Investigate Safety, Tolerability, PK, PD and Efficacy of Risdiplam (RO7034067) in Infants With Type1 Spinal Muscular Atrophy
NCT ID: NCT02913482
Last Updated: 2024-08-07
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE2
62 participants
INTERVENTIONAL
2016-12-23
2023-12-22
Brief Summary
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Detailed Description
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Conditions
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Study Design
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NON_RANDOMIZED
SEQUENTIAL
TREATMENT
NONE
Study Groups
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Part 1 (Dose Finding): Risdiplam (RO7034067)
Participants will receive multiple ascending doses of risdiplam (RO7034067), administered orally once daily for a minimum of 4 weeks to select the dose for Part 2. During the first year of treatment, most participants will switch to the Part 2 dose. During the second year of treatment, all Part 1 participants will be receiving the Part 2 dose. They will thereafter enter a 3-year open-label extension phase and continue to receive risdiplam at the same dose.
Risdiplam
Risdiplam will be administered orally.
Part 2 (Confirmatory): Risdiplam (RO7034067)
Participants will receive risdiplam (RO7034067), administered orally once daily at the dose defined in Part 1 of the study, for a duration of 24 months. They will thereafter enter a 3-year open-label extension phase and continue to receive risdiplam at the same dose.
Risdiplam
Risdiplam will be administered orally.
Interventions
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Risdiplam
Risdiplam will be administered orally.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Gestational age of 37 to 42 weeks
* Confirmed diagnosis of 5q-autosomal recessive SMA
* Participants has two survival motor neuron 2 (SMN2) gene copies, as confirmed by central testing
* Body weight greater than or equal to (\>=) third percentile for age, using appropriate country-specific guidelines
* 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
Exclusion Criteria
* Concomitant or previous administration of SMN2-targeting antisense oligonucleotide, SMN2 splicing modifier or gene therapy study
* Any history of cell therapy
* Hospitalization for pulmonary event within the last 2 months, or planned at the time of screening
* Presence of clinically relevant electrocardiogram (ECG) abnormalities before study drug administration
* Unstable gastrointestinal, renal, hepatic, endocrine or cardiovascular system diseases
* Participants requiring invasive ventilation or tracheostomy
* Participants requiring awake non-invasive ventilation or with awake hypoxemia (arterial oxygen saturation less than \[\<\] 95 percent \[%\]) with or without ventilator support
* Participants 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
* 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
* Any inhibitor of cytochrome P450 (CYP) 3A4 and/or any Organic Cation Transporter 2 (OCT-2) and multidrug and toxin extrusion (MATE) substrates taken within 2 weeks and/or any inducer of CYP3A4 taken within 4 weeks (or within 5-times the elimination half-life, whichever is longer) prior to dosing or participants (and the mother, if breastfeeding the infant) taking any nutrients known to modulate CYP3A activity and any known flavin containing monooxygenase (FMO) 1 or FMO3 inhibitors or substrates
* Prior use (at any time in the participants lives) and/or anticipated need for quinolones (chloroquine and hydroxychloroquine), thioridazine, 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
* Therapeutic use, defined as use for 8 weeks or longer, of the following medications within 90 days prior to enrollment: riluzole, valproic acid, hydroxyurea, sodium phenylbutyrate, butyrate derivatives, creatine, carnitine, growth hormone, anabolic steroids, probenecid, agents anticipated to increase or decrease muscle strength, agents with known or presumed histone deacetylase (HDAC) inhibitory effect, medications known to or suspected of causing retinal toxicity (deferoxamine, topiramate, latanoprost, niacin, rosiglitazone, tamoxifen, canthaxanthine, sildenafil, and interferon) and medications with known phototoxicity liabilities (e.g., oral retinoids including over-the-counter \[OTC\] formulations, amiodarone, phenothiazines and use of minocycline)
1 Month
7 Months
ALL
No
Sponsors
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Hoffmann-La Roche
INDUSTRY
Responsible Party
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Principal Investigators
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Clinical Trials
Role: STUDY_DIRECTOR
Hoffmann-La Roche
Locations
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Stanford University Medical Center
Palo Alto, California, United States
Ann and Robert H. Lurie Children Hospital of Chicago
Chicago, Illinois, United States
Boston Childrens Hospital
Boston, Massachusetts, United States
Columbia University Medical Center; The Neurological Institute of New York
New York, New York, United States
UZ Gent
Ghent, , Belgium
UZ Leuven Gasthuisberg
Leuven, , Belgium
Chr de La Citadelle
Liège, , Belgium
Instituto de Puericultura E Pediatria Martagão Gesteira
Rio de Janeiro, Rio de Janeiro, Brazil
Hospital das Clinicas - FMUSP_X; Neurologia
São Paulo, São Paulo, Brazil
Peking University First Hospital
Beijing, , China
Children's Hospital of Fudan University
Shanghai, , China
Clinical Medical Center Zagreb; University Hospital Rebro Department of Paediatrics
Zagreb, , Croatia
Hopital Femme Mere Enfant; Medecine Physique et Readaptation Pediatrique ? L?ESCALE
Bron, , France
Hopital Armand Trousseau
Paris, , France
IRCCS Ospedale Pediatrico Bambino Gesù; U.O. Malattie Neuromuscolari e Neurodegenerative
Rome, Lazio, Italy
Policlinico Agostino Gemelli; Dipartimento di Neuropsichiatria Infantile
Rome, Lazio, Italy
IRCCS Istituto Giannina Gaslini; U.O.S.D. Centro di Miologia e Patologie Neurodegenerative
Genoa, Liguria, Italy
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico; Unità Operativa Complessa di Neurologia
Milan, Lombardy, Italy
Fondazione IRCCS Istituto Neurologico ?Carlo Besta?; UO di Neurologia dello Sviluppo
Milan, Lombardy, Italy
Hyogo Medical University Hospital
Hyōgo, , Japan
Szpital Gdanskiego Uniwersytetu Medycznego; Clinic of developmental neurology
Gda?sk, , Poland
The Children?s Memorial Health Institute Department of Neurology and Epileptology
Warsaw, , Poland
Russian Children Neuromuscular Center of Veltischev
Moscow, Moscow Oblast, Russia
King Faisal Specialist Hospital and Research Centre Building
Riyadh, , Saudi Arabia
Institute for Mother and Child Dr. Vukan Cupic
Belgrade, , Serbia
Hospital Sant Joan De Deu
Esplugues de Llobregas, Barcelona, Spain
Hospital Universitari Vall d'Hebron; Area Genética Clínica y Molecular
Barcelona, , Spain
Hospital Universitario Virgen del Rocio
Seville, , Spain
Universitäts-Kinderspital (UKBB) Neuropädiatrie
Basel, , Switzerland
Hacettepe University, School of Medicine; Pediatrics Department; Pediatrics Child Neurology Unit
Ankara, , Turkey (Türkiye)
Hospital Yeditepe University Kozyatagi; Pediatry
Atasehir- Istanbul, , Turkey (Türkiye)
Ams of Ukraine; Inst. of Neurology, Psychiatry & Narcology
Kharkiv, , Ukraine
Countries
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References
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Cleary Y, Kletzl H, Grimsey P, Heinig K, Ogungbenro K, Silber Baumann HE, Frey N, Aarons L, Galetin A, Gertz M. Estimation of FMO3 Ontogeny by Mechanistic Population Pharmacokinetic Modelling of Risdiplam and Its Impact on Drug-Drug Interactions in Children. Clin Pharmacokinet. 2023 Jun;62(6):891-904. doi: 10.1007/s40262-023-01241-7. Epub 2023 May 6.
Masson R, Mazurkiewicz-Beldzinska M, Rose K, Servais L, Xiong H, Zanoteli E, Baranello G, Bruno C, Day JW, Deconinck N, Klein A, Mercuri E, Vlodavets D, Wang Y, Dodman A, El-Khairi M, Gorni K, Jaber B, Kletzl H, Gaki E, Fontoura P, Darras BT; FIREFISH Study Group. Safety and efficacy of risdiplam in patients with type 1 spinal muscular atrophy (FIREFISH part 2): secondary analyses from an open-label trial. Lancet Neurol. 2022 Dec;21(12):1110-1119. doi: 10.1016/S1474-4422(22)00339-8. Epub 2022 Oct 14.
Cances C, Vlodavets D, Comi GP, Masson R, Mazurkiewicz-Beldzinska M, Saito K, Zanoteli E, Dodman A, El-Khairi M, Gorni K, Gravestock I, Hoffart J, Scalco RS, Darras BT; ANCHOVY Working Group. Natural history of Type 1 spinal muscular atrophy: a retrospective, global, multicenter study. Orphanet J Rare Dis. 2022 Jul 29;17(1):300. doi: 10.1186/s13023-022-02455-x.
Darras BT, Masson R, Mazurkiewicz-Beldzinska M, Rose K, Xiong H, Zanoteli E, Baranello G, Bruno C, Vlodavets D, Wang Y, El-Khairi M, Gerber M, Gorni K, Khwaja O, Kletzl H, Scalco RS, Fontoura P, Servais L; FIREFISH Working Group. Risdiplam-Treated Infants with Type 1 Spinal Muscular Atrophy versus Historical Controls. N Engl J Med. 2021 Jul 29;385(5):427-435. doi: 10.1056/NEJMoa2102047.
Baranello G, Darras BT, Day JW, Deconinck N, Klein A, Masson R, Mercuri E, Rose K, El-Khairi M, Gerber M, Gorni K, Khwaja O, Kletzl H, Scalco RS, Seabrook T, Fontoura P, Servais L; FIREFISH Working Group. Risdiplam in Type 1 Spinal Muscular Atrophy. N Engl J Med. 2021 Mar 11;384(10):915-923. doi: 10.1056/NEJMoa2009965. Epub 2021 Feb 24.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Related Links
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roche-sma-clinicaltrials.com provides information about the Roche Firefish clinical trial NCT02913482 and molecule being investigated in SMA.
Other Identifiers
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2016-000778-40
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
BP39056
Identifier Type: -
Identifier Source: org_study_id
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