Muscular Atrophy, Spinal
Conditions
Brief 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.
Interventions
DRUGPlacebo
Placebo will be administered orally (via mouth) or through a feeding tube (naso-gastric or gastrostomy tube).
DRUGRisdiplam
Risdiplam will be administered orally (via mouth) or through a feeding tube (naso-gastric or gastrostomy tube).
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
2 Years to 25 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Selected Part 2 Dose of Risdiplam for Participants With a Body Weight (BW) of >/=20kg | Day 1 up to at least 4 weeks on study (Up to CCOD of 25 July 2017) | 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. |
| Part 1: Selected Part 2 Dose of Risdiplam for Participants With BW of <20kg | Day 1 up to at least 4 weeks on study (Up to CCOD of 25 July 2017) | 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. |
| Part 2: Change From Baseline in the Total Motor Function Measure 32 (MFM-32) Total Score at Month 12 | Baseline (Day-1) and 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Percentage of Participants With Marked Improvement (Defined as >= 3) in the Total Motor Function Measure (MFM32) Score at Month 12 | 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. |
| Part 2: Change From Baseline in the Total Score of the Revised Upper Limb Module (RULM) at Month 12 | Baseline (Day-1) and 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. |
| Part 2: Change From Baseline in Total Score of Hammersmith Functional Motor Scale Expanded (HFMSE) at Month 12 | Baseline (Day-1) and 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. |
| Part 2: Change From Baseline in Forced Vital Capacity (FVC) at Month 12 in Participants Aged 6-25 Years | Baseline (Day-1) and Month 12 | 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. |
| Part 2: Change From Baseline in the Caregiver-Reported SMA Independence Scale (SMAIS) Total Score at Month 12 | Baseline (Day-1) and 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. |
| Part 2: Percentage of Participants Rated by Clinicians as Improved in the Clinical Global Impression of Change (CGI-C) Scale Ratings at Month 12 | 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. |
| 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 | 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. |
| 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 | 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. |
| Part 2: Change From Baseline in the MFM-32 Domain 1 (D1) Score at Month 12 | Baseline (Day-1) and 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. |
| Part 2: Change From Baseline in the MFM-32 Domain 2 (D2) Score at Month 12 | Baseline (Day-1) and 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. |
| Part 2: Change From Baseline in the MFM-32 Domain 3 (D3) Score at Month 12 | Baseline (Day-1) and 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. |
| Part 2: Change From Baseline in the Total Combined Scores of MFM-32 Domains 1 and 2 at Month 12 | Baseline (Day-1) and 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. |
| Part 2: Change From Baseline in the Total Combined Scores of MFM-32 Domains 2 and 3 at Month 12 | Baseline (Day-1) and 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. |
| Part 2: Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Month 12 in Participants Aged 6-25 Years | Baseline (Day-1) and Month 12 | 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. |
| Part 2: Change From Baseline in the Peak Cough Flow (PCF) at Month 12 in Participants Aged 6-25 Years | Baseline (Day-1) and Month 12 | 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. |
| Part 2: Change From Baseline in the Best Sniff Nasal Inspiratory Pressure (SNIP) at Month 12 | Baseline (Day-1) and 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. |
| Part 2: Change From Baseline in Maximal Inspiratory Pressure (MIP) at Month 12 in Participants Aged 6-25 Years | Baseline (Day-1) and Month 12 | 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. |
| Part 2: Change From Baseline in Maximal Expiratory Pressure (MEP) at Month 12 in Participants Aged 6-25 Years | Baseline (Day-1) and Month 12 | 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. |
| Part 2: Change From Baseline in the Participant-Reported SMA Independence Scale (SMAIS) Total Score at Month 12 | Baseline (Day-1) and 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. |
| 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 | 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. |
| Part 2: Percentage of Participants Who Experience at Least One Disease-Related Adverse Event at Month 12 | Baseline up to Month 12 (Week 52; up to CCOD of 06 September 2019) | 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. |
| Part 2: Number of Disease-related Adverse Events Per Patient-years at Month 12 | Baseline up to Month 12 (Week 52; up to CCOD of 06 September 2019) | 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. |
| Part 2: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period | Day 1 up to 12 months of 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. |
| Part 2: Percentage of Participants With Treatment Discontinuation Due to Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period | Day 1 up to 12 months of 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. |
| 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 | Day 1 up to 12 months of 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. |
| 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 | Day 1 up to 12 months of 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. |
| Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood | 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 | 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 | Reported here is the maximum observed concentration throughout the observation period. |
| Part 1 and 2: Area Under the Curve (AUC) From 0 to 24 Hours of Risdiplam at Year 5 Visit | 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 | The last predose sample collected from each participant who had at least 1400 days of risdiplam treatment duration. | — |
Countries
Belgium, Brazil, Canada, China, Croatia, France, Germany, Italy, Japan, Poland, Russia, Serbia, Spain, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
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.
Pre-assignment details
In Part 1 participants were initially enrolled by age and in a dose-escalating design; each group included participants on active and placebo treatment in a 2:1 ratio. After Part 2 dose selection the study enrolled additional participants in a 2:1 ratio in Part 2.
Participants by arm
| Arm | Count |
|---|---|
| Part 1 Group A Cohort 1: Adolescents and Adults (3 mg Risdiplam) Adolescent and adult participants aged 12-25 years received risdiplam for at least 12 weeks. Once the placebo-controlled period was completed and Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. | 7 |
| Part 1 Group A Cohort 2: Adolescents and Adults (5 mg Risdiplam) Adolescent and adult participants aged 12-25 years received risdiplam for at least 12 weeks. Once the placebo-controlled period was completed and Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. | 7 |
| Part 1 Group A Cohort 1: Adolescents and Adults (Placebo) Adolescent and adult participants aged 12-25 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, participants first switched to their cohort risdiplam dose (i.e. 3 mg). After the Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. | 3 |
| Part 1 Group A Cohort 2: Adolescents and Adults (Placebo) Adolescent and adult participants aged 12-25 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, participants first switched to their cohort risdiplam dose (i.e. 5 mg). After the Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. | 3 |
| Part 1 Group B Cohort 1: Children (0.02 mg/kg Risdiplam) Children aged 2-11 years received risdiplam for at least 12 weeks. During the placebo-controlled period, participants escalated to 0.05 mg/kg and then to 0.15 mg/kg in two steps. Once the placebo-controlled period was completed, and after Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. | 7 |
| Part 1 Group B Cohort 2: Children (0.05 mg/kg Risdiplam) Children aged 2-11 years received risdiplam for at least 12 weeks. During the placebo-controlled period, participants escalated to 0.15 mg/kg in one step. Once the placebo-controlled period was completed, and after Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. | 7 |
| Part 1 Group B Cohort 3: Children (0.25 mg/kg Risdiplam) Children aged 2-11 years received risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, and after Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. | 7 |
| Part 1 Group B Cohort 1: Children (Placebo) Children aged 2-11 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, participants first switched to the final 0.15 mg/kg cohort risdiplam dose. After the Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. | 3 |
| Part 1 Group B Cohort 2: Children (Placebo) Children aged 2-11 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, participants first switched to the final 0.15 mg/kg cohort risdiplam dose. After the Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. | 4 |
| Part 1 Group B Cohort 3: Children (Placebo) Children aged 2-11 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, and after Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. | 3 |
| Part 2: Risdiplam Participants aged 2-25 years received risdiplam at the dose of 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 12 months. | 120 |
| Part 2: Placebo Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants 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 and observations. | 60 |
| Total | 231 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Part 1 OLE | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 | 0 | 0 |
| Part 2 OLE: > Month 24 | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Part 2 OLE: > Month 24 | Reason not specified | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 |
| Part 2 OLE: > Month 24 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 10 | 5 |
| Part 2 OLT: Month 12-24 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Part 2 Placebo-Controlled: Month 1-12 | Changed to other treatment | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Part 2 Placebo-Controlled: Month 1-12 | Changed to Spinraza | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 |
Baseline characteristics
| Characteristic | 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 A Cohort 1: Adolescents and Adults (3 mg 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) | Total | Part 2: Risdiplam | Part 2: Placebo |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous Part 1 | 18.1 Years STANDARD_DEVIATION 4.6 | 14.7 Years STANDARD_DEVIATION 1.5 | 17.3 Years STANDARD_DEVIATION 5.1 | 6.1 Years STANDARD_DEVIATION 2.9 | 4.3 Years STANDARD_DEVIATION 1.7 | 13.3 Years STANDARD_DEVIATION 1.1 | 6.0 Years STANDARD_DEVIATION 2.7 | 5.3 Years STANDARD_DEVIATION 2.1 | 3.5 Years STANDARD_DEVIATION 0.6 | 5.3 Years STANDARD_DEVIATION 2.9 | 9.4 Years STANDARD_DEVIATION 6 | — | — |
| Age, Continuous Part 2 | — | — | — | — | — | — | — | — | — | — | 10.0 Years STANDARD_DEVIATION 5.8 | 9.9 Years STANDARD_DEVIATION 5.8 | 10.3 Years STANDARD_DEVIATION 6 |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 36 Participants | 23 Participants | 12 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 7 Participants | 5 Participants | 2 Participants |
| Race/Ethnicity, Customized Multiple | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 7 Participants | 3 Participants | 3 Participants | 6 Participants | 7 Participants | 7 Participants | 7 Participants | 3 Participants | 4 Participants | 3 Participants | 221 Participants | 114 Participants | 57 Participants |
| Race/Ethnicity, Customized Not Stated | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 7 Participants | 3 Participants | 3 Participants | 6 Participants | 6 Participants | 7 Participants | 7 Participants | 3 Participants | 3 Participants | 3 Participants | 169 Participants | 80 Participants | 41 Participants |
| Sex: Female, Male Female | 5 Participants | 1 Participants | 2 Participants | 5 Participants | 3 Participants | 5 Participants | 4 Participants | 0 Participants | 2 Participants | 0 Participants | 118 Participants | 61 Participants | 30 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 1 Participants | 2 Participants | 4 Participants | 2 Participants | 3 Participants | 3 Participants | 2 Participants | 3 Participants | 113 Participants | 59 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 | 0 / 6 | 0 / 7 | 0 / 14 | 0 / 21 | 0 / 7 | 0 / 10 | 0 / 20 | 0 / 31 | 0 / 120 | 0 / 60 | 0 / 117 | 0 / 59 | 1 / 175 |
| other Total, other adverse events | 9 / 10 | 8 / 10 | 4 / 6 | 6 / 7 | 12 / 14 | 18 / 21 | 6 / 7 | 9 / 10 | 17 / 20 | 28 / 31 | 101 / 120 | 50 / 60 | 88 / 117 | 40 / 59 | 140 / 175 |
| serious Total, serious adverse events | 1 / 10 | 0 / 10 | 0 / 6 | 0 / 7 | 0 / 14 | 0 / 21 | 0 / 7 | 1 / 10 | 5 / 20 | 9 / 31 | 24 / 120 | 11 / 60 | 25 / 117 | 4 / 59 | 34 / 175 |
Outcome results
Primary
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)
Population: All participants in Part 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: All Risdiplam | Part 1: Selected Part 2 Dose of Risdiplam for Participants With a Body Weight (BW) of >/=20kg | 5 milligram (mg) |
Primary
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)
Population: All participants in Part 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: All Risdiplam | Part 1: Selected Part 2 Dose of Risdiplam for Participants With BW of <20kg | 0.25 milligram/kilogram (mg/kg) |
Primary
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
Population: The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing MFM32 total score at Baseline were not included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: All Risdiplam | Part 2: Change From Baseline in the Total Motor Function Measure 32 (MFM-32) Total Score at Month 12 | 1.36 Scores on a Scale |
| Part 2: Placebo | Part 2: Change From Baseline in the Total Motor Function Measure 32 (MFM-32) Total Score at Month 12 | -0.19 Scores on a Scale |
p-value: 0.015695% CI: [0.3, 2.81]Mixed Model Repeated Measure Analysis
Secondary
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.
Population: All participants with at least one time point with a protein measurement were included in the pharmacodynamic (PD) analysis data set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: All Risdiplam | Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood | 2.91 unitless |
| Part 2: Placebo | Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood | 1.96 unitless |
Secondary
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
Population: All participants with at least one time point with a risdiplam concentration measurement were included in the PK analysis data set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: All Risdiplam | Part 1 and 2: Area Under the Curve (AUC) From 0 to 24 Hours of Risdiplam at Year 5 Visit | 1700 ng*h/mL |
| Part 2: Placebo | Part 1 and 2: Area Under the Curve (AUC) From 0 to 24 Hours of Risdiplam at Year 5 Visit | 1880 ng*h/mL |
Secondary
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.
Population: All participants with at least one time point with a risdiplam concentration measurement were included in the PK analysis data set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: All Risdiplam | Part 1 and 2: Concentration at the End of a Dosing Interval (Ctrough) of Risdiplam at Year 5 | 54.1 ng/mL |
| Part 2: Placebo | Part 1 and 2: Concentration at the End of a Dosing Interval (Ctrough) of Risdiplam at Year 5 | 57.2 ng/mL |
Secondary
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
Population: All participants with at least one time point with a risdiplam concentration measurement were included in the pharmacokinetic (PK) analysis data set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: All Risdiplam | Part 1 and 2: Maximum Plasma Concentration (Cmax) of Risdiplam at Year 5 | 137 nanograms/milliliter (ng/mL) |
| Part 2: Placebo | Part 1 and 2: Maximum Plasma Concentration (Cmax) of Risdiplam at Year 5 | 140 nanograms/milliliter (ng/mL) |
Secondary
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
Population: The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing FEV1 data at Baseline were not included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: All Risdiplam | Part 2: Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Month 12 in Participants Aged 6-25 Years | -4.22 Percentage Predicted |
| 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 | -1.35 Percentage Predicted |
p-value: 0.302995% CI: [-8.36, 2.62]Mixed Model Repeated Measure Analysis
Secondary
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
Population: The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing FVC data at Baseline were not included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: All Risdiplam | Part 2: Change From Baseline in Forced Vital Capacity (FVC) at Month 12 in Participants Aged 6-25 Years | -5.16 Percentage Predicted |
| Part 2: Placebo | Part 2: Change From Baseline in Forced Vital Capacity (FVC) at Month 12 in Participants Aged 6-25 Years | -3.11 Percentage Predicted |
p-value: 0.390295% CI: [-6.67, 2.56]Mixed Model Repeated Measure Analysis
Secondary
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
Population: The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing MEP data at Baseline were not included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: All Risdiplam | Part 2: Change From Baseline in Maximal Expiratory Pressure (MEP) at Month 12 in Participants Aged 6-25 Years | -2.75 Percentage Predicted |
| Part 2: Placebo | Part 2: Change From Baseline in Maximal Expiratory Pressure (MEP) at Month 12 in Participants Aged 6-25 Years | -2.33 Percentage Predicted |
p-value: 0.885695% CI: [-6.3, 5.45]Mixed Model Repeated Measure Analysis
Secondary
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
Population: The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing MIP data at Baseline were not included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: All Risdiplam | Part 2: Change From Baseline in Maximal Inspiratory Pressure (MIP) at Month 12 in Participants Aged 6-25 Years | 1.99 Percentage Predicted |
| Part 2: Placebo | Part 2: Change From Baseline in Maximal Inspiratory Pressure (MIP) at Month 12 in Participants Aged 6-25 Years | -0.97 Percentage Predicted |
p-value: 0.670495% CI: [-10.78, 16.7]Mixed Model Repeated Measure Analysis
Secondary
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
Population: The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing SNIP data at Baseline were not included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: All Risdiplam | Part 2: Change From Baseline in the Best Sniff Nasal Inspiratory Pressure (SNIP) at Month 12 | 3.42 Percentage Predicted |
| Part 2: Placebo | Part 2: Change From Baseline in the Best Sniff Nasal Inspiratory Pressure (SNIP) at Month 12 | 1.07 Percentage Predicted |
p-value: 0.396795% CI: [-3.11, 7.8]Mixed Model Repeated Measure Analysis
Secondary
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
Population: The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing SMAIS total score at Baseline were not included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: All Risdiplam | Part 2: Change From Baseline in the Caregiver-Reported SMA Independence Scale (SMAIS) Total Score at Month 12 | 1.65 Scores on a Scale |
| Part 2: Placebo | Part 2: Change From Baseline in the Caregiver-Reported SMA Independence Scale (SMAIS) Total Score at Month 12 | -0.91 Scores on a Scale |
p-value: 0.390295% CI: [0.93, 4.17]Mixed Model Repeated Measure Analysis
Secondary
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
Population: The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing MFM32 D1 score at Baseline were not included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: All Risdiplam | Part 2: Change From Baseline in the MFM-32 Domain 1 (D1) Score at Month 12 | 0.37 Scores on a Scale |
| Part 2: Placebo | Part 2: Change From Baseline in the MFM-32 Domain 1 (D1) Score at Month 12 | -0.26 Scores on a Scale |
p-value: 0.132895% CI: [-0.2, 1.47]Mixed Model Repeated Measure Analysis
Secondary
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
Population: The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing MFM32 D2 score at Baseline were not included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: All Risdiplam | Part 2: Change From Baseline in the MFM-32 Domain 2 (D2) Score at Month 12 | 1.04 Scores on a Scale |
| Part 2: Placebo | Part 2: Change From Baseline in the MFM-32 Domain 2 (D2) Score at Month 12 | -0.93 Scores on a Scale |
p-value: 0.10395% CI: [-0.4, 4.34]Mixed Model Repeated Measure Analysis
Secondary
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
Population: The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing MFM32 D3 score at Baseline were not included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: All Risdiplam | Part 2: Change From Baseline in the MFM-32 Domain 3 (D3) Score at Month 12 | 3.68 Scores on a Scale |
| Part 2: Placebo | Part 2: Change From Baseline in the MFM-32 Domain 3 (D3) Score at Month 12 | 1.34 Scores on a Scale |
p-value: 0.045195% CI: [0.05, 4.62]Mixed Model Repeated Measure Analysis
Secondary
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
Population: The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing SMAIS total score at Baseline were not included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: All Risdiplam | Part 2: Change From Baseline in the Participant-Reported SMA Independence Scale (SMAIS) Total Score at Month 12 | 1.04 Scores on a Scale |
| Part 2: Placebo | Part 2: Change From Baseline in the Participant-Reported SMA Independence Scale (SMAIS) Total Score at Month 12 | -0.40 Scores on a Scale |
p-value: 0.177895% CI: [-0.68, 3.57]Mixed Model Repeated Measure Analysis
Secondary
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
Population: The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing PCF data at Baseline were not included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: All Risdiplam | Part 2: Change From Baseline in the Peak Cough Flow (PCF) at Month 12 in Participants Aged 6-25 Years | 1.06 Percent Predicted |
| Part 2: Placebo | Part 2: Change From Baseline in the Peak Cough Flow (PCF) at Month 12 in Participants Aged 6-25 Years | -0.22 Percent Predicted |
p-value: 0.493795% CI: [-2.42, 4.99]Mixed Model Repeated Measure Analysis
Secondary
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
Population: The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing MFM32 D1+D2 scores at Baseline were not included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: All Risdiplam | Part 2: Change From Baseline in the Total Combined Scores of MFM-32 Domains 1 and 2 at Month 12 | 0.69 Scores on a Scale |
| Part 2: Placebo | Part 2: Change From Baseline in the Total Combined Scores of MFM-32 Domains 1 and 2 at Month 12 | -0.59 Scores on a Scale |
p-value: 0.048995% CI: [0.01, 2.56]Mixed Model Repeated Measure Analysis
Secondary
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
Population: The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing MFM32 D2+D3 scores at Baseline were not included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: All Risdiplam | Part 2: Change From Baseline in the Total Combined Scores of MFM-32 Domains 2 and 3 at Month 12 | 2.02 Scores on a Scale |
| Part 2: Placebo | Part 2: Change From Baseline in the Total Combined Scores of MFM-32 Domains 2 and 3 at Month 12 | -0.14 Scores on a Scale |
p-value: 0.032695% CI: [0.18, 4.14]Mixed Model Repeated Measure Analysis
Secondary
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
Population: The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing RULM total score at Baseline were not included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: All Risdiplam | Part 2: Change From Baseline in the Total Score of the Revised Upper Limb Module (RULM) at Month 12 | 1.61 Scores on a Scale |
| Part 2: Placebo | Part 2: Change From Baseline in the Total Score of the Revised Upper Limb Module (RULM) at Month 12 | 0.02 Scores on a Scale |
p-value: 0.046995% CI: [0.55, 2.62]Mixed Model Repeated Measure Analysis
Secondary
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
Population: The intent-to-treat (ITT) population defined as all randomized participants in Part 2.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: All Risdiplam | Part 2: Change From Baseline in Total Score of Hammersmith Functional Motor Scale Expanded (HFMSE) at Month 12 | 0.95 Scores on a Scale |
| Part 2: Placebo | Part 2: Change From Baseline in Total Score of Hammersmith Functional Motor Scale Expanded (HFMSE) at Month 12 | 0.37 Scores on a Scale |
p-value: 0.390295% CI: [-0.53, 1.69]Mixed Model Repeated Measure Analysis
Secondary
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)
Population: The intent-to-treat (ITT) population defined as all randomized participants in Part 2.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: All Risdiplam | Part 2: Number of Disease-related Adverse Events Per Patient-years at Month 12 | Narrow Basket AEs | 101.51 Number of Events per 100 Patient-Years |
| Part 1: All Risdiplam | Part 2: Number of Disease-related Adverse Events Per Patient-years at Month 12 | Broad Basket AEs | 217.29 Number of Events per 100 Patient-Years |
| Part 2: Placebo | Part 2: Number of Disease-related Adverse Events Per Patient-years at Month 12 | Broad Basket AEs | 199.61 Number of Events per 100 Patient-Years |
| Part 2: Placebo | Part 2: Number of Disease-related Adverse Events Per Patient-years at Month 12 | Narrow Basket AEs | 119.77 Number of Events per 100 Patient-Years |
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
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
Population: The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Data was collected for participants aged 6-25 years.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: All Risdiplam | 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 | Aborted Attempt | 0 Number of Participants |
| Part 1: All Risdiplam | 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 | Actual Attempt (non-fatal) | 0 Number of Participants |
| Part 1: All Risdiplam | 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 | Interrupted Attempt | 0 Number of Participants |
| Part 1: All Risdiplam | 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 | Completed Suicide | 0 Number of Participants |
| Part 1: All Risdiplam | 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 | Preparatory Acts or Behavior | 0 Number of Participants |
| Part 2: Placebo | 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 | Completed Suicide | 0 Number of Participants |
| Part 2: Placebo | 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 | Preparatory Acts or Behavior | 0 Number of Participants |
| Part 2: Placebo | 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 | Aborted Attempt | 0 Number of Participants |
| Part 2: Placebo | 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 | Interrupted Attempt | 0 Number of Participants |
| Part 2: Placebo | 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 | Actual Attempt (non-fatal) | 0 Number of Participants |
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
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
Population: The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Data was collected for participants aged 6-25 years.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: All Risdiplam | 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 | Non-specific Active Suicidal Thoughts | 1 Number of Participants |
| Part 1: All Risdiplam | 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 | Ideation with Some Intent to Act, No Plan | 0 Number of Participants |
| Part 1: All Risdiplam | 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 | Ideation with Any Methods, No Intent to Act | 1 Number of Participants |
| Part 1: All Risdiplam | 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 | Ideation with Specific Plan and Intent | 0 Number of Participants |
| Part 1: All Risdiplam | 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 | Wish to be Dead | 1 Number of Participants |
| Part 2: Placebo | 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 | Ideation with Specific Plan and Intent | 1 Number of Participants |
| Part 2: Placebo | 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 | Wish to be Dead | 1 Number of Participants |
| Part 2: Placebo | 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 | Non-specific Active Suicidal Thoughts | 1 Number of Participants |
| Part 2: Placebo | 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 | Ideation with Any Methods, No Intent to Act | 1 Number of Participants |
| Part 2: Placebo | 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 | Ideation with Some Intent to Act, No Plan | 1 Number of Participants |
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
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
Population: The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Missing results at Month 12 are considered as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: All Risdiplam | 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 Percentage of Participants |
| 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 | 40.0 Percentage of Participants |
Comparison: CGI Improvedp-value: 0.390295% CI: [0.7, 2.74]Wald-test
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
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
Population: The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Missing results at Month 12 are considered as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: All Risdiplam | 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 Percentage of Participants |
| 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 | 83.3 Percentage of Participants |
Comparison: CGI No Change or Improvedp-value: 0.663695% CI: [0.52, 2.83]Wald-test
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
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
Population: The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing MFM32 total score at Baseline were not included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: All Risdiplam | 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 Percentage of Participants |
| 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 | 16.9 Percentage of Participants |
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
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
Population: The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing MFM32 total score at Baseline were not included in the analysis. Missing results at Month 12 are considered as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: All Risdiplam | 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 Percentage of Participants |
| 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 | 54.2 Percentage of Participants |
p-value: 0.04395% CI: [1.02, 3.93]Wald test
Secondary
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)
Population: The intent-to-treat (ITT) population defined as all randomized participants in Part 2.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: All Risdiplam | Part 2: Percentage of Participants Who Experience at Least One Disease-Related Adverse Event at Month 12 | Narrow Basket AEs | 46.7 Percentage of Participants |
| Part 1: All Risdiplam | Part 2: Percentage of Participants Who Experience at Least One Disease-Related Adverse Event at Month 12 | Broad Basket AEs | 65.0 Percentage of Participants |
| Part 2: Placebo | Part 2: Percentage of Participants Who Experience at Least One Disease-Related Adverse Event at Month 12 | Broad Basket AEs | 60.0 Percentage of Participants |
| Part 2: Placebo | Part 2: Percentage of Participants Who Experience at Least One Disease-Related Adverse Event at Month 12 | Narrow Basket AEs | 53.3 Percentage of Participants |
Secondary
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
Population: All participants in Part 2 who receive at least one dose of study medication (risdiplam or placebo) were included in the safety population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: All Risdiplam | Part 2: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period | With at Least One AE | 92.5 Percentage of Participants |
| Part 1: All Risdiplam | Part 2: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period | With at Least One SAE | 20.0 Percentage of Participants |
| Part 2: Placebo | Part 2: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period | With at Least One AE | 91.7 Percentage of Participants |
| Part 2: Placebo | Part 2: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period | With at Least One SAE | 18.3 Percentage of Participants |
Secondary
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
Population: The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing MFM32 total score at Baseline were not included in the analysis. Missing results at Month 12 are considered as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: All Risdiplam | Part 2: Percentage of Participants With Marked Improvement (Defined as >= 3) in the Total Motor Function Measure (MFM32) Score at Month 12 | 38.3 Percentage of Participants |
| 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 | 23.7 Percentage of Participants |
p-value: 0.046995% CI: [1.01, 5.44]Wald test
Secondary
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
Population: All participants in Part 2 who received at least one dose of study medication (risdiplam or placebo) were included in the safety population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: All Risdiplam | Part 2: Percentage of Participants With Treatment Discontinuation Due to Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period | Due to AE | 0.0 Percentage of Participants |
| Part 1: All Risdiplam | Part 2: Percentage of Participants With Treatment Discontinuation Due to Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period | Due to SAE | 0.0 Percentage of Participants |
| Part 2: Placebo | Part 2: Percentage of Participants With Treatment Discontinuation Due to Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period | Due to AE | 0.0 Percentage of Participants |
| Part 2: Placebo | Part 2: Percentage of Participants With Treatment Discontinuation Due to Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period | Due to SAE | 0.0 Percentage of Participants |