En undersøgelse for at undersøge sikkerheden og effektiviteten af RO7204239 i kombination med Risdiplam (RO7034067) hos ambulante børn med spinal muskelatrofi (MANATEE)
En todelt, sømløs, multicenter, randomiseret, placebokontrolleret, dobbeltblind undersøgelse til undersøgelse af sikkerhed, tolerabilitet, farmakokinetik, farmakodynamik og effektivitet af RO7204239 i kombination med Risdiplam (RO7034067) hos ambulante patienter med spinal muskelatrofi
Risdiplam works by helping the body produce more survival motor neuron (SMN) protein throughout the body. This means fewer motor neurons - nerve cells that pass impulses from nerves to muscles to cause movement - are lost, which may improve how well muscles work in people with SMA. RO7204239 is an investigational anti-myostatin antibody that is designed to target myostatin. Myostatin plays an important role in the regulation of skeletal muscle size by controlling growth. Inhibiting myostatin may help muscles grow in size and strength. RO7204239 in combination with risdiplam, which is designed to increase the amount of SMN protein throughout the body, has the potential to further improve motor function and clinical outcomes for people living with SMA.
This trial will study the safety and efficacy of RO7204239 in combination with risdiplam in patients with spinal muscular atrophy (SMA). The trial has two parts; Part 1 is the dose-finding part in SMA patients that are either ambulant (aged 2-10 years) or non-ambulant (aged 5-10 years) within separate cohorts, and Part 2 is the pivotal part in SMA patients aged 2-25 years that are ambulant.
Studieoversigt
Status
Betingelser
Intervention / Behandling
Undersøgelsestype
Tilmelding (Faktiske)
Fase
- Fase 2
- Fase 3
Kontakter og lokationer
Studiesteder
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New South Wales
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Randwick, New South Wales, Australien, 2031
- Sydney Children's Hospital
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Ghent, Belgien, 9000
- UZ Gent
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Liège, Belgien, 4000
- Chr de La Citadelle
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British Columbia
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Vancouver, British Columbia, Canada, V6H 3N1
- British Columbia Children's Hospital
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Ontario
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Toronto, Ontario, Canada, M5G 1X8
- The Hospital for Sick Children
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Quebec
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Montreal, Quebec, Canada, H4A 3J1
- McGill University Health Centre - Glen Site
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Birmingham, Det Forenede Kongerige, B9 5SS
- Birmingham Heartlands Hospital
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Oxford, Det Forenede Kongerige, OX3 9DU
- John Radcliffe Hospital
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Massachusetts
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Boston, Massachusetts, Forenede Stater, 02115
- Boston Childrens Hospital
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New York
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New York, New York, Forenede Stater, 10032
- Columbia University Medical Center
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Utrecht, Holland, 3584 CX
- Universitair Medisch Centrum Utrecht
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Lazio
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Rome, Lazio, Italien, 00168
- Policlinico Agostino Gemelli
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Lombardy
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Milan, Lombardy, Italien, 20133
- Fondazione IRCCS Istituto Neurologico ?Carlo Besta?
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Milan, Lombardy, Italien, 20162
- Asst Grande Ospedale Metropolitano Niguarda
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The Marches
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Ancona, The Marches, Italien, 60126
- Ospedali Riuniti Torrette di Ancona
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Hyōgo, Japan, 650-0017
- Kobe University Hospital
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Kagoshima, Japan, 890-8520
- Kagoshima University Hospital
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Shinjuku-ku, Japan, 162-8655
- National Center for Global Health and Medicine
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Zagreb, Kroatien, 10000
- Clinical Hospital Centre Zagreb
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?ód?, Polen, 93-338
- Instytut Centrum Zdrowia Matki Polki
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Gda?sk, Polen, 80-952
- Uniwersyteckie Centrum Kliniczne
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Późna, Polen, 60-355
- Uniwersytecki Szpital Kliniczny w Poznaniu
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Warsaw, Polen, 04-730
- Instytut Pomnik Centrum Zdrowia Dziecka
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Warsaw, Polen, 02-097
- Klinika Neurologii I Wydzialu Lekarskiego WUM w Warszawie
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Lisbon, Portugal, 1649-035
- Hospital de Santa Maria
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Lisbon, Portugal, 1169-045
- CHULC, E.P.E. - Hospital Dona Estefania
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Madrid, Spanien, 28046
- Hospital Universitario La Paz
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Valencia, Spanien, 46026
- Hospital Universitario la Fe
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Barcelona
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Esplugues de Llobregas, Barcelona, Spanien, 08950
- Hospital Sant Joan De Deu
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Deltagelseskriterier
Berettigelseskriterier
Aldre berettiget til at studere
Tager imod sunde frivillige
Køn, der er berettiget til at studere
Beskrivelse
Inclusion Criteria:
- Age at screening: Part 1 Cohorts A (ambulant participants), B (ambulant participants), and D (non-ambulant participants): 5-10 years, inclusive; Part 1 Cohort C (ambulant participants): 2-4 years, inclusive; Part 2 (ambulant participants): 2-25 years, inclusive
- Participants who have a confirmed genetic diagnosis of 5q-autosomal recessive SMA
- Symptomatic SMA disease, as per investigator's clinical judgement
- Participants who have received previous SMA disease-modifying therapies may be included provided that: 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; Nusinersen last dose was received at least 90 days prior to screening; Risdiplam is switched to the investigational medicinal product (IMP) provided by the site
Inclusion Criteria for Part 1 Cohorts A, B, and C and Part 2 only:
- 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 measures by the Timed 10-Meter Walk/Run Test [10MWRT] at screening
Inclusion Criteria for Part 1 Cohort D only:
- Participants who are able to sit, defined by: A score of 3 on Item 9 of the MFM32 (sitting without upper limb support while maintaining contact between the two hands for 5 seconds); A score of at least 2 on Item 10 of the MFM32 (while seated, leaning forward to touch a tennis ball and sitting back again, either with or without upper limb support)
- Participants who are able to raise a standardized plastic cup with a 200g weight in it to the mouth, using both hands if necessary, defined by a score of 3 on the entry item of the Revised Upper Limb Module (RULM)
Exclusion Criteria:
- 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
- Receiving or have received previous administration of anti-myostatin therapies
- Any history of cell therapy
- Hospitalization for a pulmonary event within the last 2 months or planned hospitalization at the time of screening
- Past 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)
- Unstable gastrointestinal, renal, hepatic, endocrine, or cardiovascular system diseases considered to be clinically significant
- Clinically significant ECG abnormalities at screening from average of triplicate measurement, abnormal findings at echocardiography, or cardiovascular disease indicating a safety risk for participants at the time of screening
- Any major illness within 1 month before screening
- Received any multidrug and toxin extrusion (MATE1/2K) substrates within 2 weeks before screening
- Hereditary fructose intolerance
- 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
- Clinically significant abnormalities in laboratory test results at the time of screening
- Ascertained or presumptive hypersensitivity to RO7204239 or risdiplam, or to the constituents of its formulations
- Clinically relevant history of anaphylactic reaction requiring inotropic support
- Any abnormal skin conditions, pigmentation or lesions in the area intended for SC injection (abdomen) and that would prevent visualization of potential injection site reactions to RO7204239
- Immobilization, surgical procedures, fracture, or trauma to the upper or lower limbs within 90 days prior to screening
Exclusion Criteria for Part 1 Cohorts A and B only:
- Participants with contraindications for MRI scan (including, but not restricted to, claustrophobia, pacemaker, artificial heart valves, cochlear implants, presence of foreign metal objects in heart or body, including spinal rods, intracranial vascular clips, insulin pumps, etc.), difficulties maintaining a prolonged supine position, or any other clinical history or examination finding that would pose a potential hazard in combination with MRI
Exclusion Criteria for Part 1 Cohort D only:
- Participants who are unable to adopt the correct position to endure adequate quality of DXA scan acquisition, as determined by the DXA scan technologist
- Participants who have contractures at screening that would interfere with DXA scan acquisition or functional assessments, as confirmed by the DXA scan technologist and clinical evaluator
- For participants able to take steps only: Able to walk 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 10MWRT at screening
- Participants who have severe scoliosis (curvature > 40°) at screening based on the participant's most recent X-ray as performed per standard of care or scoliosis that would interfere with functional assessments, as confirmed by the clinical evaluator. An X-ray is not required if it is not clinically indicated (e.g., in participants with mild scoliosis)
- Participants who require invasive ventilation, tracheostomy, or the use of noninvasive ventilation (e.g., bilevel positive airway pressure) during the daytime
Studieplan
Hvordan er undersøgelsen tilrettelagt?
Design detaljer
- Primært formål: Behandling
- Tildeling: Randomiseret
- Interventionel model: Parallel tildeling
- Maskning: Dobbelt
Våben og indgreb
Deltagergruppe / Arm |
Intervention / Behandling |
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Eksperimentel: RO7204239 + Risdiplam
Participants who have not previously been treated with risdiplam will receive risdiplam for at least 8 weeks prior to randomization into a treatment group (Part 1 only). Participants that have been treated with risdiplam for at least 8 continuous weeks immediately prior to joining the study may be immediately randomized to combination therapy, or join the study run-in period (the period between screening and randomization to a treatment group) where they will continue to receive risdiplam monotherapy until randomization. Participants enrolled in Part 1 will receive RO7204239 (low or high dose) + risdiplam for 24 weeks, followed by RO7204239 + risdiplam for 72 weeks. Participants enrolled in Part 2 will receive risdiplam for 8 weeks and then treatment with RO7204239 + risdiplam for 72 weeks. Once the treatment period has completed (Part 1 or Part 2), participants will have the option of treatment with RO7204239 + risdiplam for 2 additional years. |
RO7204239 will administered every 4 weeks (Q4W) by subcutaneous (SC) injection into the abdomen. RO7204239 will be investigated at low- and high-dose in Part 1. Risdiplam will be administered orally once daily (QD) for the duration of the study.
Andre navne:
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Aktiv komparator: Placebo + Risdiplam
Participants who have not previously been treated with risdiplam will receive risdiplam for at least 8 weeks prior to randomization into a treatment group (Part 1 only). Participants that have been treated with risdiplam for at least 8 continuous weeks immediately prior to joining the study may be immediately randomized to combination therapy, or join the study run-in period (the period between screening and randomization to a treatment group) where they will continue to receive risdiplam monotherapy until randomization. Participants enrolled in Part 1 will receive placebo (low or high dose-matched) + risdiplam for 24 weeks, followed by RO7204239 + risdiplam for 72 weeks. Participants enrolled in Part 2 will receive risdiplam for 8 weeks and then treatment with placebo + risdiplam for 72 weeks. Once the treatment period has completed (Part 1 or Part 2), participants will have the option of treatment with RO7204239 + risdiplam for 2 additional years. |
Risdiplam will be administered orally once daily (QD) for the duration of the study.
Andre navne:
Placebo will be administered Q4W by SC injection into the abdomen. |
Hvad måler undersøgelsen?
Primære resultatmål
Resultatmål |
Tidsramme |
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Del 1 - Procentdel af deltagere med uønskede hændelser (AE'er)
Tidsramme: Op til 4,5 år
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Op til 4,5 år
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Del 1 - Forekomst af relevante ekkokardiografiske parameter z-score > 2
Tidsramme: Op til 4,5 år
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Op til 4,5 år
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Del 1 - Serumkoncentration af RO7204239
Tidsramme: Til og med uge 96
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Til og med uge 96
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Del 1 - Tid til maksimal serumkoncentration (Cmax) af RO7204239
Tidsramme: Til og med uge 96
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Til og med uge 96
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Del 1 - Areal under kurven (AUC) af RO7204239
Tidsramme: Til og med uge 96
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Til og med uge 96
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Del 1 - Trogkoncentration (Ctrough) af RO7204239
Tidsramme: Til og med uge 96
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Til og med uge 96
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Del 1 - Plasmakoncentration af risdiplam
Tidsramme: Uge 21
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Uge 21
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Del 1 - Plasmakoncentration af risdiplammetabolit (M1)
Tidsramme: Uge 21
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Uge 21
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Del 1 - Cmax for risdiplam
Tidsramme: Uge 21
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Uge 21
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Del 1 - AUC for risdiplam
Tidsramme: Uge 21
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Uge 21
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Del 1 - Gennemgang af risdiplam
Tidsramme: Uge 21
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Uge 21
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Del 1 - Forekomst af antistof-antistoffer (ADA'er)
Tidsramme: Til og med uge 96
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Til og med uge 96
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Del 1 - Ændring fra baseline i serumkoncentration af total myostatin
Tidsramme: Til og med uge 85
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Til og med uge 85
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Del 1 - Ændring fra baseline i serumkoncentration af frit latent myostatin
Tidsramme: Til og med uge 85
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Til og med uge 85
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Del 1 - Ændring fra baseline i serumkoncentration af modent myostatin
Tidsramme: Til og med uge 85
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Til og med uge 85
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Del 2 - Ændring fra baseline i Revised Hammersmith Scale (RHS) totalscore
Tidsramme: Uge 72 af kombinationsbehandling (undersøgelse uge 80)
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Uge 72 af kombinationsbehandling (undersøgelse uge 80)
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Del 1 - Procentvis ændring fra baseline i det kontraktile område af skeletmuskulaturen i de dominerende lårmuskler vurderet ved magnetisk resonansbilleddannelse (MRI) hos deltagere i alderen mindst 5 år
Tidsramme: Uge 24 i kombinationsbehandling
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Uge 24 i kombinationsbehandling
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Del 1 - Procent ændring fra baseline i det kontraktile område af skeletmuskulaturen i de dominerende lægmuskler vurderet ved MR hos deltagere på mindst 5 år
Tidsramme: Uge 24 i kombinationsbehandling
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Uge 24 i kombinationsbehandling
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Sekundære resultatmål
Resultatmål |
Tidsramme |
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Del 2 - Ændring fra baseline i Motor Function Measure (MFM) Domain 1 + Domain 2 (D1 + D2) score
Tidsramme: Uge 72 af kombinationsbehandling (undersøgelse uge 80)
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Uge 72 af kombinationsbehandling (undersøgelse uge 80)
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Del 2 - Ændring fra baseline i MFM-32 totalscore
Tidsramme: Uge 72 af kombinationsbehandling (undersøgelse uge 80)
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Uge 72 af kombinationsbehandling (undersøgelse uge 80)
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Del 2 - Ændring fra baseline i den tid, det tager at rejse sig fra gulvet målt ved RHS-punkt 25
Tidsramme: Uge 72 af kombinationsbehandling (undersøgelse uge 80)
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Uge 72 af kombinationsbehandling (undersøgelse uge 80)
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Del 2 - Ændring fra baseline i tid det tager at gå/løbe 10 meter som målt ved RHS punkt 19
Tidsramme: Uge 72 af kombinationsbehandling (undersøgelse uge 80)
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Uge 72 af kombinationsbehandling (undersøgelse uge 80)
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Del 2 - Procentdel af deltagere med uønskede hændelser (AE'er)
Tidsramme: Op til 4,5 år
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Op til 4,5 år
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Del 2 - Serumkoncentration af RO7204239
Tidsramme: Til og med uge 80
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Til og med uge 80
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Del 2 - Cmax af RO7204239
Tidsramme: Til og med uge 80
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Til og med uge 80
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Del 2 - AUC af RO7204239
Tidsramme: Til og med uge 80
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Til og med uge 80
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Del 2 - Gennemgang af RO7204239
Tidsramme: Til og med uge 80
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Til og med uge 80
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Del 2 - Plasmakoncentration af risdiplam
Tidsramme: Uge 32
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Uge 32
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Del 2 - Plasmakoncentration af risdiplammetabolit (M1)
Tidsramme: Uge 32
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Uge 32
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Del 2 - Cmax for risdiplam
Tidsramme: Uge 32
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Uge 32
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Del 2 - AUC for risdiplam
Tidsramme: Uge 32
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Uge 32
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Del 2 - Gennemgang af risdiplam
Tidsramme: Uge 32
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Uge 32
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Del 2 - Forekomst af ADA'er
Tidsramme: Til og med uge 80
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Til og med uge 80
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Del 2 - Procentvis ændring fra baseline i mager masse vurderet ved fuldkrops dobbeltenergi røntgenabsorptiometri (DXA) scanning hos deltagere i alderen mindst 5 år
Tidsramme: Uge 72 af kombinationsbehandling (undersøgelse uge 80)
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Uge 72 af kombinationsbehandling (undersøgelse uge 80)
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Samarbejdspartnere og efterforskere
Sponsor
Efterforskere
- Studieleder: Clinical Trials, Hoffmann-La Roche
Datoer for undersøgelser
Studer store datoer
Studiestart (Faktiske)
Primær færdiggørelse (Faktiske)
Studieafslutning (Faktiske)
Datoer for studieregistrering
Først indsendt
Først indsendt, der opfyldte QC-kriterier
Først opslået (Faktiske)
Opdateringer af undersøgelsesjournaler
Sidste opdatering sendt (Faktiske)
Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier
Sidst verificeret
Mere information
Begreber relateret til denne undersøgelse
Yderligere relevante MeSH-vilkår
Andre undersøgelses-id-numre
- BN42644
- 2023-506761-65-00 (Anden identifikator: CTIS (EU CTR))
- 2023 (U.S. NIH-bevilling/kontrakt)
Plan for individuelle deltagerdata (IPD)
Planlægger du at dele individuelle deltagerdata (IPD)?
IPD-planbeskrivelse
For eligible studies, qualified researchers may request access to individual patient level clinical data. See Roche's commitment to transparency of clinical study information here: https://go.roche.com/data_sharing
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