Type 1 Spinal Muscular Atrophy (SMA) MedDRA version: 19.0 Level: PT Classification code 10041582 Term: Spinal muscular atrophy System Organ Class: 10010331 - Congenital, familial and genetic disorders
Conditions
Sponsors
F. Hoffmann-La Roche Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: - Males and females aged between 28 days (1 month) of life and 210 days (7 months) (inclusive) at enrollment - A legally authorized representative must be able to consent for the patient according to International Conference on Harmonisation and local regulations - Gestational age of 37 to 42 weeks - Confirmed diagnosis of 5q-autosomal recessive SMA, including: •Genetic confirmation of homozygous deletion or compound heterozygosity predictive of loss of function of the survival motor neuron 1 (SMN1) gene •Clinical history, signs or symptoms attributable to Type 1 SMA, i.e., hypotonia, absent deep tendon reflexes and/or tongue fasciculations with onset after the age of 28 days, but prior to the age of 3 months (inclusive), and inability to sit independently (without support) at the time of screening - Patient has two SMN2 gene copies, as confirmed by central testing - Body weight >= 3rd percentile for age, using appropriate country-specific guidelines (for the first infant only > 7 kg) - 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 Are the trial subjects under 18? yes Number of subjects for this age range: 64 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 within 90 days prior to screening or 5 half-lives, whichever is longer - Concomitant or previous participation in a SMN2 targeting antisense oligonucleotide or 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 - Unstable gastrointestinal, renal, hepatic, endocrine or cardiovascular system diseases - Inadequate venous or capillary blood access for the study procedures - Patients requiring invasive ventilation or tracheostomy - Patients requiring awake non-invasive ventilation or with awake hypoxemia (arterial oxygen saturation 170 bpm - Presence of clinically relevant electrocardiogram (ECG) abnormalities before study drug administration - History of malignancy if not considered cured - 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 - Taking any nutrients known to modulate cytochrome [CYP] 3A activity within 2 weeks prior to administration of study drugs - The infant (and the mother, if breastfeeding the infant): • Any inhibitor of CYP3A4 taken within 2 weeks (or within 5 times the elimination half life, whichever is longer) prior to dosing, including but not limited to ketoconazole, miconazole, itraconazole, fluconazole, erythromycin, clarithromycin, ranitidine, cimetidine • Any inducer of CYP3A4 taken within 4 weeks (or within 5 times the elimination half-life, whichever is longer) prior to dosing, including but not limited to rifampicin, rifabutin, glucocorticoids, carbamazepine, phenytoin, phenobarbital, St. John's wort • Any organic cation transporter-2 and multidrug and toxic compound extrusion substrates shall be avoided • Any known flavin containing monooxygenase (FMO) 1 or FMO3 inhibitors or substrates - Clinically significant abnormalities in laboratory test results - Ascertained or presumptive hypersensitivity to RO7034067 or the constituents of its formulation - Prior use, anticipated need for hydroxychloroquine, vigabatrin, retigabine, or any other drug known to cause retinal toxicity during the study - Recent history (less than 6 months) of ophthalmic disease that would interfere with the conduct of the study as assessed by an ophthalmologist
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part 1 •To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of RO7034067 in infants with Type 1 SMA and to select the dose for Part 2 Part 2 •To assess the efficacy of RO7034067 measured as the proportion of infants sitting without support after 12 months of treatment ;Secondary Objective: •To assess:Safety and tolerability of RO7034067,Pharmacokinetics of RO7034067,Pharmacodynamic effects of RO7034067 •To assess at 12 months of treatment with RO7034067 the effect on motor development milestones •To assess at 24 months of treatment with RO7034067 the effect on sitting without support and further motor development milestones •To assess the proportion of infants who achieve a score of 40 or higher in the Childrens Hospital of Philadelphia Infant Test of Neuromuscular Disorders scale at 12 months of treatment •To assess the proportion of infants who achieve a reduction of 30 degrees in phase angle (respiratory inductance plethysmography) at 12 months of treatment •To assess at 12 and 24 months of treatment the proportion of infants who are alive without permanent ventilation •To assess the impact of treatment with RO7034067 on time to event (death, permanent ventilation) •To assess the effect at 12 and 24 months of treatment with RO7034067 on muscle electrophysiology;Primary end point(s): Part 1 and 2: Safety 1. Incidence and severity of adverse events (AE) and serious adverse events 2. Incidence of treatment discontinuations due to AE 3. Incidence of abnormal laboratory and ECG values 4. Clinically significant vital signs abnormalities 5. Anthropometric and ophthalmological examination Pharmacokinetics 6.Plasma concentrations of RO7034067, and its metabolite(s) Pharmacodynamic 7. Assessment of SMN protein in blood 8.Assessment of SMN messenger ribonucleic acid (mRNA) in blood Part 2: Efficacy 9.Proportion of infants who are sitting without support at 12 months of treatment assessed by the Gross Motor Scale of the Bayley Scal | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Part 2 1. Plasma concentrations of RO7034067 and its metabolite(s) 2. Assessment of SMN protein in blood 3. Assessment of SMN mRNA in blood 4. Change from baseline in the Total Raw Score of the BSID-III gross motor scale at Month 12 and 24 5. Proportion of infants who achieve the attainment levels of the motor milestones assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 and 24 6. Proportion of infants who achieve a score of 40 or higher in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) at Month 12 7. Proportion of infants who achieve a reduction of 30 degrees in their phase angle from baseline, as measured by respiratory inductance plethysmography, at Month 12 8. Proportion of infants who achieve an increase of at least 0.3 millivolt from baseline in their compound muscle action potential negative peak amplitude at Month 12 and 24 9. Time to permanent ventilation (from enrollment) 10. Proportion of infants who are alive without permanent ventilation at Month 12 and 24 ;Timepoint(s) of evaluation of this end point: 1. D1, D2, D14, D28, D56, D119, D182, D245, D301, D364, D427, D490, D546, D609, D672, D728 2. D1, D28, D119, D245, D364, D609, D728 3. D1, D28, D245, D364, D609, D728 4. Baseline, Month 12 and 24 5. Month 12 and 24 6. Month 12 7. Baseline and Month 12 8. Baseline, Month 12 and 24 9. Up to 2 years 10. At Month 12 and 24 | — |
Countries
Belgium, Croatia, France, Germany, Italy, Poland, Spain
Contacts
Public ContactTrial Information Support Line-TISL
F.Hoffmann-La Roche Ltd
Outcome results
None listed