A Phase 2 interventional study of Placebo and Risdiplam in Muscular Atrophy, Spinal, sponsored by Hoffmann-La Roche. Completed at 45 sites in 16 countries. Open to participants aged 2 Years to 25 Years. Per ClinicalTrials.gov, last updated 2024-04-24.
Sponsored by Hoffmann-La Roche · Phase 2, Interventional, and Treatment
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.
494 studies on the registry are indexed under Muscular Atrophy; 94 are open to participants now.
This study's enrollment of 231 is above the median of 33 across 335 interventional studies indexed under Muscular Atrophy.
Browse Muscular Atrophy studies →Hoffmann-La Roche is the lead sponsor of 2,061 studies on the registry; 85 are open to participants now.
Of its 319 completed or terminated interventional studies of FDA-regulated products, 239 (75%) have results posted.
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Exclusion Criteria:
Adolescent and adult participants aged 12-25 years will receive risdiplam for at least 12 weeks. Once the placebo-controlled period is completed and Part 2 dose is selected, participants will be switched to Part 2 dose and will be treated in an open-label phase.
Drug: Risdiplam
Adolescent and adult participants aged 12-25 years will receive placebo matching to risdiplam for at least 12 weeks. Once placebo-controlled period is completed, participants will be first switched to their cohort risdiplam dose. After the Part 2 dose is selected, participants will be switched to Part 2 dose and will be treated in an open-label phase.
Drug: Placebo · Drug: Risdiplam
Children aged 2-11 years will receive placebo matching to risdiplam for at least 12 weeks. Once placebo-controlled period is completed, participants will be first switched to their cohort risdiplam dose. After the Part 2 dose is selected, participants will be switched to Part 2 dose and will be treated in an open-label phase.
Drug: Placebo · Drug: Risdiplam
Children aged 2-11 years will receive risdiplam for at least 12 weeks. Once the placebo-controlled period is completed and Part 2 dose is selected, participants will be switched to Part 2 dose and will be treated in an open-label phase.
Drug: Risdiplam
Participants aged 2-25 years will receive placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants will be switched to risdiplam (5 mg once daily for participants with a body weight (BW) \>/=20kg or 0.25 mg/kg for participants with a BW \<20) in a blinded manner and participants will continue with treatment until Month 24. After Month 24, participants will be offered the opportunity to enter the open-label phase.
Drug: Placebo · Drug: Risdiplam
Participants aged 2-25 years will receive risdiplam at the dose selected based on the results from Part 1 of the study (5 mg once daily for participants with a body weight (BW) \>/=20kg or 0.25 mg/kg for participants with a BW \<20 kg), for 24 months. After 24-month treatment, participants will be offered the opportunity to enter the open-label phase.
Drug: Risdiplam
Placebo will be administered orally (via mouth) or through a feeding tube (naso-gastric or gastrostomy tube).
Risdiplam will be administered orally (via mouth) or through a feeding tube (naso-gastric or gastrostomy tube).
Also known as: RO7034067
Part 1: Selected Part 2 Dose of Risdiplam for Participants With a Body Weight (BW) of >/=20kg
The Internal Monitoring Committee (IMC) was responsible for selecting the dose for Part 2 of the study (pivotal dose). An external Independent Data Monitoring Committee (iDMC) reviewed data from Part 1 and confirmed the dose-selection decision of the IMC. The dose for Part 2 selected by the IMC was a dose that: 1.Was judged to be safe and well-tolerated, based on all available safety data from Part 1 and as confirmed by the iDMC; 2. Resulted in an exposure at steady-state below the exposure cap (mean value) of AUC0-24h,ss 2000 ng\*h/mL (adjusted for free-fraction, if required); 3. Resulted in an SMN protein increase that was expected to be clinically relevant.
Time frame: Day 1 up to at least 4 weeks on study (Up to CCOD of 25 July 2017)
Part 1: Selected Part 2 Dose of Risdiplam for Participants With BW of <20kg
The Internal Monitoring Committee (IMC) was responsible for selecting the dose for Part 2 of the study (pivotal dose). An external Independent Data Monitoring Committee (iDMC) reviewed data from Part 1 and confirmed the dose-selection decision of the IMC. The dose for Part 2 selected by the IMC was a dose that: 1.Was judged to be safe and well-tolerated, based on all available safety data from Part 1 and as confirmed by the iDMC; 2. Resulted in an exposure at steady-state below the exposure cap (mean value) of AUC0-24h,ss 2000 ng\*h/mL (adjusted for free-fraction, if required); 3. Resulted in an SMN protein increase that was expected to be clinically relevant.
Time frame: Day 1 up to at least 4 weeks on study (Up to CCOD of 25 July 2017)
Part 2: Change From Baseline in the Total Motor Function Measure 32 (MFM-32) Total Score at Month 12
The Motor Function Measure 32 (MFM32) is a scale constructed for use in neuromuscular disorders. It comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The 32 scores are summed and expressed on a 0-100 scale for the MFM32 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on primary efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
Time frame: Baseline (Day-1) and Month 12
Part 2: Percentage of Participants With Marked Improvement (Defined as >= 3) in the Total Motor Function Measure (MFM32) Score at Month 12
The MFM32 comprises 32 items that evaluate physical function. The scoring of each task uses a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The 32 scores are summed and expressed on a 0-100 scale for the MFM32 total score. A change in MFM32 total score of threshold \>/=3 represents marked improvement in this measure. Logistic regression analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
Time frame: At Month 12
Part 2: Change From Baseline in the Total Score of the Revised Upper Limb Module (RULM) at Month 12
The RULM is a 20 items scale that assesses the proximal and distal motor functions of the arm. There is an entry item and the remaining 18 items are scored on the 3 point scale of: 0: cannot complete task independently; 1: modified method but can complete task independently; 2: completes task without any assistance, and with 1 item scored on a 2 point scale of as a can/cannot score with 1 as the highest score. The RULM total score is the sum of 19 items scores with range of 0-37, and the entry item does not contribute to the total score. Higher scores indicate greater upper limb function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on the efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
Time frame: Baseline (Day-1) and Month 12
Part 2: Change From Baseline in Total Score of Hammersmith Functional Motor Scale Expanded (HFMSE) at Month 12
The HFMSE scale contains 33 items, which are scored on a 3-point Likert-type scale (0-2) and summed to derive the total score, with lower scores indicating greater impairment. The HFMSE contains a series of assessments designed to assess important functional abilities, including standing, transfers, ambulation, and proximal and axial function. The overall score is the sum of the scores for all activities with a maximum achievable score of 66. Higher scores indicate greater motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on the efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
Time frame: Baseline (Day-1) and Month 12
Part 2: Change From Baseline in Forced Vital Capacity (FVC) at Month 12 in Participants Aged 6-25 Years
Spirometry is a pulmonary function test that assesses how the lungs work by measuring how much air moves through the airways. Spirometry was performed by all participants aged 6 or older. Forced vital capacity (FVC) is the total volume that can be exhaled after inhaling maximally. The best % predicted value out of all attempts were used for the analysis. MMRM analysis was performed based on the efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
Time frame: Baseline (Day-1) and Month 12
Part 2: Change From Baseline in the Caregiver-Reported SMA Independence Scale (SMAIS) Total Score at Month 12
The SMA Independence Scale (SMAIS) was developed specifically for SMA participants in order to assess function-related independence. The SMAIS contains 29 items, assessing the amount of assistance required from another individual to perform daily activities such as eating, or bathing. Each item is scored on a 0-4 scale (with an additional option to indicate that an item is non-applicable). The SMAIS total score ranging from 0-44 is obtained based on 22 items with each item on the 0-2 scale. Lower scores indicate greater dependence on another individual. The SMAIS was completed by participants aged 12 years or older and caregivers of participants aged 2-25 years. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
Time frame: Baseline (Day-1) and Month 12
Part 2: Percentage of Participants Rated by Clinicians as Improved in the Clinical Global Impression of Change (CGI-C) Scale Ratings at Month 12
The Clinical Global Impression of Change (CGI-C) is used to score a clinician's impression of a participant's change in global health. The CGI-C is a single item measure of change in global health, using seven response options: "very much improved", "much improved", "minimally improved", "no change", "minimally worse", "much worse", and "very much worse". Participants considered as "improved" included responses of "very much improved, "much improved" and "minimally improved". Logistic regression analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
Time frame: At Month 12
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
The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The 32 scores are summed and expressed on a 0-100 scale for the MFM32 total score. Higher scores indicate increased motor function. Logistic regression analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
Time frame: At Month 12
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
The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0-cannot initiate the task or maintain the starting position; 1-performs the task partially; 2-performs the task incompletely or imperfectly; 3-performs the task fully and "normally". The 32 scores are summed and expressed on a 0-100 scale for the total score. Higher scores indicate increased motor function. Standard error of measurement (SEM) is derived using 32 items scores and total scores at baseline. Change from baseline \> = one SEM is equivalent to a change \>= 4. Logistic regression analysis was performed based on efficacy hypothetical estimand included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
Time frame: At Month 12
Part 2: Change From Baseline in the MFM-32 Domain 1 (D1) Score at Month 12
The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The D1 items score are summed and expressed on 0-100 scale for the MFM D1 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
Time frame: Baseline (Day-1) and Month 12
Part 2: Change From Baseline in the MFM-32 Domain 2 (D2) Score at Month 12
The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The D2 items score are summed and expressed on 0-100 scale for the MFM D2 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
Time frame: Baseline (Day-1) and Month 12
Part 2: Change From Baseline in the MFM-32 Domain 3 (D3) Score at Month 12
The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The D3 items score are summed and expressed on 0-100 scale for the MFM D3 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
Time frame: Baseline (Day-1) and Month 12
Part 2: Change From Baseline in the Total Combined Scores of MFM-32 Domains 1 and 2 at Month 12
The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The D1+D2 items score are summed and expressed on 0-100 scale for the MFM D1+D2 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
Time frame: Baseline (Day-1) and Month 12
Part 2: Change From Baseline in the Total Combined Scores of MFM-32 Domains 2 and 3 at Month 12
The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The D2+D3 items score are summed and expressed on 0-100 scale for the MFM D2+D3 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
Time frame: Baseline (Day-1) and Month 12
Part 2: Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Month 12 in Participants Aged 6-25 Years
Spirometry is a pulmonary function test that assesses how the lungs work by measuring how much air moves through the airways. Spirometry was performed by all participants aged 6 or older. Forced expiratory volume (FEV1) is the volume forcefully exhaled in the first second of the forced vital capacity test. The best % predicted value out of all attempts were used for the analysis. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
Time frame: Baseline (Day-1) and Month 12
Part 2: Change From Baseline in the Peak Cough Flow (PCF) at Month 12 in Participants Aged 6-25 Years
Spirometry is a pulmonary function test that assesses how the lungs work by measuring how much air moves through the airways. Spirometry was performed by all participants aged 6 or older. Peak cough flow (PCF) is an assessment of cough strength. The best % predicted value out of all attempts were used for the analysis MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
Time frame: Baseline (Day-1) and Month 12
Part 2: Change From Baseline in the Best Sniff Nasal Inspiratory Pressure (SNIP) at Month 12
The Sniff Nasal Inspiratory Pressure (SNIP) is a volitional, non-invasive test of inspiratory muscle strength that has been successfully applied to children \> 2 years of age. Advantages include the simplicity of the maneuver and the absence of a mouthpiece, which is particularly helpful for participants with SMA, who may have bulbar weakness. SNIP also has the advantage of measuring inspiratory pressure during a natural maneuver that is easily performed even by young children with neuromuscular disorders. The best % predicted value out of all attempts were used for the analysis. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
Time frame: Baseline (Day-1) and Month 12
Part 2: Change From Baseline in Maximal Inspiratory Pressure (MIP) at Month 12 in Participants Aged 6-25 Years
The maximal inspiratory pressure (MIP) is a non-invasive test of muscle strength, which measures the maximum strength of the diaphragm and other inspiratory muscles. MIP was measured in participants aged 6 or older. Participants were asked to perform a forceful inspiration against an occluded mouth piece. The best % predicted value out of all attempts were used for the analysis. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
Time frame: Baseline (Day-1) and Month 12
Part 2: Change From Baseline in Maximal Expiratory Pressure (MEP) at Month 12 in Participants Aged 6-25 Years
The maximal expiratory pressure (MEP) is a non-invasive test of muscle strength, which measures the maximum strength of the abdominal muscles and other expiratory muscles. MEP was measured in participants aged 6 or older. Participants were asked to perform a forceful inspiration against an occluded mouth piece. The best % predicted value out of all attempts were used for the analysis. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
Time frame: Baseline (Day-1) and Month 12
Part 2: Change From Baseline in the Participant-Reported SMA Independence Scale (SMAIS) Total Score at Month 12
The SMAIS was developed specifically for SMA participants in order to assess function-related independence. It contains 29 items, assessing the amount of assistance required from another individual to perform daily activities such as eating, or bathing. Each item is scored on a 0-4 scale (with an additional option to indicate that an item is non-applicable). The SMAIS total score ranging from 0-44 is obtained based on 22 items with each item on the 0-2 scale. Lower scores indicate greater dependence on another individual. The SMAIS was completed by participants aged 12 years or older and caregivers of participants aged 2-25 years. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
Time frame: Baseline (Day-1) and Month 12
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
The CGI-C is used to score a clinician's impression of a participant's change in global health. It is a single item measure of change in global health, using seven response options: "very much improved", "much improved", "minimally improved", "no change", "minimally worse", "much worse", and "very much worse". Participants considered as "no change or improved" included responses of "no change", "very much improved", "much improved" and "minimally improved". Logistic regression analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
Time frame: At Month 12
Part 2: Percentage of Participants Who Experience at Least One Disease-Related Adverse Event at Month 12
Disease-related adverse events (AEs) were identified by applying two different types of baskets to the AE dataset: Narrow prospectively defined baskets of MedDRA lowest level terms. This basket was defined based on a group of CDC terms selected from an age and gender matched case control study comparing CDC code rates observed in participants with and without SMA using commercially available insurance claim data (CLAIMS and Market scan data). The lowest level terms included in each basket, coded using the latest version of MedDRA; Broad prospectively defined basket with events selected at preferred term level from all AEs reported in ongoing clinical trials up to January 2019, i.e., prior to unblinding of Part 2 of Study BP39055.
Time frame: Baseline up to Month 12 (Week 52; up to CCOD of 06 September 2019)
Part 2: Number of Disease-related Adverse Events Per Patient-years at Month 12
Disease-related AEs were collected through the AE reporting of the study, and the disease-related AE rate was adjusted for patient years (AE rate per 100 patient-years). They were identified by applying two different types of baskets to the AE dataset: Narrow prospectively defined baskets of MedDRA lowest level terms and Broad prospectively defined basket with events selected at preferred term level from all AEs reported in ongoing clinical trials up to January 2019, i.e., prior to unblinding of Part 2 of Study BP39055.
Time frame: Baseline up to Month 12 (Week 52; up to CCOD of 06 September 2019)
Part 2: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period
An adverse event (AE) is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Time frame: Day 1 up to 12 months of the placebo-controlled period
Part 2: Percentage of Participants With Treatment Discontinuation Due to Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period
An adverse event (AE) is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Time frame: Day 1 up to 12 months of the placebo-controlled period
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
The Columbia Suicide Severity Rating Scale (C-SSRS) is used to assess the lifetime suicidality of a participant (C-SSRS baseline) as well as any new instances of suicidality (C-SSRS since last visit). The structured interview prompts recollection of suicidal ideation, including the intensity of the ideation, behavior, and attempts with actual/potential lethality. The C-SSRS assessments results were collected for participants aged 6 years and older.
Time frame: Day 1 up to 12 months of the placebo-controlled period
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
The Columbia Suicide Severity Rating Scale (C-SSRS) is used to assess the lifetime suicidality of a participant (C-SSRS baseline) as well as any new instances of suicidality (C-SSRS since last visit). The structured interview prompts recollection of suicidal ideation, including the intensity of the ideation, behavior, and attempts with actual/potential lethality. The C-SSRS assessments results were collected for participants aged 6 years and older.
Time frame: Day 1 up to 12 months of the placebo-controlled period
Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood
Time frame: Part 1: Day -1, pre-dose of Weeks 1, 2 (>/= 12 years only), 17, 35 and 104, and at 4h post-dose of Weeks 4 and 52. Part 2: Day -1, pre-dose of Weeks 1, 17, 35 and 104, and at 4h post-dose of Weeks 4 and 52.
Part 1 and 2: Maximum Plasma Concentration (Cmax) of Risdiplam at Year 5
Reported here is the maximum observed concentration throughout the observation period.
Time frame: Day 1: 1, 2, 4, 6 h postdose, Weeks 4, 8 (Part 1 only), 52, 87: pre-dose, 1, 2, 4, 6 h post-dose and Weeks 1 (Day 7), 2, 8 (Part 2 only) 17, 35, 70, 104: predose
Part 1 and 2: Area Under the Curve (AUC) From 0 to 24 Hours of Risdiplam at Year 5 Visit
Time frame: Year 5 visit pre-dose, 1, 2, 4, 6, 24 hours post-dose
Part 1 and 2: Concentration at the End of a Dosing Interval (Ctrough) of Risdiplam at Year 5
Time frame: The last predose sample collected from each participant who had at least 1400 days of risdiplam treatment duration.
Study Part 1 was conducted at 5 investigational sites across 4 countries, and Part 2 was conducted at 42 investigational sites across 14 countries. Screening in both Part 1 and 2 was up to 30 days prior to first dose.
| Milestone | Part 1 Group A Cohort 1: Adolescents and Adults (3 mg Risdiplam) | Part 1 Group A Cohort 2: Adolescents and Adults (5 mg Risdiplam) | Part 1 Group A Cohort 1: Adolescents and Adults (Placebo) | Part 1 Group A Cohort 2: Adolescents and Adults (Placebo) | Part 1 Group B Cohort 1: Children (0.02 mg/kg Risdiplam) | Part 1 Group B Cohort 2: Children (0.05 mg/kg Risdiplam) | Part 1 Group B Cohort 3: Children (0.25 mg/kg Risdiplam) | Part 1 Group B Cohort 1: Children (Placebo) | Part 1 Group B Cohort 2: Children (Placebo) | Part 1 Group B Cohort 3: Children (Placebo) | Part 1 Group A: OLE | Part 1 Group B: OLE | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Started | 7 | 7 | 3 | 3 | 7 | 7 | 7 | 3 | 4 | 3 | 0 | 0 | 0 | 0 |
| Completed | 7 | 7 | 3 | 3 | 7 | 7 | 7 | 3 | 4 | 3 | 0 | 0 | 0 | 0 |
| Not completed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Milestone | Part 1 Group A Cohort 1: Adolescents and Adults (3 mg Risdiplam) | Part 1 Group A Cohort 2: Adolescents and Adults (5 mg Risdiplam) | Part 1 Group A Cohort 1: Adolescents and Adults (Placebo) | Part 1 Group A Cohort 2: Adolescents and Adults (Placebo) | Part 1 Group B Cohort 1: Children (0.02 mg/kg Risdiplam) | Part 1 Group B Cohort 2: Children (0.05 mg/kg Risdiplam) | Part 1 Group B Cohort 3: Children (0.25 mg/kg Risdiplam) | Part 1 Group B Cohort 1: Children (Placebo) | Part 1 Group B Cohort 2: Children (Placebo) | Part 1 Group B Cohort 3: Children (Placebo) | Part 1 Group A: OLE | Part 1 Group B: OLE | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Started | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 20 | 31 | 0 | 0 |
| Completed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 18 | 30 | 0 | 0 |
| Not completed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 | 0 | 0 |
| Withdrew: Withdrawal by subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 | 0 | 0 |
| Milestone | Part 1 Group A Cohort 1: Adolescents and Adults (3 mg Risdiplam) | Part 1 Group A Cohort 2: Adolescents and Adults (5 mg Risdiplam) | Part 1 Group A Cohort 1: Adolescents and Adults (Placebo) | Part 1 Group A Cohort 2: Adolescents and Adults (Placebo) | Part 1 Group B Cohort 1: Children (0.02 mg/kg Risdiplam) | Part 1 Group B Cohort 2: Children (0.05 mg/kg Risdiplam) | Part 1 Group B Cohort 3: Children (0.25 mg/kg Risdiplam) | Part 1 Group B Cohort 1: Children (Placebo) | Part 1 Group B Cohort 2: Children (Placebo) | Part 1 Group B Cohort 3: Children (Placebo) | Part 1 Group A: OLE | Part 1 Group B: OLE | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Started | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 120 | 60 |
| Completed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 117 | 59 |
| Not completed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 1 |
| Withdrew: Changed to spinraza | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 |
| Withdrew: Changed to other treatment | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Milestone | Part 1 Group A Cohort 1: Adolescents and Adults (3 mg Risdiplam) | Part 1 Group A Cohort 2: Adolescents and Adults (5 mg Risdiplam) | Part 1 Group A Cohort 1: Adolescents and Adults (Placebo) | Part 1 Group A Cohort 2: Adolescents and Adults (Placebo) | Part 1 Group B Cohort 1: Children (0.02 mg/kg Risdiplam) | Part 1 Group B Cohort 2: Children (0.05 mg/kg Risdiplam) | Part 1 Group B Cohort 3: Children (0.25 mg/kg Risdiplam) | Part 1 Group B Cohort 1: Children (Placebo) | Part 1 Group B Cohort 2: Children (Placebo) | Part 1 Group B Cohort 3: Children (Placebo) | Part 1 Group A: OLE | Part 1 Group B: OLE | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Started | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 117 | 59 |
| Completed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 116 | 59 |
| Not completed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Withdrew: Withdrawal by subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Milestone | Part 1 Group A Cohort 1: Adolescents and Adults (3 mg Risdiplam) | Part 1 Group A Cohort 2: Adolescents and Adults (5 mg Risdiplam) | Part 1 Group A Cohort 1: Adolescents and Adults (Placebo) | Part 1 Group A Cohort 2: Adolescents and Adults (Placebo) | Part 1 Group B Cohort 1: Children (0.02 mg/kg Risdiplam) | Part 1 Group B Cohort 2: Children (0.05 mg/kg Risdiplam) | Part 1 Group B Cohort 3: Children (0.25 mg/kg Risdiplam) | Part 1 Group B Cohort 1: Children (Placebo) | Part 1 Group B Cohort 2: Children (Placebo) | Part 1 Group B Cohort 3: Children (Placebo) | Part 1 Group A: OLE | Part 1 Group B: OLE | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Started | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 116 | 59 |
| Completed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 103 | 53 |
| Not completed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 13 | 6 |
| Withdrew: Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Withdrew: Reason not specified | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 |
| Withdrew: Withdrawal by subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 10 | 5 |
The Internal Monitoring Committee (IMC) was responsible for selecting the dose for Part 2 of the study (pivotal dose). An external Independent Data Monitoring Committee (iDMC) reviewed data from Part 1 and confirmed the dose-selection decision of the IMC. The dose for Part 2 selected by the IMC was a dose that: 1.Was judged to be safe and well-tolerated, based on all available safety data from Part 1 and as confirmed by the iDMC; 2. Resulted in an exposure at steady-state below the exposure cap (mean value) of AUC0-24h,ss 2000 ng\*h/mL (adjusted for free-fraction, if required); 3. Resulted in an SMN protein increase that was expected to be clinically relevant.
| milligram (mg) | Part 1: All Risdiplam |
|---|---|
| Part 1: Selected Part 2 Dose of Risdiplam for Participants With a Body Weight (BW) of >/=20kg | 5 |
The Internal Monitoring Committee (IMC) was responsible for selecting the dose for Part 2 of the study (pivotal dose). An external Independent Data Monitoring Committee (iDMC) reviewed data from Part 1 and confirmed the dose-selection decision of the IMC. The dose for Part 2 selected by the IMC was a dose that: 1.Was judged to be safe and well-tolerated, based on all available safety data from Part 1 and as confirmed by the iDMC; 2. Resulted in an exposure at steady-state below the exposure cap (mean value) of AUC0-24h,ss 2000 ng\*h/mL (adjusted for free-fraction, if required); 3. Resulted in an SMN protein increase that was expected to be clinically relevant.
| milligram/kilogram (mg/kg) | Part 1: All Risdiplam |
|---|---|
| Part 1: Selected Part 2 Dose of Risdiplam for Participants With BW of <20kg | 0.25 |
The Motor Function Measure 32 (MFM32) is a scale constructed for use in neuromuscular disorders. It comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The 32 scores are summed and expressed on a 0-100 scale for the MFM32 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on primary efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
| Scores on a Scale | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| Part 2: Change From Baseline in the Total Motor Function Measure 32 (MFM-32) Total Score at Month 12 | 1.36 (0.61 to 2.11) | -0.19 (-1.22 to 0.84) |
The MFM32 comprises 32 items that evaluate physical function. The scoring of each task uses a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The 32 scores are summed and expressed on a 0-100 scale for the MFM32 total score. A change in MFM32 total score of threshold \>/=3 represents marked improvement in this measure. Logistic regression analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
| Percentage of Participants | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| Part 2: Percentage of Participants With Marked Improvement (Defined as >= 3) in the Total Motor Function Measure (MFM32) Score at Month 12 | 38.3 (28.94 to 47.58) | 23.7 (12.03 to 35.43) |
The RULM is a 20 items scale that assesses the proximal and distal motor functions of the arm. There is an entry item and the remaining 18 items are scored on the 3 point scale of: 0: cannot complete task independently; 1: modified method but can complete task independently; 2: completes task without any assistance, and with 1 item scored on a 2 point scale of as a can/cannot score with 1 as the highest score. The RULM total score is the sum of 19 items scores with range of 0-37, and the entry item does not contribute to the total score. Higher scores indicate greater upper limb function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on the efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
| Scores on a Scale | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| Part 2: Change From Baseline in the Total Score of the Revised Upper Limb Module (RULM) at Month 12 | 1.61 (1.00 to 2.22) | 0.02 (-0.83 to 0.87) |
The HFMSE scale contains 33 items, which are scored on a 3-point Likert-type scale (0-2) and summed to derive the total score, with lower scores indicating greater impairment. The HFMSE contains a series of assessments designed to assess important functional abilities, including standing, transfers, ambulation, and proximal and axial function. The overall score is the sum of the scores for all activities with a maximum achievable score of 66. Higher scores indicate greater motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on the efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
| Scores on a Scale | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| Part 2: Change From Baseline in Total Score of Hammersmith Functional Motor Scale Expanded (HFMSE) at Month 12 | 0.95 (0.29 to 1.61) | 0.37 (-0.54 to 1.28) |
Spirometry is a pulmonary function test that assesses how the lungs work by measuring how much air moves through the airways. Spirometry was performed by all participants aged 6 or older. Forced vital capacity (FVC) is the total volume that can be exhaled after inhaling maximally. The best % predicted value out of all attempts were used for the analysis. MMRM analysis was performed based on the efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
| Percentage Predicted | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| Part 2: Change From Baseline in Forced Vital Capacity (FVC) at Month 12 in Participants Aged 6-25 Years | -5.16 (-7.93 to -2.39) | -3.11 (-6.59 to 0.74) |
The SMA Independence Scale (SMAIS) was developed specifically for SMA participants in order to assess function-related independence. The SMAIS contains 29 items, assessing the amount of assistance required from another individual to perform daily activities such as eating, or bathing. Each item is scored on a 0-4 scale (with an additional option to indicate that an item is non-applicable). The SMAIS total score ranging from 0-44 is obtained based on 22 items with each item on the 0-2 scale. Lower scores indicate greater dependence on another individual. The SMAIS was completed by participants aged 12 years or older and caregivers of participants aged 2-25 years. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
| Scores on a Scale | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| Part 2: Change From Baseline in the Caregiver-Reported SMA Independence Scale (SMAIS) Total Score at Month 12 | 1.65 (0.66 to 2.63) | -0.91 (-2.23 to 0.42) |
The Clinical Global Impression of Change (CGI-C) is used to score a clinician's impression of a participant's change in global health. The CGI-C is a single item measure of change in global health, using seven response options: "very much improved", "much improved", "minimally improved", "no change", "minimally worse", "much worse", and "very much worse". Participants considered as "improved" included responses of "very much improved, "much improved" and "minimally improved". Logistic regression analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
| Percentage of Participants | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| 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 (38.15 to 56.86) | 40.0 (26.77 to 53.23) |
The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The 32 scores are summed and expressed on a 0-100 scale for the MFM32 total score. Higher scores indicate increased motor function. Logistic regression analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
| Percentage of Participants | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| 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 (60.72 to 78.41) | 54.2 (40.68 to 67.80) |
The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0-cannot initiate the task or maintain the starting position; 1-performs the task partially; 2-performs the task incompletely or imperfectly; 3-performs the task fully and "normally". The 32 scores are summed and expressed on a 0-100 scale for the total score. Higher scores indicate increased motor function. Standard error of measurement (SEM) is derived using 32 items scores and total scores at baseline. Change from baseline \> = one SEM is equivalent to a change \>= 4. Logistic regression analysis was performed based on efficacy hypothetical estimand included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
| Percentage of Participants | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| 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 (20.65 to 37.88) | 16.9 (8.44 to 28.97) |
The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The D1 items score are summed and expressed on 0-100 scale for the MFM D1 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
| Scores on a Scale | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| Part 2: Change From Baseline in the MFM-32 Domain 1 (D1) Score at Month 12 | 0.37 (-0.12 to 0.87) | -0.26 (-0.94 to 0.42) |
The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The D2 items score are summed and expressed on 0-100 scale for the MFM D2 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
| Scores on a Scale | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| Part 2: Change From Baseline in the MFM-32 Domain 2 (D2) Score at Month 12 | 1.04 (-0.38 to 2.46) | -0.93 (-2.87 to 1.02) |
The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The D3 items score are summed and expressed on 0-100 scale for the MFM D3 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
| Scores on a Scale | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| Part 2: Change From Baseline in the MFM-32 Domain 3 (D3) Score at Month 12 | 3.68 (2.31 to 5.04) | 1.34 (-0.54 to 3.22) |
The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The D1+D2 items score are summed and expressed on 0-100 scale for the MFM D1+D2 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
| Scores on a Scale | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| Part 2: Change From Baseline in the Total Combined Scores of MFM-32 Domains 1 and 2 at Month 12 | 0.69 (-0.07 to 1.45) | -0.59 (-1.64 to 0.45) |
The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The D2+D3 items score are summed and expressed on 0-100 scale for the MFM D2+D3 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
| Scores on a Scale | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| Part 2: Change From Baseline in the Total Combined Scores of MFM-32 Domains 2 and 3 at Month 12 | 2.02 (0.84 to 3.20) | -0.14 (-1.76 to 1.48) |
Spirometry is a pulmonary function test that assesses how the lungs work by measuring how much air moves through the airways. Spirometry was performed by all participants aged 6 or older. Forced expiratory volume (FEV1) is the volume forcefully exhaled in the first second of the forced vital capacity test. The best % predicted value out of all attempts were used for the analysis. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
| Percentage Predicted | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| Part 2: Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Month 12 in Participants Aged 6-25 Years | -4.22 (-7.49 to -0.96) | -1.35 (-5.91 to 3.20) |
Spirometry is a pulmonary function test that assesses how the lungs work by measuring how much air moves through the airways. Spirometry was performed by all participants aged 6 or older. Peak cough flow (PCF) is an assessment of cough strength. The best % predicted value out of all attempts were used for the analysis MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
| Percent Predicted | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| Part 2: Change From Baseline in the Peak Cough Flow (PCF) at Month 12 in Participants Aged 6-25 Years | 1.06 (-1.18 to 3.31) | -0.22 (-3.27 to 2.83) |
The Sniff Nasal Inspiratory Pressure (SNIP) is a volitional, non-invasive test of inspiratory muscle strength that has been successfully applied to children \> 2 years of age. Advantages include the simplicity of the maneuver and the absence of a mouthpiece, which is particularly helpful for participants with SMA, who may have bulbar weakness. SNIP also has the advantage of measuring inspiratory pressure during a natural maneuver that is easily performed even by young children with neuromuscular disorders. The best % predicted value out of all attempts were used for the analysis. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
| Percentage Predicted | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| Part 2: Change From Baseline in the Best Sniff Nasal Inspiratory Pressure (SNIP) at Month 12 | 3.42 (0.22 to 6.62) | 1.07 (-3.42 to 5.57) |
The maximal inspiratory pressure (MIP) is a non-invasive test of muscle strength, which measures the maximum strength of the diaphragm and other inspiratory muscles. MIP was measured in participants aged 6 or older. Participants were asked to perform a forceful inspiration against an occluded mouth piece. The best % predicted value out of all attempts were used for the analysis. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
| Percentage Predicted | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| Part 2: Change From Baseline in Maximal Inspiratory Pressure (MIP) at Month 12 in Participants Aged 6-25 Years | 1.99 (-6.13 to 10.11) | -0.97 (-12.33 to 10.38) |
The maximal expiratory pressure (MEP) is a non-invasive test of muscle strength, which measures the maximum strength of the abdominal muscles and other expiratory muscles. MEP was measured in participants aged 6 or older. Participants were asked to perform a forceful inspiration against an occluded mouth piece. The best % predicted value out of all attempts were used for the analysis. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
| Percentage Predicted | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| Part 2: Change From Baseline in Maximal Expiratory Pressure (MEP) at Month 12 in Participants Aged 6-25 Years | -2.75 (-6.22 to 0.72) | -2.33 (-7.21 to 2.56) |
The SMAIS was developed specifically for SMA participants in order to assess function-related independence. It contains 29 items, assessing the amount of assistance required from another individual to perform daily activities such as eating, or bathing. Each item is scored on a 0-4 scale (with an additional option to indicate that an item is non-applicable). The SMAIS total score ranging from 0-44 is obtained based on 22 items with each item on the 0-2 scale. Lower scores indicate greater dependence on another individual. The SMAIS was completed by participants aged 12 years or older and caregivers of participants aged 2-25 years. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
| Scores on a Scale | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| Part 2: Change From Baseline in the Participant-Reported SMA Independence Scale (SMAIS) Total Score at Month 12 | 1.04 (-0.26 to 2.35) | -0.40 (-2.13 to 1.32) |
The CGI-C is used to score a clinician's impression of a participant's change in global health. It is a single item measure of change in global health, using seven response options: "very much improved", "much improved", "minimally improved", "no change", "minimally worse", "much worse", and "very much worse". Participants considered as "no change or improved" included responses of "no change", "very much improved", "much improved" and "minimally improved". Logistic regression analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
| Percentage of Participants | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| 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 (79.18 to 92.49) | 83.3 (73.07 to 93.60) |
Disease-related adverse events (AEs) were identified by applying two different types of baskets to the AE dataset: Narrow prospectively defined baskets of MedDRA lowest level terms. This basket was defined based on a group of CDC terms selected from an age and gender matched case control study comparing CDC code rates observed in participants with and without SMA using commercially available insurance claim data (CLAIMS and Market scan data). The lowest level terms included in each basket, coded using the latest version of MedDRA; Broad prospectively defined basket with events selected at preferred term level from all AEs reported in ongoing clinical trials up to January 2019, i.e., prior to unblinding of Part 2 of Study BP39055.
| Percentage of Participants | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| Narrow Basket AEs | 46.7 (37.51 to 55.99) | 53.3 (40.00 to 66.33) |
| Broad Basket AEs | 65.0 (55.76 to 73.48) | 60.0 (46.54 to 72.44) |
Disease-related AEs were collected through the AE reporting of the study, and the disease-related AE rate was adjusted for patient years (AE rate per 100 patient-years). They were identified by applying two different types of baskets to the AE dataset: Narrow prospectively defined baskets of MedDRA lowest level terms and Broad prospectively defined basket with events selected at preferred term level from all AEs reported in ongoing clinical trials up to January 2019, i.e., prior to unblinding of Part 2 of Study BP39055.
| Number of Events per 100 Patient-Years | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| Narrow Basket AEs | 101.51 (84.23 to 121.29) | 119.77 (93.71 to 150.82) |
| Broad Basket AEs | 217.29 (191.63 to 245.42) | 199.61 (165.50 to 238.68) |
An adverse event (AE) is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
| Percentage of Participants | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| With at Least One AE | 92.5 | 91.7 |
| With at Least One SAE | 20.0 | 18.3 |
An adverse event (AE) is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
| Percentage of Participants | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| Due to AE | 0.0 | 0.0 |
| Due to SAE | 0.0 | 0.0 |
The Columbia Suicide Severity Rating Scale (C-SSRS) is used to assess the lifetime suicidality of a participant (C-SSRS baseline) as well as any new instances of suicidality (C-SSRS since last visit). The structured interview prompts recollection of suicidal ideation, including the intensity of the ideation, behavior, and attempts with actual/potential lethality. The C-SSRS assessments results were collected for participants aged 6 years and older.
| Number of Participants | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| Wish to be Dead | 1 | 1 |
| Non-specific Active Suicidal Thoughts | 1 | 1 |
| Ideation with Any Methods, No Intent to Act | 1 | 1 |
| Ideation with Some Intent to Act, No Plan | 0 | 1 |
| Ideation with Specific Plan and Intent | 0 | 1 |
The Columbia Suicide Severity Rating Scale (C-SSRS) is used to assess the lifetime suicidality of a participant (C-SSRS baseline) as well as any new instances of suicidality (C-SSRS since last visit). The structured interview prompts recollection of suicidal ideation, including the intensity of the ideation, behavior, and attempts with actual/potential lethality. The C-SSRS assessments results were collected for participants aged 6 years and older.
| Number of Participants | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|
| Preparatory Acts or Behavior | 0 | 0 |
| Aborted Attempt | 0 | 0 |
| Interrupted Attempt | 0 | 0 |
| Actual Attempt (non-fatal) | 0 | 0 |
| Completed Suicide | 0 | 0 |
| unitless | Part 1: All Risdiplam | Part 2: All Risdiplam |
|---|---|---|
| Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood | 2.91 (2.14 to 4.18) | 1.96 (0.2 to 4.48) |
Reported here is the maximum observed concentration throughout the observation period.
| nanograms/milliliter (ng/mL) | Part 1: All Risdiplam | Part 2: All Risdiplam |
|---|---|---|
| Part 1 and 2: Maximum Plasma Concentration (Cmax) of Risdiplam at Year 5 | 137 (58.2 to 242) | 140 (42.7 to 313) |
| ng*h/mL | Part 1: All Risdiplam | Part 2: All Risdiplam |
|---|---|---|
| Part 1 and 2: Area Under the Curve (AUC) From 0 to 24 Hours of Risdiplam at Year 5 Visit | 1700 (1160 to 2590) | 1880 (1200 to 2890) |
| ng/mL | Part 1: All Risdiplam | Part 2: All Risdiplam |
|---|---|---|
| Part 1 and 2: Concentration at the End of a Dosing Interval (Ctrough) of Risdiplam at Year 5 | 54.1 (21.3 to 108) | 57.2 (4.50 to 229) |
Collected over Part 1 and Part 2: Up to approximately 5 years. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Part 1 Group A: Adolescents and Adults (3 mg Risdiplam) | 0/10 (0%) | 1/10 (10%) | 9/10 (90%) |
| Part 1 Group A: Adolescents and Adults (5 mg Risdiplam) | 0/10 (0%) | 0/10 (0%) | 8/10 (80%) |
| Part 1 Group A: Adolescents and Adults (Placebo-Control Period Pooled) | 0/6 (0%) | 0/6 (0%) | 4/6 (66.7%) |
| Part 1 Group B: Children (0.02 mg/kg Risdiplam) | 0/7 (0%) | 0/7 (0%) | 6/7 (85.7%) |
| Part 1 Group B: Children (0.05 mg/kg Risdiplam) | 0/14 (0%) | 0/14 (0%) | 12/14 (85.7%) |
| Part 1 Group B: Children (0.15 mg/kg Risdiplam) | 0/21 (0%) | 0/21 (0%) | 18/21 (85.7%) |
| Part 1 Group B: Children (0.25 mg/kg Risdiplam) | 0/7 (0%) | 0/7 (0%) | 6/7 (85.7%) |
| Part 1 Group B: Children (Placebo-Control Period Pooled) | 0/10 (0%) | 1/10 (10%) | 9/10 (90%) |
| Part 1 Group A: OLE | 0/20 (0%) | 5/20 (25%) | 17/20 (85%) |
| Part 1 Group B: OLE | 0/31 (0%) | 9/31 (29%) | 28/31 (90.3%) |
| Part 2 Placebo-Controlled: Risdiplam | 0/120 (0%) | 24/120 (20%) | 101/120 (84.2%) |
| Part 2 Placebo-Controlled: Placebo | 0/60 (0%) | 11/60 (18.3%) | 50/60 (83.3%) |
| Part 2 OLT: Risdiplam/Risdiplam | 0/117 (0%) | 25/117 (21.4%) | 88/117 (75.2%) |
| Part 2 OLT: Placebo/Risdiplam | 0/59 (0%) | 4/59 (6.8%) | 40/59 (67.8%) |
| Part 2 OLE: Risdiplam | 1/175 (0.6%) | 34/175 (19.4%) | 140/175 (80%) |
| Event | Part 1 Group A: Adolescents and Adults (3 mg Risdiplam) | Part 1 Group A: Adolescents and Adults (5 mg Risdiplam) | Part 1 Group A: Adolescents and Adults (Placebo-Control Period Pooled) | Part 1 Group B: Children (0.02 mg/kg Risdiplam) | Part 1 Group B: Children (0.05 mg/kg Risdiplam) | Part 1 Group B: Children (0.15 mg/kg Risdiplam) | Part 1 Group B: Children (0.25 mg/kg Risdiplam) | Part 1 Group B: Children (Placebo-Control Period Pooled) | Part 1 Group A: OLE | Part 1 Group B: OLE | Part 2 Placebo-Controlled: Risdiplam | Part 2 Placebo-Controlled: Placebo | Part 2 OLT: Risdiplam/Risdiplam | Part 2 OLT: Placebo/Risdiplam | Part 2 OLE: Risdiplam |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| VomitingGastrointestinal disorders | 0/10 | 0/10 | 0/6 | 0/7 | 0/14 | 0/21 | 0/7 | 1/10 | 0/20 | 0/31 | 0/120 | 0/60 | 1/117 | 0/59 | 1/175 |
| PneumoniaInfections and infestations | 1/10 | 0/10 | 0/6 | 0/7 | 0/14 | 0/21 | 0/7 | 0/10 | 2/20 | 1/31 | 10/120 | 2/60 | 8/117 | 0/59 | 8/175 |
| Femur fractureInjury, poisoning and procedural complications | 0/10 | 0/10 | 0/6 | 0/7 | 0/14 | 0/21 | 0/7 | 0/10 | 0/20 | 2/31 | 1/120 | 1/60 | 0/117 | 0/59 | 3/175 |
| Abdominal painGastrointestinal disorders | 0/10 | 0/10 | 0/6 | 0/7 | 0/14 | 0/21 | 0/7 | 0/10 | 1/20 | 0/31 | 0/120 | 0/60 | 0/117 | 0/59 | 0/175 |
| OesophagitisGastrointestinal disorders | 0/10 | 0/10 | 0/6 | 0/7 | 0/14 | 0/21 | 0/7 | 0/10 | 1/20 | 0/31 | 0/120 | 0/60 | 0/117 | 0/59 | 0/175 |
| AppendicitisInfections and infestations | 0/10 | 0/10 | 0/6 | 0/7 | 0/14 | 0/21 | 0/7 | 0/10 | 1/20 | 0/31 | 0/120 | 1/60 | 0/117 | 0/59 | 0/175 |
| Respiratory tract infectionInfections and infestations | 0/10 | 0/10 | 0/6 | 0/7 | 0/14 | 0/21 | 0/7 | 0/10 | 1/20 | 0/31 | 0/120 | 0/60 | 1/117 | 1/59 | 0/175 |
| GastroenteritisInfections and infestations | 0/10 | 0/10 | 0/6 | 0/7 | 0/14 | 0/21 | 0/7 | 0/10 | 0/20 | 1/31 | 2/120 | 2/60 | 0/117 | 0/59 | 2/175 |
| InfluenzaInfections and infestations | 0/10 | 0/10 | 0/6 | 0/7 | 0/14 | 0/21 | 0/7 | 0/10 | 0/20 | 1/31 | 2/120 | 0/60 | 1/117 | 0/59 | 1/175 |
| Pneumonia mycoplasmalInfections and infestations | 0/10 | 0/10 | 0/6 | 0/7 | 0/14 | 0/21 | 0/7 | 0/10 | 0/20 | 1/31 | 0/120 | 0/60 | 1/117 | 0/59 | 0/175 |
| Event | Part 1 Group A: Adolescents and Adults (3 mg Risdiplam) | Part 1 Group A: Adolescents and Adults (5 mg Risdiplam) | Part 1 Group A: Adolescents and Adults (Placebo-Control Period Pooled) | Part 1 Group B: Children (0.02 mg/kg Risdiplam) | Part 1 Group B: Children (0.05 mg/kg Risdiplam) | Part 1 Group B: Children (0.15 mg/kg Risdiplam) | Part 1 Group B: Children (0.25 mg/kg Risdiplam) | Part 1 Group B: Children (Placebo-Control Period Pooled) | Part 1 Group A: OLE | Part 1 Group B: OLE | Part 2 Placebo-Controlled: Risdiplam | Part 2 Placebo-Controlled: Placebo | Part 2 OLT: Risdiplam/Risdiplam | Part 2 OLT: Placebo/Risdiplam | Part 2 OLE: Risdiplam |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PyrexiaGeneral disorders | 2/10 | 1/10 | 0/6 | 2/7 | 3/14 | 4/21 | 1/7 | 3/10 | 9/20 | 18/31 | 25/120 | 10/60 | 15/117 | 6/59 | 30/175 |
| Upper respiratory tract infectionInfections and infestations | 0/10 | 0/10 | 0/6 | 0/7 | 2/14 | 4/21 | 2/7 | 0/10 | 3/20 | 14/31 | 38/120 | 18/60 | 18/117 | 10/59 | 49/175 |
| NasopharyngitisInfections and infestations | 0/10 | 0/10 | 0/6 | 0/7 | 1/14 | 2/21 | 1/7 | 1/10 | 3/20 | 12/31 | 31/120 | 15/60 | 26/117 | 6/59 | 34/175 |
| CoughRespiratory, thoracic and mediastinal disorders | 1/10 | 0/10 | 0/6 | 1/7 | 2/14 | 3/21 | 1/7 | 2/10 | 4/20 | 11/31 | 17/120 | 12/60 | 12/117 | 5/59 | 14/175 |
| VomitingGastrointestinal disorders | 0/10 | 1/10 | 0/6 | 2/7 | 4/14 | 5/21 | 1/7 | 1/10 | 4/20 | 10/31 | 17/120 | 14/60 | 15/117 | 9/59 | 20/175 |
| COVID-19Infections and infestations | 0/10 | 0/10 | 0/6 | 0/7 | 0/14 | 0/21 | 0/7 | 0/10 | 3/20 | 9/31 | 0/120 | 0/60 | 0/117 | 1/59 | 55/175 |
| TachycardiaCardiac disorders | 3/10 | 0/10 | 1/6 | 0/7 | 0/14 | 0/21 | 0/7 | 0/10 | 0/20 | 1/31 | 0/120 | 0/60 | 1/117 | 1/59 | 2/175 |
| Oropharyngeal painRespiratory, thoracic and mediastinal disorders | 2/10 | 3/10 | 1/6 | 1/7 | 1/14 | 1/21 | 0/7 | 1/10 | 3/20 | 6/31 | 6/120 | 7/60 | 4/117 | 1/59 | 11/175 |
| GastroenteritisInfections and infestations | 0/10 | 0/10 | 0/6 | 0/7 | 0/14 | 1/21 | 1/7 | 1/10 | 4/20 | 9/31 | 7/120 | 5/60 | 9/117 | 5/59 | 12/175 |
| PharyngitisInfections and infestations | 1/10 | 0/10 | 0/6 | 2/7 | 2/14 | 2/21 | 0/7 | 0/10 | 1/20 | 4/31 | 6/120 | 3/60 | 6/117 | 4/59 | 7/175 |
| Age, Continuous(Years) | Part 1 Group A Cohort 1: Adolescents and Adults (3 mg Risdiplam) | Part 1 Group A Cohort 2: Adolescents and Adults (5 mg Risdiplam) | Part 1 Group A Cohort 1: Adolescents and Adults (Placebo) | Part 1 Group A Cohort 2: Adolescents and Adults (Placebo) | Part 1 Group B Cohort 1: Children (0.02 mg/kg Risdiplam) | Part 1 Group B Cohort 2: Children (0.05 mg/kg Risdiplam) | Part 1 Group B Cohort 3: Children (0.25 mg/kg Risdiplam) | Part 1 Group B Cohort 1: Children (Placebo) | Part 1 Group B Cohort 2: Children (Placebo) | Part 1 Group B Cohort 3: Children (Placebo) | Part 2: Risdiplam | Part 2: Placebo | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Part 1 | 13.3 ± 1.1 | 18.1 ± 4.6 | 14.7 ± 1.5 | 17.3 ± 5.1 | 6.1 ± 2.9 | 4.3 ± 1.7 | 6.0 ± 2.7 | 5.3 ± 2.1 | 3.5 ± 0.6 | 5.3 ± 2.9 | — | — | 9.4 ± 6.0 |
| Part 2 | — | — | — | — | — | — | — | — | — | — | 9.9 ± 5.8 | 10.3 ± 6.0 | 10.0 ± 5.8 |
| Sex: Female, Male(Participants) | Part 1 Group A Cohort 1: Adolescents and Adults (3 mg Risdiplam) | Part 1 Group A Cohort 2: Adolescents and Adults (5 mg Risdiplam) | Part 1 Group A Cohort 1: Adolescents and Adults (Placebo) | Part 1 Group A Cohort 2: Adolescents and Adults (Placebo) | Part 1 Group B Cohort 1: Children (0.02 mg/kg Risdiplam) | Part 1 Group B Cohort 2: Children (0.05 mg/kg Risdiplam) | Part 1 Group B Cohort 3: Children (0.25 mg/kg Risdiplam) | Part 1 Group B Cohort 1: Children (Placebo) | Part 1 Group B Cohort 2: Children (Placebo) | Part 1 Group B Cohort 3: Children (Placebo) | Part 2: Risdiplam | Part 2: Placebo | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Female | 5 | 5 | 1 | 2 | 5 | 3 | 4 | 0 | 2 | 0 | 61 | 30 | 118 |
| Male | 2 | 2 | 2 | 1 | 2 | 4 | 3 | 3 | 2 | 3 | 59 | 30 | 113 |
| Race/Ethnicity, Customized(Participants) | Part 1 Group A Cohort 1: Adolescents and Adults (3 mg Risdiplam) | Part 1 Group A Cohort 2: Adolescents and Adults (5 mg Risdiplam) | Part 1 Group A Cohort 1: Adolescents and Adults (Placebo) | Part 1 Group A Cohort 2: Adolescents and Adults (Placebo) | Part 1 Group B Cohort 1: Children (0.02 mg/kg Risdiplam) | Part 1 Group B Cohort 2: Children (0.05 mg/kg Risdiplam) | Part 1 Group B Cohort 3: Children (0.25 mg/kg Risdiplam) | Part 1 Group B Cohort 1: Children (Placebo) | Part 1 Group B Cohort 2: Children (Placebo) | Part 1 Group B Cohort 3: Children (Placebo) | Part 2: Risdiplam | Part 2: Placebo | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Asian | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 23 | 12 | 36 |
| White | 7 | 7 | 3 | 3 | 6 | 6 | 7 | 3 | 3 | 3 | 80 | 41 | 169 |
| Multiple | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 1 | 0 | 3 |
| Black or African American | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 2 |
| Unknown | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 14 | 7 | 21 |
| Race/Ethnicity, Customized(Participants) | Part 1 Group A Cohort 1: Adolescents and Adults (3 mg Risdiplam) | Part 1 Group A Cohort 2: Adolescents and Adults (5 mg Risdiplam) | Part 1 Group A Cohort 1: Adolescents and Adults (Placebo) | Part 1 Group A Cohort 2: Adolescents and Adults (Placebo) | Part 1 Group B Cohort 1: Children (0.02 mg/kg Risdiplam) | Part 1 Group B Cohort 2: Children (0.05 mg/kg Risdiplam) | Part 1 Group B Cohort 3: Children (0.25 mg/kg Risdiplam) | Part 1 Group B Cohort 1: Children (Placebo) | Part 1 Group B Cohort 2: Children (Placebo) | Part 1 Group B Cohort 3: Children (Placebo) | Part 2: Risdiplam | Part 2: Placebo | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Hispanic or Latino | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 5 | 2 | 7 |
| Not Hispanic or Latino | 7 | 7 | 3 | 3 | 6 | 7 | 7 | 3 | 4 | 3 | 114 | 57 | 221 |
| Not Stated | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 2 |
| Unknown | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 |
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Hoffmann-La Roche