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    Summary
    EudraCT Number:2021-003417-19
    Sponsor's Protocol Code Number:BN42644
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-10-18
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT 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
    STUDIO IN DUE PARTI, IN CONTINUO,
    MULTICENTRICO, RANDOMIZZATO, CONTROLLATO
    CON PLACEBO E IN DOPPIO CIECO PER VALUTARE
    SICUREZZA, TOLLERABILITÀ, FARMACOCINETICA,
    FARMACODINAMICA ED EFFICACIA DI RO7204239 IN
    ASSOCIAZIONE A RISDIPLAM (RO7034067) IN
    PAZIENTI DEAMBULANTI CON ATROFIA MUSCOLARE
    SPINALE
    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
    Uno studio per indagare su sicurezza, tollerabilità, farmacocinetica, Farmacodinamica ed efficacia di RO7204239 in combinazione con Risdiplam (RO7034067) in pazienti ambulatoriali con atrofia muscolare spinale
    A.3.2Name or abbreviated title of the trial where available
    NA
    NA
    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 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 number00000000
    B.5.5Fax number00000000
    B.5.6E-mailglobal.rochegenentechtrials@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/infusion
    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.3.9.2Current sponsor codeRO7204239
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product 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/ EU/1/21/1531/001
    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.3.1Product nameRisdiplam
    D.3.2Product code [RO7034067]
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection/infusion
    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 muscolare spinale (SMA)
    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.
    SMA è un gruppo di malattie ereditarie che distrugge le cellule nervose nel midollo spinale che controllano l'attività muscolare scheletrica essenziale come parlare, camminare, respirare e deglutire.
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    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 20.1
    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 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 10079419
    E.1.2Term Spinal muscular atrophy pre-symptomatic
    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.1.3Condition 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
    - Valutazione della sicurezza di RO7204239 in ssociazione a risdiplam rispetto al placebo in associazione a risdiplam
    - Valutazione dei parametri PK di RO7204239 somministrato in associazione a risdiplam
    - Valutazione dei parametri PK di risdiplam somministrato in associazione a RO7204239
    - Valutazione della risposta immunitaria a RO7204239 in associazione a risdiplam
    - Valutazione degli effetti PD di RO7204239 in ssociazione a risdiplam rispetto al placebo in associazione a risdiplam
    - Valutazione degli effetti PK/PD di RO7204239
    Parte 2
    - Valutazione dell’efficacia di RO7204239 in associazione a
    risdiplam rispetto al placebo in associazione a 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
    - Valutazione dell’efficacia e della PD di RO7204239 in associazione a risdiplam rispetto al placebo in associazione a risdiplam
    - Valutazione della sicurezza di RO7204239 in associazione a
    risdiplam rispetto al placebo in associazione a risdiplam
    - Valutazione dei parametri PK di RO7204239 somministrato in associazione a risdiplam
    - Valutazione dei parametri PK di risdiplam somministrato in associazione a RO7204239
    - Valutazione della risposta immunitaria a RO7204239 in
    associazione a 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 10 meters in <=30 seconds 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, coagulatory 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
    • For females of childbearing potential, or who will reach childbearing potential during the study: participants who have a negative blood pregnancy test at screening and 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 who 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
    - Partecipanti di età compresa tra 2 e 10 anni inclusi allo screening
    - Partecipanti che hanno una diagnosi genetica confermata di SMA autosomica recessiva 5q
    - Malattia SMA sintomatica, secondo il giudizio clinico dello sperimentatore
    - Partecipanti che sono ambulanti, dove ambulante è definito come in grado di camminare/correre 10 metri in <=30 secondi allo screening
    - I partecipanti che hanno ricevuto precedenti terapie modificanti la malattia della SMA possono essere inclusi a condizione che
    -Onasemnogene abeparvovec è stato ricevuto almeno 90 giorni prima dello screening. Ai partecipanti devono essere ridotti gradualmente gli steroidi prima di ricevere risdiplam. Inoltre, i partecipanti devono avere livelli normali di test di funzionalità epatica, parametri coagulativi, piastrine e troponina-I 90 giorni dopo la somministrazione di onasemnogene abeparvovec o almeno 1 mese dopo la riduzione graduale dei corticosteroidi, a seconda di quale evento si verifica dopo.
    - L'ultima dose di Nusinersen è stata ricevuta almeno 90 giorni prima dello screening
    - Risdiplam è passato a medicinale sperimentale (IMP) fornito dal centro
    - Partecipanti che hanno un rappresentante legalmente autorizzato in grado di dare il consenso per il partecipante
    - Partecipanti che sono in grado e disposti a rispettare il protocollo di studio e a completare tutte le procedure, misurazioni e visite dello studio
    - Per le donne in età fertile, o che raggiungeranno l'età fertile durante lo studio: partecipanti che hanno un test di gravidanza del sangue negativo allo screening e accettano di rimanere astinenti (astenersi da rapporti eterosessuali) o utilizzare la contraccezione durante il periodo di trattamento e per entrambi i 17 mesi dopo la dose finale di RO7204239 e 28 giorni dopo la dose finale di risdiplam
    - Per i maschi che dovrebbero raggiungere la maturità sessuale durante lo studio: partecipanti che accettano di rimanere astinenti (astenersi da rapporti eterosessuali) o utilizzare metodi contraccettivi e accettano di astenersi dal donare sperma durante il periodo di trattamento e per 28 giorni dopo la dose finale di risdiplam e 4 mesi dopo la dose finale di 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 multidrug and toxin extrusion (MATE1/2K) substrates within 2 weeks before screening
    • 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 ß2-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
    1. Partecipanti con adesione concomitante o precedente a qualsiasi studio su farmaci o dispositivi sperimentali entro 90 giorni prima dello screening o 5 emivite del farmaco, a seconda di quale sia più lunga, ad eccezione di coloro che hanno completato uno studio sul risdiplam o hanno partecipato a uno studio con onasemnogene abeparvovec o nusinersen
    2. Partecipanti che stanno ricevendo o hanno ricevuto una precedente somministrazione di terapie anti-miostatina
    3. Solo per i partecipanti alla Parte 1 di età compresa tra 5 e 10 anni: partecipanti che hanno controindicazioni per le scansioni di risonanza magnetica (MRI), difficoltà a mantenere una posizione supina prolungata o qualsiasi altra storia clinica o risultato dell'esame che rappresenterebbe un potenziale rischio in combinazione con la risonanza magnetica
    4. partecipanti con anamnesi di terapia cellulare
    5. Partecipanti che sono stati ricoverati per un evento polmonare negli ultimi 2 mesi o ospedalizzazioni programmate al momento dello screening
    6. Partecipanti che hanno subito un intervento chirurgico per scoliosi o fissazione dell'anca nei 6 mesi precedenti lo screening o pianificato entro i successivi 9 mesi (Parte 1) o 21 mesi (Parte 2)
    7- Partecipanti con malattie del sistema gastrointestinale, renale, epatico, endocrino o cardiovascolare instabili considerate clinicamente significative
    8. Partecipanti che presentano anomalie clinicamente significative dell'elettrocardiografia (ECG) allo screening
    9. Partecipanti con risultati anormali clinicamente significativi all'ecocardiografia allo screening dalla media di misurazioni triplicate o malattie cardiovascolari che indicano un rischio per la sicurezza per i partecipanti
    10. Partecipanti che hanno avuto una malattia grave entro 1 mese prima dello screening
    11. Partecipanti che hanno ricevuto substrati di estrusione multifarmaco e tossina (MATE1/2K) entro 2 settimane prima dello screening
    12. Partecipanti che hanno utilizzato uno dei seguenti farmaci nei 90 giorni precedenti lo screening: riluzolo, acido valproico, idrossiurea, sodio fenilbutirrato, derivati del butirrato, creatina, carnitina, ormone della crescita, steroidi anabolizzanti, probenecid, inibitori dell'acetil colinesterasi, agenti che potrebbero potenzialmente aumentare o diminuire la forza muscolare e agenti con effetto inibitorio noto o presunto dell'istone deacetilasi (HDAC)
    13. Solo per la Parte 2: i partecipanti che hanno iniziato di recente il trattamento (entro <6 mesi prima dello screening) con salbutamolo orale o un altro agonista ß2-adrenergico assunto per via orale non sono ammessi
    14. Partecipanti che presentano anomalie clinicamente significative nei risultati dei test di laboratorio
    15. Partecipanti che hanno un accertata o presunta ipersensibilità a RO7204239 o risdiplam, o ai costituenti delle loro formulazioni
    16. Partecipanti con malattie concomitanti o una condizione che potrebbe interferire o il cui trattamento potrebbe interferire con la conduzione dello studio, o che rappresenterebbe un rischio inaccettabile per il partecipante a questo studio
    17. Partecipanti che hanno una storia di qualsiasi neoplasia
    18. Partecipanti che hanno una storia clinicamente rilevante di reazione anafilattica che richiede supporto inotropo
    19. Partecipanti che presentano condizioni cutanee anomali, pigmentazione o lesioni nell'area destinata all'iniezione sottocutanea (SC) (addome) e che impedirebbero la visualizzazione di potenziali reazioni nel sito di iniezione a RO7204239
    20. Partecipanti con immobilizzazione, procedure chirurgiche, fratture o traumi agli arti superiori o inferiori entro 90 giorni prima dello screening
    21. Partecipanti donne in gravidanza o allattamento o che intendono iniziare una gravidanza durante lo studio o entro 17 mesi dalla dose finale di RO7204239 o 28 giorni dopo la dose finale di 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. Change from baseline in the contractile area of skeletal muscle in the thigh as assessed by MRI (participants >=5 years) at Week 24 of combination treatment
    19. Change from baseline in the contractile area of skeletal muscle in the 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 Incidenza, severità e nesso causale degli AE, con severità stabilita in funzione dei criteri NCI CTCAE v5.0
    2 Variazione di segni vitali, obiettività, ECG, ecocardiogramma, parametri ecocardiografici rilevanti e risultati clinici di laboratorio rispetto al basale
    3 Incidenza di reazioni all’iniezione localizzate e sistemiche
    4 Incidenza di anomalie nei risultati degli esami di laboratorio
    5 Incidenza di anomalie nei parametri ECG
    6 Incidenza di parametri ecocardiografici rilevanti z score > 2
    7 Incidenza di anomalie nei segni vitali
    8. Concentrazione sierica di RO7204239 in punti temporali specificati
    9.Concentrazione massima (Cmax) di RO7204239 in punti temporali specificati
    10. AUC di RO7204239 in punti temporali specificati
    11. Ctrough di RO7204239 in punti temporali specificati
    12. Concentrazione plasmatica di risdiplam (e del suo metabolita M1) in punti temporali specifici
    13. Cmax di risdiplam (e del suo metabolita M1) in punti temporali specifici
    14. AUC di risdiplam (e del suo metabolita M1) in punti temporali specifici
    15. Ctrough di risdiplam (e del suo metabolita M1) in punti temporali specifici
    16. Prevalenza di ADA al basale e incidenza di ADA durante lo studio
    17. Variazione delle concentrazioni sieriche di miostatina latente e matura, totale e libera, rispetto al basale
    18. Variazione dell’unità contrattile del tessuto muscolare scheletrico dei muscoli della coscia valutata mediante RM (partecipanti di età >= 5 anni) rispetto al basale alla Settimana 24 di trattamento combinato
    19. Variazione dell’unità contrattile del tessuto muscolare scheletrico dei muscoli del polpaccio valutata mediante
    RM (partecipanti di età ¿ 5 anni) dal basale alla Settimana 24 del trattamento combinato
    20. Correlazione tra gli endpoint PK e PD, lo stato ADA, la sicurezza e l’efficacia
    21. Variazione del punteggio RHS totale dal basale alla Settimana 72 di trattamento combinato (Settimana 80 dello studio)
    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. Fino alla settimana 96
    2. Dal basale alla settimana 96
    3-7. Fino alla settimana 96
    8-11. Alle settimane 1, 2, 3, 5, 9, 13, 17, 21, 22, 23, 24, 29, 41, 53, 65, 72, 85 e 96
    12-15. Alla settimana 21
    16. Alle settimane 1, 9, 17, 24, 29, 41, 53, 65, 72, 85 e 96
    17. Dal basale alla settimana 85
    18-19. Dal basale alla settimana 24
    20. Fino alla settimana 96
    21. Dal basale alla settimana 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
    Part2
    1. Variazione del punteggio MFM D1 + D2 dal basale alla Settimana 72 di trattamento combinato (Settimana 80 dello studio)
    2. Variazione del punteggio MFM32 totale dal basale alla Settimana 72 di trattamento combinato (Settimana 80 dello studio)
    3. Variazione del tempo impiegato per alzarsi dal pavimento misurato in funzione dell’item 25 della scala RHS dal basale alla Settimana 72 di trattamento combinato (Settimana 80 dello studio)
    4. Variazione del tempo impiegato per camminare/correre 10 metri misurato in funzione dell’item 19 della scala RHS dal basale alla Settimana 72 di trattamento combinato (Settimana 80 dello studio)
    5. Variazione della massa muscolare magra valutata mediante DXA total body (partecipanti di età >= 5 anni) dal basale alla Settimana 72 di trattamento combinato (Settimana 80 dello studio)
    6. Incidenza, severità e nessi causali degli AE con severità stabilita in funzione dei criteri NCI CTCAE v5.0
    7. Variazione di segni vitali, obiettività, ECG, ecocardiogramma, parametri ecocardiografici rilevanti e risultati clinici di laboratorio rispetto al basale
    8. Incidenza di reazioni all’iniezione localizzate e sistemiche
    9. Incidenza di anomalie nei risultati degli esami di laboratorio
    10. Incidenza di anomalie nei parametri ECG
    11. Incidenza dei parametri ecocardiografici rilevanti z score > 2
    12. Incidenza di anomalie nei segni vitali
    13. Concentrazione sierica di RO7204239 in punti temporali specifici
    14. Cmax di RO7204239 in punti temporali specifici
    15. AUC di RO7204239 in punti temporali specifici
    16. Ctrough di RO7204239 in punti temporali specifici
    17. Concentrazione plasmatica di risdiplam (e del suo metabolita M1) in punti temporali specifici
    18. Cmax di risdiplam (e del suo metabolita M1) in punti temporali specifici
    19. AUC di risdiplam (e del suo metabolita M1) in punti temporali specifici
    20. Ctrough di risdiplam (e del suo metabolita M1) in punti temporali specifici
    21. impatto degli ADA sui parametri PK, PD, di sicurezza ed efficacia
    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. Dal basale alla settimana 72 del trattamento combinato (Settimana 80 di studio)
    6. Fino alla settimana 72 di trattamento combinato (settimana 80 di studio)
    7. Dal basale alla settimana 72 del trattamento di associazione (Settimana 80 di studio)
    8-12. Fino alla settimana 72 del trattamento combinato (settimana di studio 80)
    13-16. Alle settimane 1, 5, 9, 13, 17, 21, 24, 37, 48, 61 e 72 (di
    trattamento combinato)
    17-20. Alla settimana 24
    21. Fino alla settimana 72 di trattamento combinato (Settimana 80 di studio)
    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
    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 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 concerned3
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    Italy
    Netherlands
    Poland
    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 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.
    La fine di questo studio è definita come la data dell'ultima visita dell'ultimo partecipante allo studio o la data in cui l'ultimo data point richiesto per l'analisi statistica (cioè per l'analisi finale) o il follow-up di sicurezza è ricevuto dall'ultimo partecipante allo studio, a seconda di quale evento si verifica dopo
    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.1.1.1In 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
    Il consenso informato per la partecipazione allo studio sarà ottenuto dai genitori o dal tutore legale
    F.3.3.7Others Yes
    F.3.3.7.1Details of other specific vulnerable populations
    Pediatric population
    Popolazione pediatrica
    F.4 Planned number of subjects to be included
    F.4.1In the member state11
    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.
    Lo sponsor offrirà un accesso continuo a Roche IMP RO7204239 o Risdiplam a titolo gratuito agli aventi diritto ai sensi del Politica globale di Roche sull'accesso continuo ai medicinali sperimentali. Per informazioni dettagliate fare riferimento al protocollo BN42644, sezione
    6.7 Accesso continuato al trattamento in studio dopo la fine dello studio.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-01-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-11-04
    P. End of Trial
    P.End of Trial StatusOngoing
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