Spinal Muscular Atrophy (SMA) MedDRA version: 20.1 Level: PT Classification code 10041582 Term: Spinal muscular atrophy System Organ Class: 10010331 - Congenital, familial and genetic disorders MedDRA version: 20.0 Level: LLT Classification code 10079419 Term: Spinal muscular atrophy pre-symptomatic System Organ Class: 10010331 - Congenital, familial and genetic disorders
Conditions
Interventions
Trade Name: EVRYSDI
Product Name: RO7034067
Product Code: RO7034067/F13
Pharmaceutical Form: Powder for oral solution
INN or Proposed INN: Risdiplam
CAS Number: 1825352-65-5
Current Sponsor code: RO7
Sponsors
F. Hoffmann-La Roche Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: - Males and females aged from birth (1 day) to 6 weeks (42 days) of age at the time of first dose (Day 1); a minimum age of 7 days at first dose is required for the first infant to be enrolled - Gestational age of 37-42 weeks for singleton births; gestational age of 34-42 weeks for twins - Body weight >= 3rd percentile for age, using appropriate country-specific guidelines - Genetic diagnosis of 5q-autosomal recessive SMA, including confirmation of homozygous deletion or compound heterozygosity predictive of loss of function of the SMN1 gene - Absence of clinical signs or symptoms at screening (Day -42 to Day -2) or at baseline (Day -1) that are, in the opinion of the investigator, strongly suggestive of SMA - Receiving adequate nutrition and hydration at the time of screening, in the opinion of the investigator - Adequately recovered from any acute illness at baseline and considered well enough to participate in the study, in the opinion of the investigator - Able and expected to be able to safely travel to the study site for the entire duration of the study and in accordance to the frequency of required study visits, in the opinion of the investigator - Able to complete all study procedures, measurements, and visits, and the parent (or caregiver), in the opinion of the investigator, has adequately supportive psychosocial circumstances - Parent (or caregiver) is willing to consider nasogastric, naso-jejunal, or gastrostomy tube placement during the study to maintain safe hydration, nutrition, and treatment delivery, if recommended by the investigator - Parent (or caregiver) is willing to consider the use of non-invasive ventilation during the study, if recommended by the investigator Are the trial subjects under 18? yes Number of subjects for this age range: 25 F.1.2 Adults (18-64 years) no F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: - Concomitant or previous participation in any investigational drug or device study at any time - Concomitant or previous administration of an SMN2-targeting antisense oligonucleotide, SMN2-splicing modifier, or gene therapy either in a clinical study or as part of medical care - Presence of significant concurrent syndromes or diseases - In the opinion of the investigator, inadequate venous or capillary blood access for the study procedures - Requiring invasive ventilation, tracheostomy or awake non-invasive ventilation - Awake hypoxemia (SaO2 460 ms; personal or family history (first degree relatives) of congenital long QT syndrome indicating a safety risk for patients as determined by the investigator. First-degree atrioventricular block or isolated right bundle branch block are allowed - The infant (and the mother, if breastfeeding the infant) taking any inhibitor of CYP3A4 taken within 2 weeks, any inducer of CYP3A4 taken within 4 weeks, any OCT 2 and MATE substrates within 2 weeks and known FMO1 or FMO3 inhibitors or substrates - Clinically significant abnormalities in laboratory test results - Ascertained or presumptive hypersensitivity to risdiplam or to the constituents of its formulation - Treatment with oral salbutamol or another beta-2 adrenergic agonist taken orally for SMA is not allowed. Use of inhaled beta-2 adrenergic agonists is allowed - Infants exposed to drugs with known retinal toxicity given to mothers during pregnancy (and lactation) should not be enrolled. Anticipated need for drugs known to cause retinal toxicity during the study. - Diagnosis of ophthalmic diseases
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: •To evaluate the efficacy of risdiplam in patients with two copies of the survival motor neuron (SMN)2 gene (excluding the known SMN2 gene modifier mutation c.859G> C) and baseline compound muscle action potential (CMAP) amplitude = 1.5 mV, as determined by the proportion of patients who are sitting without support after 12 months of treatment;Secondary Objective: •To evaluate the efficacy of risdiplam on the development of clinically manifested SMA •To evaluate the efficacy of risdiplam on survival and permanent ventilation •To evaluate the efficacy of risdiplam on achievement of motor milestones •To evaluate the efficacy of risdiplam on motor function •To evaluate the efficacy of risdiplam on growth measures •To evaluate the efficacy of risdiplam on nutritional status of the patients •To evaluate the efficacy of risdiplam on the degree of innervation upon treatment with risdiplam •To evaluate the pharmacodynamic effects of risdiplam •To evaluate the safety of risdiplam •To characterize the pharmacokinetics profile of risdiplam •To identify biomarkers that are predictive of response to risdiplam •To evaluate parent (or caregiver)-rated health status and health-related quality of life ;Primary end point(s): 1.The proportion of infants with two copies of the survival motor neuron (SMN) 2 gene (excluding the known SMN2 gene modifier mutation c.859G> C) and baseline compound muscle action potential (CMAP) amplitude >=1.5 mV who are sitting without support. Sitting is defined as “sits without support for 5 seconds” as assessed in Item 22 of the Bayley Scales of Infant and Toddler Development®, Third Edition [BSID-III] Gross Motor Scale.;Timepoint(s) of evaluation of this end point: 1. At Month 12 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1.Proportion of infants developing clinically manifested SMA at month 12 and 24 of treatment 2.Time to death or permanent ventilation 3.Proportion of infants who are alive without permanent ventilation at Month 12 and 24 of treatment 4.Proportion of patients alive (at Month 12 and Month 24 of treatment) 5.Proportion of infants who achieve the attainment level of the motor milestones as assessed in the Hammersmith Infant Neurological Examination-2 (head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking) at Month 12 and 24 of treatment 6.Proportion of infants with two copies of the SMN2 gene sitting without support at Month 12 of treatment (as assessed in Item 22 of BSID-III Gross Motor Scale) for 5 seconds (independent of the CMAP value at baseline) 7.Proportion of infants sitting without support at Month 24 of treatment (as assessed in Item 22 of the BSID-III Gross Motor Scale) for 5 seconds 8. Proportion of patients with two copies of the SMN2 gene sitting without support (at Month 12 of treatment [as assessed in Item 22 of BSID III Gross Motor Scale]) for 5 seconds (independent of the CMAP value at baseline) 9.Proportion of infants sitting without support at Month 12 of treatment (as assessed in Item 26 of the BSID-III Gross Motor Scale) for 30 seconds 10.Proportion of infants sitting without support at Month 24 of treatment (as assessed in Item 26 of the BSID-III Gross Motor Scale) for 30 seconds 11.Proportion of infants standing at Month 24 of treatment (defined as “Stands Alone” for at least 3 seconds as assessed in Item 40 and 42 of the BSID-III Gross Motor Scale) 12.Proportion of infants walking at Month 24 of treatment (defined as “Walks Alone” takes at least 3 steps as assessed in Item 42 of the BSID-III Gross Motor Scale) 13.Change from baseline score in the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) motor function scale at Month 12 of treatmen | — |
Countries
Australia, Belgium, Brazil, China, Italy, Poland, Russian Federation, Saudi Arabia, United States
Contacts
Public ContactTrial Information Support Line
F.Hoffmann-La Roche Ltd
Outcome results
None listed