Phase 2
N=51
A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of Risdiplam (RO7034067) in Type 2 and 3 Spinal Muscular Atrophy (SMA) Participants
Muscular Atrophy, Spinal
Bottom Line
View on ClinicalTrials.gov: NCT02908685 ↗Enrolled (actual)
51
Serious AEs
17.1%
Results posted
Jun 2021
Primary outcome: Primary: Part 1: Selected Part 2 Dose of Risdiplam for Participants With a Body Weight (BW) of >/=20kg — 5 milligram (mg)
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- Placebo (Drug); Risdiplam (Drug)
- Age
- Pediatric, Adult · 2+ yrs
- Sex
- All
- Sponsor
- Hoffmann-La Roche
- Primary completion
- Sep 2019
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Part 1: Selected Part 2 Dose of Risdiplam for Participants With a Body Weight (BW) of >/=20kg |
5 | — |
| PRIMARY Part 1: Selected Part 2 Dose of Risdiplam for Participants With BW of <20kg |
0.25 | — |
| PRIMARY Part 2: Change From Baseline in the Total Motor Function Measure 32 (MFM-32) Total Score at Month 12 |
1.36; -0.19 | 0.0156 sig |
| SECONDARY Part 2: Percentage of Participants With Marked Improvement (Defined as >= 3) in the Total Motor Function Measure (MFM32) Score at Month 12 |
38.3; 23.7 | 0.0469 sig |
| SECONDARY Part 2: Change From Baseline in the Total Score of the Revised Upper Limb Module (RULM) at Month 12 |
1.61; 0.02 | 0.0469 sig |
| SECONDARY Part 2: Change From Baseline in Total Score of Hammersmith Functional Motor Scale Expanded (HFMSE) at Month 12 |
0.95; 0.37 | 0.3902 |
| SECONDARY Part 2: Change From Baseline in Forced Vital Capacity (FVC) at Month 12 in Participants Aged 6-25 Years |
-5.16; -3.11 | 0.3902 |
| SECONDARY Part 2: Change From Baseline in the Caregiver-Reported SMA Independence Scale (SMAIS) Total Score at Month 12 |
1.65; -0.91 | 0.3902 |
| SECONDARY Part 2: Percentage of Participants Rated by Clinicians as Improved in the Clinical Global Impression of Change (CGI-C) Scale Ratings at Month 12 |
47.5; 40.0 | 0.3902 |
| SECONDARY Part 2: Percentage of Participants Who Achieve Stabilization or Improvement (Defined as >= 0) in the Total Motor Function Measure (MFM-32) Score at Month 12 |
69.6; 54.2 | 0.0430 sig |
| SECONDARY Part 2: Percentage of Participants Who Achieve an Improvement of at Least One Standard Error of Measurement on the Total MFM-32 Score at Month 12 |
28.7; 16.9 | — |
| SECONDARY Part 2: Change From Baseline in the MFM-32 Domain 1 (D1) Score at Month 12 |
0.37; -0.26 | 0.1328 |
| SECONDARY Part 2: Change From Baseline in the MFM-32 Domain 2 (D2) Score at Month 12 |
1.04; -0.93 | 0.1030 |
| SECONDARY Part 2: Change From Baseline in the MFM-32 Domain 3 (D3) Score at Month 12 |
3.68; 1.34 | 0.0451 sig |
| SECONDARY Part 2: Change From Baseline in the Total Combined Scores of MFM-32 Domains 1 and 2 at Month 12 |
0.69; -0.59 | 0.0489 sig |
| SECONDARY Part 2: Change From Baseline in the Total Combined Scores of MFM-32 Domains 2 and 3 at Month 12 |
2.02; -0.14 | 0.0326 sig |
| SECONDARY Part 2: Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Month 12 in Participants Aged 6-25 Years |
-4.22; -1.35 | 0.3029 |
| SECONDARY Part 2: Change From Baseline in the Peak Cough Flow (PCF) at Month 12 in Participants Aged 6-25 Years |
1.06; -0.22 | 0.4937 |
| SECONDARY Part 2: Change From Baseline in the Best Sniff Nasal Inspiratory Pressure (SNIP) at Month 12 |
3.42; 1.07 | 0.3967 |
| SECONDARY Part 2: Change From Baseline in Maximal Inspiratory Pressure (MIP) at Month 12 in Participants Aged 6-25 Years |
1.99; -0.97 | 0.6704 |
| SECONDARY Part 2: Change From Baseline in Maximal Expiratory Pressure (MEP) at Month 12 in Participants Aged 6-25 Years |
-2.75; -2.33 | 0.8856 |
| SECONDARY Part 2: Change From Baseline in the Participant-Reported SMA Independence Scale (SMAIS) Total Score at Month 12 |
1.04; -0.40 | 0.1778 |
| SECONDARY Part 2: Percentage of Participants Rated by Clinicians as No Change or Improved in the Clinical Global Impression of Change (CGI-C) Scale Ratings at Month 12 |
85.8; 83.3 | 0.6636 |
| SECONDARY Part 2: Percentage of Participants Who Experience at Least One Disease-Related Adverse Event at Month 12 |
46.7; 53.3; 65.0; 60.0 | — |
| SECONDARY Part 2: Number of Disease-related Adverse Events Per Patient-years at Month 12 |
101.51; 119.77; 217.29; 199.61 | — |
| SECONDARY Part 2: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period |
92.5; 91.7; 20.0; 18.3 | — |
| SECONDARY Part 2: Percentage of Participants With Treatment Discontinuation Due to Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period |
0.0; 0.0; 0.0; 0.0 | — |
| SECONDARY Part 2: Number of Participants Aged 6-25 Years With Suicidal Ideation Based on Columbia-Suicide Severity Rating Scale (C-SSRS) in the Placebo-Controlled Period |
1; 1; 1; 1; 1; 1 | — |
| SECONDARY Part 2: Number of Participants Aged 6-25 Years With Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) in the Placebo-Controlled Period |
0; 0; 0; 0; 0; 0 | — |
| SECONDARY Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood |
2.91; 1.96 | — |
| SECONDARY Part 1 and 2: Maximum Plasma Concentration (Cmax) of Risdiplam at Year 5 |
137; 140 | — |
| SECONDARY Part 1 and 2: Area Under the Curve (AUC) From 0 to 24 Hours of Risdiplam at Year 5 Visit |
1700; 1880 | — |
| SECONDARY Part 1 and 2: Concentration at the End of a Dosing Interval (Ctrough) of Risdiplam at Year 5 |
54.1; 57.2 | — |
Summary
Multi-center, randomized, double-blind, placebo-controlled study to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of Risdiplam in adult and pediatric participants with Type 2 and Type 3 SMA. The study consists of two parts, an exploratory dose finding part (Part 1) of Risdiplam for 12 weeks and a confirmatory part (Part 2) of Risdiplam for 24 months.
Eligibility Criteria
Inclusion Criteria
- 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
- For Part 1: Type 2 or 3 SMA ambulant or non-ambulant
- For Part 2: 1) Type 2 or 3 SMA non-ambulant; 2) RULM entry item A greater than or equal to 2; 3) ability to sit independently as assessed by item 9 of the MFM
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 electrocardiogram abnormalities before study drug administration from average of triplicate measurement or cardiovascular disease indicating a safety risk for participants as determined by the Investigator
- 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
- Recently initiated treatment (within less than [<] 6 months prior to randomization) with oral salbutamol or another beta 2-adrenergic agonist taken orally
- Any prior use of chloroquine, hydroxychloroquine, retigabin, vigabatrin or thioridazine, is not allowed
- 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
- Participants requiring invasive ventilation or tracheostomy
Data sourced from ClinicalTrials.gov (NCT02908685). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.