica por escoliosis o fijación de la cadera en los seis meses previos a la selección o previsión de practicarla en los 9 meses (parte 1) o 21 meses (parte 2) siguientes.
    •Presencia de enfermedades gastrointestinales, renales, hepáticas, endocrinas o del aparato cardiovascular inestables que se consideren clínicamente significativas.
    •Presencia de anomalías electrocardiográficas clínicamente significativas en el período de selección, según el promedio de tres determinaciones, o enfermedades cardiovasculares indicativas de un riesgo para la seguridad de los participantes.
    •Hallazgos anormales clínicamente significativos en el ecocardiograma de selección.
    •Presencia de cualquier enfermedad importante en el mes previo a la selección.
    •Recepción de cualquier sustrato de MATE1/2K en las dos semanas previas a la selección.
    •Intolerancia hereditaria a la fructosa.
    •Uso de cualquiera de los siguientes medicamentos en los 90 días previos a la selección: riluzol, ácido valproico, hidroxicarbamida, fenilbutirato sódico, derivados del butirato, creatina, carnitina, hormona del crecimiento, esteroides anabolizantes, probenecid, inhibidores de la acetilcolinesterasa, fármacos que podrían aumentar o disminuir la fuerza muscular y fármacos con un efecto inhibidor conocido o supuesto de la histona desacetilasa (HDAC).
    •Exclusivamente para la parte 2: Inicio reciente del tratamiento (en los 6 meses previos a la selección) con salbutamol oral u otro agonista adrenérgico β2 por vía oral.
    •Anomalías clínicamente significativas en los resultados analíticos.
    •Hipersensibilidad confirmada o presunta a RO7204239 o risdiplam o a los componentes de sus formulaciones.
    •Presencia de una enfermedad o trastorno concomitante que podría interferir, o cuyo tratamiento podría interferir, en la realización del estudio o que suponga un riesgo inaceptable para el participante en el estudio.
    •Antecedentes de cualquier neoplasia maligna.
    •Antecedentes clínicamente relevantes de reacción anafiláctica con necesidad de apoyo inotrópico.
    •Presencia de condiciones anormales de la piel, pigmentación o lesiones en la zona prevista para la inyección SC (abdomen) que podrían impedir la visualización de posibles reacciones en el lugar de inyección a RO7204239.
    •Inmovilización, intervención quirúrgica, fractura o traumatismo de las extremidades superiores o inferiores en los 90 días previos a la selección.
    •Mujer embarazada o en período de lactancia o con intención de quedarse embarazada durante el estudio o en los 17 meses siguientes a la última dosis de RO7204239 o en los 28 días siguientes a la última dosis de risdiplam.
    E.5 End points
    E.5.1Primary end point(s)
    Part 1
    1. Incidence, severity, and causal relationship of adverse events (AEs), with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0)
    2. Change from baseline in vital signs, physical findings, ECG, echocardiogram, relevant echocardiographic parameters and clinical laboratory results
    3. Incidence of local and systemic injection reactions
    4. Incidence of abnormal laboratory findings
    5. Incidence of abnormal ECG parameters
    6. Incidence of relevant echocardiographic parameter z scores >2
    7. Incidence of abnormal vital signs
    8. Serum concentration of RO7204239 at specified timepoints
    9. Maximum observed concentration (Cmax) of RO7204239 at specified timepoints
    10. Area under the concentration-time curve (AUC) of RO7204239 at specified timepoints
    11. Trough concentration (Ctrough) of RO7204239 at specified timepoints
    12. Plasma concentration of risdiplam (and its metabolite M1) at specified timepoints
    13. Cmax of risdiplam (and its metabolite M1) at specified timepoints
    14. AUC of risdiplam (and its metabolite M1) at specified timepoints
    15. Ctrough of risdiplam (and its metabolite M1) at specified timepoints
    16. Prevalence of anti-drug antibodies (ADAs) against RO7204239 at baseline and incidence of ADAs during the study
    17. Change from baseline in serum concentrations of total and free latent myostatin, and mature myostatin
    18. Percentage change from baseline in the contractile area of skeletal muscle in the dominant thigh as assessed by MRI (participants >=5 years) at Week 24 of combination treatment
    19. Percentage change from baseline in the contractile area of skeletal muscle in the dominant calf as assessed by MRI (participants >=5 years) at Week 24 of combination treatment
    20. Relationship between PK/PD endpoints, ADA status, and safety or efficacy
    Part 2
    21. Change from baseline in the RHS total score at Week 72 of combination treatment (Study Week 80)
    1. Incidencia, intensidad y relación causal de los AA, con determinación de la intensidad conforme a los criterios NCI-CTCAE, versión 5.0.
    2. Variación con respecto al momento basal de las constantes vitales, datos de la exploración clínica, ECG, ecocardiogramas, parámetros ecocardiográficos relevantes y resultados analíticos.
    3. Incidencia de reacciones locales y sistémicas a la inyección.
    4. Incidencia de anomalías analíticas.
    5. Incidencia de parámetros electrocardiográficos anormales.
    6. Incidencia de puntuaciones z de parámetros ecocardiográficos relevantes >2.
    7. Incidencia de anomalías de las constantes vitales.
    8. Concentración sérica de RO7204239 en los momentos especificados.
    9. Cmáx.
    10. AUC.
    11. Cmín.
    12. Concentración plasmática de risdiplam (y su metabolito M1) en los momentos especificados.
    13. Cmáx.
    14. AUC.
    15. Cmín.
    16. Prevalencia de AcAT en el momento basal e incidencia de AcAT durante el estudio.
    17. Variación con respecto al momento basal de las concentraciones séricas de miostatina latente total y libre y miostatina madura.
    18. Variación porcentual con respecto al momento basal de la superficie contráctil de músculo esquelético en los músculos del muslo dominante, evaluada mediante RM (participantes ≥ de 5 años) en la semana 24 de tratamiento combinado.
    19. Variación porcentual con respecto al momento basal de la superficie contráctil de músculo esquelético en los músculos de la pantorrilla dominante, evaluada mediante RM (participantes ≥ de 5 años) en la semana 24 de tratamiento combinado.
    20. Relación entre los criterios de valoración FC y FD, la presencia o ausencia de AcAT, la seguridad y la eficacia.
    Parte 2:
    21. Variación de la puntuación RHS total entre el momento basal y la semana 72 de tratamiento combinado (semana 80 del estudio).
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Up to Week 96
    2. Baseline to Week 96
    3-7. Up to Week 96
    8-11. At Weeks 1, 2, 3, 5, 9, 13, 17, 21, 22, 23, 24, 29, 41, 53, 65, 72, 85 and 96
    12-15. At Week 21
    16. At Weeks 1, 9, 17, 24, 29, 41, 53, 65, 72, 85 and 96
    17. Baseline to Week 85
    18-19. Baseline to Week 24
    20. Up to Week 96
    21. Baseline to Week 72
    1. Hasta la semana 96
    2. Momento basal a la semana 96
    3-7. Hasta la Semana 96
    8-11. En las Semanas 1, 2, 3, 5, 9, 13, 17, 21, 22, 23, 24, 29, 41, 53, 65, 72, 85 y 96
    12-15. En la semana 21
    16. En las semanas 1, 9, 17, 24, 29, 41, 53, 65, 72, 85 y 96
    17. Momento basal hasta la semana 85
    18-19. Momento basal hasta la semana 24
    20. Hasta la semana 96
    21. Momento basal hasta la semana 72
    E.5.2Secondary end point(s)
    Part 2
    1. Change from baseline in Motor Function Measure (MFM) Domain 1 + Domain 2 (D1 + D2) score at Week 72 of combination treatment (Study Week 80)
    2. Change from baseline in Motor Function Measure-32 item (MFM32) total score at Week 72 of combination treatment (Study Week 80)
    3. Change from baseline in the time taken to rise from floor as measured by Revised Hammersmith Scale (RHS) Item 25 at Week 72 of combination treatment (Study Week 80)
    4. Change from baseline in the time taken to walk/run 10 meters as measured by RHS Item 19 at Week 72 of combination treatment (Study Week 80)
    5. Change from baseline in lean muscle mass as assessed by full-body dual-energy X-ray absorptiometry (DXA) scan (participants >=5 years) at Week 72 of combination treatment (Study Week 80)
    6. Incidence, severity, and causal relationship of AEs, with severity determined according to NCI CTCAE v5.0
    7. Change from baseline in vital signs, physical findings, ECG, echocardiogram, relevant echocardiographic parameters and clinical laboratory results
    8. Incidence of local and systemic injection reactions
    9. Incidence of abnormal laboratory findings
    10. Incidence of abnormal ECG parameters
    11. Incidence of relevant echocardiographic parameter z scores >2
    12. Incidence of abnormal vital signs
    13. Serum concentration of RO7204239 at specified timepoints
    14. Cmax of RO7204239 at specified timepoints
    15. AUC of RO7204239 at specified timepoints
    16. Ctrough of RO7204239 at specified timepoints
    17. Plasma concentration of risdiplam (and its metabolite M1) at specified timepoints
    18. Cmax of risdiplam (and its metabolite M1) at specified timepoints
    19. AUC of risdiplam (and its metabolite M1) at specified timepoints
    20. Ctrough of risdiplam (and its metabolite M1) at specified timepoints
    21. Impact of ADA on PK, PD, safety and efficacy parameters
    Parte 2
    1. Variación de la puntuación MFM D1 + D2 entre el momento basal y la semana 72 de tratamiento combinado (semana 80 del estudio).
    2. Variación de la puntuación MFM32 total entre el momento basal y la semana 72 de tratamiento combinado (semana 80 del estudio).
    3. Variación con respecto al momento basal del tiempo invertido en levantarse del suelo, determinado mediante el apartado 25 de la escala RHS, en la semana 72 de tratamiento combinado (semana 80 del estudio).
    4. Variación con respecto al momento basal del tiempo invertido en caminar o correr 10 metros, determinado mediante el apartado 19 de la escala RHS en la semana 72 de tratamiento combinado (semana 80 del estudio).
    5. Variación con respecto al momento basal de la masa muscular magra, evaluada mediante DEXA de cuerpo entero (participantes ≥ de 5 años), en la semana 72 de tratamiento combinado (semana 80 del estudio).
    6. Incidencia, intensidad y relación causales de los AA, con determinación de la intensidad conforme a los criterios NCI-CTCAE, versión 5.0.
    7. Variación con respecto al momento basal de las constantes vitales, datos de la exploración clínica, ECG, ecocardiogramas, parámetros ecocardiográficos relevantes y resultados analíticos.
    8. Incidencia de reacciones locales y sistémicas a la inyección.
    9. Incidencia de anomalías analíticas.
    10. Incidencia de parámetros electrocardiográficos anormales.
    11. Incidencia de puntuaciones z de parámetros ecocardiográficos relevantes >2.
    12. Incidencia de anomalías de las constantes vitales.
    13. Concentración sérica de RO7204239 en los momentos especificados.
    14. Cmáx.
    15. AUC.
    16. Cmín.
    17. Concentración plasmática de risdiplam (y su metabolito M1) en los momentos especificados.
    18. Cmáx.
    19. AUC.
    20. Cmín.
    21. Efecto de los AcAT sobre parámetros FC, FD, de seguridad y de eficacia.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1-5. Baseline to Week 72 of combination treatment (Study Week 80)
    6. Up to Week 72 of combination treatment (Study Week 80)
    7. Baseline to Week 72 of combination treatment (Study Week 80)
    8-12. Up to Week 72 of combination treatment (Study Week 80)
    13-16. At Weeks 1, 5, 9, 13, 17, 21, 24, 37, 48, 61 and 72 (of combination treatment)
    17-20. At Week 24
    21. Up to Week 72 of combination treatment (Study Week 80)
    1-5. Momento basal hasta la semana 72 de tratamiento combinado (semana 80 del estudio)
    6. Hasta la semana 72 de tratamiento combinado (semana 80 del estudio)
    7. Momento basal hasta la semana 72 de tratamiento combinado (semana 80 del estudio)
    8-12. Hasta la semana 72 de tratamiento combinado (semana 80 del estudio)
    13-16. En las Semanas 1, 5, 9, 13, 17, 21, 24, 37, 48, 61 y 72 (de tratamiento combinado)
    17-20. En la semana 24
    21. Hasta la semana 72 de tratamiento combinado (semana 80 del estudio)
    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) Yes
    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 No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Placebo + Risdiplam
    E.8.2.4Number of treatment arms in the trial8
    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 EEA23
    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
    United States
    France
    Poland
    Netherlands
    Spain
    Germany
    Italy
    Belgium
    Croatia
    United Kingdom
    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 of the last visit of the last participant in the study or the date at which the last data point required for statistical analysis (i.e., for the final analysis) or safety follow-up is received from the last participant in the study, whichever occurs later.
    El final de este estudio se define como la fecha de la última visita del último participante en el estudio o la fecha en la que se recibe el último punto de datos requerido para el análisis estadístico (es decir, para el análisis final) o seguimiento de seguridad. el último participante en el estudio, lo que ocurra más tarde.
    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 months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    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 Yes
    F.1.1Number of subjects for this age range: 180
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 180
    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 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 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 Yes
    F.3.3.7.1Details of other specific vulnerable populations
    Pediatric population
    Población pediátrica
    F.4 Planned number of subjects to be included
    F.4.1In the member state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 90
    F.4.2.2In the whole clinical trial 180
    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)
    The Sponsor will offer continued access to Roche IMP RO7204239 or Risdiplam free of charge to eligible participants in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product. For detailed information refer to protocol BN42644, section 6.7 Continued access to study treatment after the end of the study.
    El Promotor ofrecerá acceso continuo al medicamento en investigación de Roche, RO7204239 o Risdiplam, de forma gratuita a los participantes elegibles de acuerdo con la Política Global de Roche sobre Acceso Continuo a Medicamentos en Investigación. Para obtener información detallada, consulte el protocolo BN42644, sección 6.7 Acceso continuo al tratamiento del estudio después de la finalización del estudio.
    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 Decision2023-04-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-12-22
    P. End of Trial
    P.End of Trial StatusOngoing
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