Spinal Muscular Atrophy (SMA) Type 2 and 3 MedDRA version: 20.1 Level: PT Classification code 10041582 Term: Spinal muscular atrophy System Organ Class: 10010331 - Congenital, familial and genetic disorders
Conditions
Interventions
Product Name: RO7034067
Product Code: RO7034067/F12
Pharmaceutical Form: Powder for oral solution
INN or Proposed INN: risdiplam
CAS Number: 1825352-65-5
Current Sponsor code: RO7034067
Concentration
Sponsors
F. Hoffmann-La Roche Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: - Males and females 2 to 25 years of age inclusive - For Part 1: Type 2 or 3 SMA ambulant or non-ambulant. For Part 2: Type 2 or 3 SMA non-ambulant. Non-ambulant is defined as not having the ability to walk unassisted for 10 m or more - Confirmed diagnosis of 5q-autosomal recessive SMA - Negative blood pregnancy test at screening and agreement to comply with measures to prevent pregnancy and restrictions on sperm donation Are the trial subjects under 18? yes Number of subjects for this age range: 185 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 34 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 of the drug, whichever is longer - Concomitant or previous administration of a SMN2 targeting antisense oligonucleotide, SMN2 splicing modifier or gene therapy either in a clinical study or as part of medical care. - Any history of cell therapy - Hospitalization for a pulmonary event within the last 2 months or planned at time of screening - Surgery for scoliosis or hip fixation in the one year preceding screening or planned within the next 18 months - Unstable gastrointestinal, renal, hepatic, endocrine, or cardiovascular system diseases as considered to be clinically significant by the Investigator - Presence of clinically significant ECG abnormalities before study drug administration from average of triplicate measurement or cardiovascular disease indicating a safety risk for patients as determined by the Investigator - History of malignancy if not considered cured - Significant risk for suicidal behavior, in the opinion of the Investigator as assessed by the C-SSRS (>6 years of age) - 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 Organic cation transporter (OCT)-2 and multidrug and toxin extrusion (MATE) substrates within 2 weeks before dosing - Use of the following medications within 90 days prior to randomization: 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, and medications with known phototoxicity liabilities - Recently initiated treatment (within = 10% of blood volume within three months prior to screening - Ascertained or presumptive hypersensitivity (e.g., anaphylactic reaction) to risdiplam or to the constituents of its formulation - Recent history (less than one year) of ophthalmological diseases - Patients requiring invasive ventilation or tracheostomy - Any inhibitor or inducer of FMO1 or FMO3 taken within 2 weeks (or within 5 times the elimination half-life, whichever is longer) prior to dosing.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part 1: •To evaluate the safety, tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of risdiplam in patients with Type 2 and Type 3 (ambulant or non-ambulant) SMA, and to select the dose for Part 2 of the study Part 2: •To evaluate efficacy of risdiplam compared to placebo in terms of motor function in Type 2 and non-ambulant Type 3 SMA patients, as assessed by the change from baseline in the total score of the Motor Function Measure (MFM) at 12 months ;Secondary Objective: Part 2:To investigate •PK/PD relationship of risdiplam by PK/PD modeling •efficacy of 12 month treatment with risdiplam in terms of motor function as assessed by the Hammersmith Functional Motor Scale Expanded (HFMSE) and the revised upper limb module (RULM) •efficacy of 12 month treatment with risdiplam in terms of responder analyses of the MFM,HFMSE,RULM •efficacy of 12 month treatment with risdiplam in terms of respiratory function as assessed by Sniff nasal inspiratory pressure and, in patients aged 6 years and older,by Maximal Inspiratory Pressure,Maximal Expiratory Pressure,Forced vital capacity,Forced expiratory volume (FEV1) and Peak cough flow •proportion of patients who experience a pre-specified disease related adverse event by Month 12 •efficacy of 12 month treatment with risdiplam in terms of global health status as assessed by the Clinical Global Impression of Change and independence as measured by the SMA Independence Scale •safety and tolerability of risdiplam ;Primary end point(s): Part 1 1. Incidence of adverse events and serious adverse events 2. Maximum plasma concentration (Cmax) of risdiplam 3. Area under the curve (AUC) of risdiplam 4. Concentration at the end of a dosing interval (Ctrough) of risdiplam Part 2 5. Change from baseline in the total MFM 32 score at Month 12;Timepoint(s) of evaluation of this end point: 1. Up to 24 months 2-4. Days 1, 7, 14, 28, 56, 120, 246, 365, 490, 609, and 729 5. Baseline (Day -1) and Month 12 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Part 2 1.SMN2 mRNA in blood 2.SMN protein levels in blood 3.Change from baseline in total score of HFMSE at Month 12 4.Change from baseline in the total score of the revised upper limb module (RULM) at Month 12 5.Proportion of patients who achieve stabilization or improvement (i.e., a change from baseline >= 0) on the total MFM score at Month 12 6.Proportion of patients who achieve an improvement of at least one standard error of measurement (SEM calculated at baseline) on the total MFM score at Month 12. 7.Proportion of patients who achieve stabilization or improvement (i.e., a change from baseline >= 0) on the total HFMSE score at Month 12. 8.Proportion of patients who achieve stabilization or improvement (i.e., a change from baseline >= 0) on the total RULM score at Month 12. 9.Change from baseline in the MFM domain scores of D1, D2, D3 and the total combined score of (D1 + D2) at Month 12. 10.Change from baseline in the best SNIP (expressed as a percentage of the predicted value) at Month 12. 11.Change from baseline in the best MIP at Month 12. 12.Change from baseline in the best MEP at Month 12 13.Change from baseline in FEV1 in patients aged 6 to 25 years at Month 12 14.Change from baseline in FVC in patients aged 6 to 25 years at Month 12. 15.Change from baseline in the peak cough flow (PCF) in patients aged 6 to 25 years at Month 12. 16.Change from baseline in the Total Score of the caregiver-reported SMA independence Scale (SMAIS) at Month 12. 17.Change from baseline in the Total score of the patient-reported SMA independence scale (SMAIS) at Month 12 18.Proportion of patients rated by clinicians as no change or improved in the Clinical Global Impression of Change (CGI-C) Scale at Month 12 (Part 2 only). 19.Proportion of patients rated by clinicians as improved in the Clinical Global Impression of Change (CGI-C) Scale at Month 12. 20.Proportion of patients who experience at least one disease related adverse event | — |
Countries
Argentina, Belgium, Brazil, Bulgaria, Canada, China, Croatia, France, Germany, Hungary, Italy, Japan, Mexico, Poland, Romania, Russian Federation, Serbia, Spain, Switzerland, Turkey, Ukraine, United Kingdom, United States
Contacts
Public ContactTrial Information Support Line-TISL
F.Hoffmann-La Roche Ltd
Outcome results
None listed