Muscular Atrophy, Spinal
Conditions
Brief summary
Open-label, multi-center clinical study is to assess the safety, tolerability, pharmacokinetic (PK), pharmacodynamics (PD), and efficacy of Risdiplam (RO7034067) in infants with Type 1 spinal muscular atrophy (SMA). The study consists of two parts, an exploratory dose finding part (Part 1) and a confirmatory part (Part 2) which will investigate Risdiplam (RO7034067) for 24-months at the dose selected in Part 1.
Interventions
DRUGRisdiplam
Risdiplam will be administered orally.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Months to 7 Months
Healthy volunteers
No
Inclusion criteria
* Clinical history, signs or symptoms attributable to Type 1 SMA with onset after 28 days but prior to the age of 3 months * Gestational age of 37 to 42 weeks * Confirmed diagnosis of 5q-autosomal recessive SMA * Participants has two survival motor neuron 2 (SMN2) gene copies, as confirmed by central testing * Body weight greater than or equal to (\>=) third percentile for age, using appropriate country-specific guidelines * Receiving adequate nutrition and hydration (with or without gastrostomy) at the time of screening, in the opinion of the Investigator * Adequately recovered from any acute illness at the time of screening and considered well-enough to participate in the opinion of the Investigator
Exclusion criteria
* Concomitant or previous participation in any investigational drug or device study within 90 days prior to screening or 5 half-lives, whichever is longer * Concomitant or previous administration of SMN2-targeting antisense oligonucleotide, SMN2 splicing modifier or gene therapy study * Any history of cell therapy * Hospitalization for pulmonary event within the last 2 months, or planned at the time of screening * Presence of clinically relevant electrocardiogram (ECG) abnormalities before study drug administration * Unstable gastrointestinal, renal, hepatic, endocrine or cardiovascular system diseases * Participants requiring invasive ventilation or tracheostomy * Participants requiring awake non-invasive ventilation or with awake hypoxemia (arterial oxygen saturation less than \[\<\] 95 percent \[%\]) with or without ventilator support * Participants with a history of respiratory failure or severe pneumonia, and have not fully recovered their pulmonary function at the time of screening * Multiple or fixed contractures and/or hip subluxation or dislocation at birth * Presence of non-SMA related concurrent syndromes or diseases * Any major illness within one month before the screening examination or any febrile illness within one week prior to screening and up to first dose administration * Any inhibitor of cytochrome P450 (CYP) 3A4 and/or any Organic Cation Transporter 2 (OCT-2) and multidrug and toxin extrusion (MATE) substrates taken within 2 weeks and/or any inducer of CYP3A4 taken within 4 weeks (or within 5-times the elimination half-life, whichever is longer) prior to dosing or participants (and the mother, if breastfeeding the infant) taking any nutrients known to modulate CYP3A activity and any known flavin containing monooxygenase (FMO) 1 or FMO3 inhibitors or substrates * Prior use (at any time in the participants lives) and/or anticipated need for quinolones (chloroquine and hydroxychloroquine), thioridazine, vigabatrin, retigabine, or any other drug known to cause retinal toxicity during the study. Infants exposed to chloroquine, hydroxycholoroquine, thioridazine, vigabatrin, retigabine or drugs with known retinal toxicity given to mothers during pregnancy (and lactation) should not be enrolled. * Recent history (less than 6 months) of ophthalmic disease that would interfere with the conduct of the study as assessed by an ophthalmologist * Therapeutic use, defined as use for 8 weeks or longer, of the following medications within 90 days prior to enrollment: riluzole, valproic acid, hydroxyurea, sodium phenylbutyrate, butyrate derivatives, creatine, carnitine, growth hormone, anabolic steroids, probenecid, agents anticipated to increase or decrease muscle strength, agents with known or presumed histone deacetylase (HDAC) inhibitory effect, medications known to or suspected of causing retinal toxicity (deferoxamine, topiramate, latanoprost, niacin, rosiglitazone, tamoxifen, canthaxanthine, sildenafil, and interferon) and medications with known phototoxicity liabilities (e.g., oral retinoids including over-the-counter \[OTC\] formulations, amiodarone, phenothiazines and use of minocycline)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Selected Part 2 Dose of Risdiplam | Minimum of 2 weeks at steady state exposure | All safety, tolerability, PK and PD data available up to the clinical cut-off date of 5 January 2018, plus data that became available prior to the database snapshot on 6 February 2018 were included in the Internal Monitoring Committee (IMC) review. The 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: Percentage of Infants Who Are Sitting Without Support for at Least 5 Seconds as Assessed by Item 22 of the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development Third Edition (BSID-III) at Month 12 | Month 12 | The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 22 is not considered achieved if the infant sits alone for less than 5 seconds before losing balance and falling over, or if the infant uses his or her arms to prop him- or herself up. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Percentage of Infants Achieving Head Control (Defined as a Score of >/= 3 for CHOP-INTEND Item 12) at Months 8, 12 and 24 | Month 8, Month 12, Month 24 | The CHOP-INTEND instrument was developed to evaluate motor function in infants with SMA from the ages of 1.4 to 37.9 months. It consists of 16 items, where each item assesses a specific motor task graded on a scale of 0 to 4, where zero is no response and 4 is a complete response. The total score ranges from 0 to 64, with higher scores consistent with better motor function. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. |
| Part 2: Change From Baseline in the Total Raw Score of the BSID-III Gross Motor Scale at Months 12 and 24 | Baseline, Month 12, Month 24 | The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). In this study the gross motor scale was assessed in a modified way compared with the standard administration. A total raw score was calculated by summing the item scores to give a maximum possible score of 72. |
| Part 2: Percentage of Infants Who Achieve the Attainment Levels of a Subset of Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 8 | Month 8 | The HINE was designed to evaluate infants between 2 months and 24 months of age. It is a simple and standardized instrument that includes 26 items assessing different aspects of neurological examinations, such as cranial nerves, posture, movements, tone, and reflexes. In this study, Module 2 of the HINE (HINE-2) was assessed. The HINE-2 evaluates 8 developmental milestones (head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking) scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform a task and a score of 2, 3, or 4 (depending on the task) indicating full milestone development. The total score is calculated by summing the item scores to give a maximum possible score of 26. This measure represents subset numbers at Month 8 for head control, ability to kick and rolling milestones only. |
| Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Month 12 | The HINE was designed to evaluate infants between 2 months and 24 months of age. It is a simple and standardized instrument that includes 26 items assessing different aspects of neurological examinations, such as cranial nerves, posture, movements, tone, and reflexes. In this study, Module 2 of the HINE (HINE-2) was assessed. The HINE-2 evaluates 8 developmental milestones (head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking) scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform a task and a score of 2, 3, or 4 (depending on the task) indicating full milestone development. The total score is calculated by summing the item scores to give a maximum possible score of 26. |
| Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Month 24 | The HINE was designed to evaluate infants between 2 months and 24 months of age. It is a simple and standardized instrument that includes 26 items assessing different aspects of neurological examinations, such as cranial nerves, posture, movements, tone, and reflexes. In this study, Module 2 of the HINE (HINE-2) was assessed. The HINE-2 evaluates 8 developmental milestones (head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking) scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform a task and a score of 2, 3, or 4 (depending on the task) indicating full milestone development. The total score is calculated by summing the item scores to give a maximum possible score of 26. |
| Part 2: Percentage of Motor Milestone Responders as Assessed by HINE-2 at Months 12 and 24 | Month 12, Month 24 | The HINE-2 evaluates 8 developmental milestones scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform a task and a score of 2, 3, or 4 (depending on the task) indicating full milestone development. The total score is calculated by summing the item scores to give a maximum possible score of 26. For the motor milestone responder definition, an improvement in a motor milestone is defined as at least a 2-point increase in ability to kick (or maximal score) or a 1-point increase in head control, rolling, sitting, crawling, standing, or walking. Worsening is similarly defined as a 2-point decrease in ability to kick (or lowest score) or a 1-point decrease in head control, rolling, sitting, crawling, standing, or walking. Voluntary grasp is excluded from the definition. An infant is classified as a responder if more motor milestones show improvement than show worsening. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. |
| Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 | Month 12, Month 24 | The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). This specific measure included 6 milestones: Item 9 'Controls head while upright for 15 seconds', Item 14 'Rolls from side to back', Item 22 'Sits without support for 5 seconds', Item 30 'Crawls on stomach', Item 40 'Stands alone' and Item 42 'Walks alone'. Reported here is the percentage of participants for whom the reported item was the highest item achieved out of these six items by Months 12 and 24. |
| Part 2: Percentage of Infants Who Are Sitting Without Support for at Least 5 Seconds as Assessed by Item 22 of the BSID-III Gross Motor Scale at Month 24 | Month 24 | The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 22 is not considered achieved if the infant sits alone for less than 5 seconds before losing balance and falling over, or if the infant uses his or her arms to prop him- or herself up. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. |
| Part 2: Percentage of Infants Who Are Sitting Without Support for at Least 30 Seconds as Assessed by Item 26 of the BSID-III Gross Motor Scale at Month 24 | Month 24 | The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 26 is not considered achieved if the infant sits alone for less than 30 seconds before losing balance and falling over, or if the infant uses his or her arms to prop him- or herself up. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. |
| Part 2: Percentage of Infants Who Are Standing Alone as Assessed by Item 40 of the BSID-III Gross Motor Scale at Month 24 | Month 24 | The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Reported here is the percentage of participants who achieved item 40 'Stands alone' at Month 24. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. |
| Part 2: Percentage of Infants Who Are Walking Alone as Assessed by Item 42 of the BSID-III Gross Motor Scale at Month 24 | Month 24 | The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Reported here is the percentage of participants who achieved item 42 'Walks alone' at Month 24. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. |
| Part 2: Time to Death | Up to 24 months | The median time to event was estimated using Kaplan-Meier methodology. 90% CI was estimated using the method of Brookmeyer and Crowley. |
| Part 2: Time to Death or Permanent Ventilation | Up to 24 months | Permanent ventilation is defined as \>/=16 hours of non-invasive ventilation per day or intubation for \>21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. The median time to event was estimated using Kaplan-Meier methodology. 90% CI was estimated using the method of Brookmeyer and Crowley. |
| Part 2: Time to Permanent Ventilation | Up to 24 months | Permanent ventilation is defined as \>/=16 hours of non-invasive ventilation per day or intubation for \>21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. The median time to event was estimated using Kaplan-Meier methodology. 90% CI was estimated using the method of Brookmeyer and Crowley. |
| Part 2: Percentage of Infants Who Achieve a Score of 40 or Higher in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) at Month 12 | Month 12 | The CHOP-INTEND instrument was developed to evaluate motor function in infants with SMA from the ages of 1.4 to 37.9 months. It consists of 16 items, where each item assesses a specific motor task graded on a scale of 0 to 4, where zero is no response and 4 is a complete response. The total score ranges from 0 to 64, with higher scores consistent with better motor function. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. |
| Part 2: Percentage of Infants Who Are Alive at Months 12 and 24 | Month 12, Month 24 | Kaplan-Meier methodology was used to estimate the percentages. 90% CI was computed using the complementary log-log transformation. |
| Part 2: Percentage of Infants Who Are Without Permanent Ventilation at Months 12 and 24 | Month 12, Month 24 | Permanent ventilation is defined as \>/=16 hours of non-invasive ventilation per day or intubation for \>21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. Kaplan-Meier methodology was used to estimate the percentages. 90% CI was computed using the complementary log-log transformation. |
| Part 2: Percentage of Infants Who Achieve a Reduction of At Least 30 Degrees in Phase Angle From Baseline, as Measured by Respiratory Plethysmography (RP) at Month 12 | Month 12 | RP measures the degree of synchrony between abdominal and thoracic cage-driven breathing. The weakness of intercostal muscles leads to asynchrony of the thorax with the diaphragm, resulting in inefficient and paradoxical breathing patterns. The degree of synchrony between the movement of the chest wall and abdomen during the respiratory cycle can be expressed as the phase angle between the two compartments and measured by placing two RP bands around the thorax and abdomen. In paradoxical breathing, the phase angle is reversed compared with the normal ventilation cycle. A phase angle of 0° indicates perfect in-phase movement, while a value of 180° indicates completely out-of-phase movement between the two compartments. In this measure, 8 or more valid breaths were used to determine the phase angle at each visit; the calculation was not performed if fewer than 8 valid breaths had been measured. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. |
| Part 2: Percentage of Infants Not Requiring Respiratory Support (Invasive or Non-Invasive) at Months 12 and 24 | Month 12, Month 24 | 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. |
| Part 2: Percentage of Infants Able to Feed Orally at Months 12 and 24 | Month 12, Month 24 | Able to feed orally includes participants fed orally and participants fed via a combination of oral and tube feeding. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. |
| Part 1 and Part 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From first dose up to 30 days after last dose of risdiplam (up to 60 months) | 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 With AEs and SAEs Leading to Treatment Discontinuation | From first dose up to 30 days after last dose of risdiplam (up to 60 months) | 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 With AEs and SAEs Leading to Treatment Modification/Interruption | From first dose up to 30 days after last dose of risdiplam (up to 60 months) | 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: Anthropometric Examination of Weight Measured in Kilograms | Month 12, Month 24 | Anthropometric examination included weight, height, head circumference and chest circumference. |
| Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeters | Month 12, Month 24 | Anthropometric examination included weight, height, head circumference and chest circumference. |
| Part 2: Maximum Plasma Concentration (Cmax) of Risdiplam | Day 1: 2, 4, 6, 24 hours post dose; Days 14, 119, 245, 364, 427, 490, 609, 728: predose ; Days 28, 56, 182, 301, 546, 672: predose, 2, 4, 6 hours post dose | Reported here is the maximum observed concentration throughout the observation period. |
| Part 2: Area Under the Curve (AUC) From 0 to 24 Hours of Risdiplam at Year 5 Visit | Year 5 visit: pre-dose | The AUC was derived by modelling & simulation via the population pharmacokinetics (PPK) method based on the Year 5 pre-dose concentration measurement only. Hence, no other timepoints have been reported. |
| Part 2: Concentration at the End of a Dosing Interval (Ctrough) of Risdiplam at Year 5 | Predose at Year 5 | Ctrough at Year 5 was the last predose sample collected from each participant who had at least 1400 days of risdiplam treatment duration. |
| Part 2: Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood | Days 1, 28, 119, 245, 364, 609, 728, 819 and 1820 | — |
| Part 2: Percentage of Infants Who Are Alive Without Permanent Ventilation at Months 12 and 24 | Month 12, Month 24 | Permanent ventilation is defined as \>/=16 hours of non-invasive ventilation per day or intubation for \>21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. Kaplan-Meier methodology was used to estimate the percentages. 90% CI was computed using the complementary log-log transformation. |
| Part 2: Percentage of Infants Achieving an Increase of >/= 4 Points in Their CHOP-INTEND Score From Baseline at Months 8 and 12 | Month 8, Month 12 | The CHOP-INTEND instrument was developed to evaluate motor function in infants with SMA from the ages of 1.4 to 37.9 months. It consists of 16 items, where each item assesses a specific motor task graded on a scale of 0 to 4, where zero is no response and 4 is a complete response. The total score ranges from 0 to 64, with higher scores consistent with better motor function. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. |
Countries
Belgium, Brazil, China, Croatia, France, Italy, Japan, Poland, Russia, Saudi Arabia, Serbia, Spain, Switzerland, Turkey (Türkiye), Ukraine, United States
Participant flow
Recruitment details
Part 1 was conducted at 7 investigational sites across 5 countries; Part 2 was conducted at 14 investigational sites across 10 countries.
Participants by arm
| Arm | Count |
|---|---|
| Exploratory Part 1 - Cohort 1 Participants received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 1 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 1 was targeting an exposure of mean AUC0-24h,ss 700 ng\*h/mL. | 4 |
| Exploratory Part 1 - Cohort 2 Participants received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 2 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 2 was targeting an exposure of mean AUC0-24h,ss \</= 2000 ng\*h/mL. | 17 |
| Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 2000 ng\*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 5 mg when the participant reached 20 kg body weight. | 41 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 0 | 2 | 2 |
| Overall Study | Progressive Disease | 1 | 1 | 1 |
| Overall Study | Reason not specified | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Exploratory Part 1 - Cohort 1 | Exploratory Part 1 - Cohort 2 | Confirmatory Part 2 - Risdiplam | Total |
|---|---|---|---|---|
| Age, Continuous | 6.84 Months STANDARD_DEVIATION 0.1 | 5.56 Months STANDARD_DEVIATION 1.43 | 5.20 Months STANDARD_DEVIATION 1.47 | 5.41 Months STANDARD_DEVIATION 1.46 |
| Race/Ethnicity, Customized Asian | 0 Participants | 4 Participants | 14 Participants | 18 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants | 0 Participants | 5 Participants | 5 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 4 Participants | 17 Participants | 36 Participants | 57 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 4 Participants | 5 Participants | 9 Participants |
| Race/Ethnicity, Customized White | 4 Participants | 9 Participants | 22 Participants | 35 Participants |
| Sex: Female, Male Female | 4 Participants | 11 Participants | 22 Participants | 37 Participants |
| Sex: Female, Male Male | 0 Participants | 6 Participants | 19 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 4 | 3 / 17 | 3 / 41 |
| other Total, other adverse events | 3 / 4 | 17 / 17 | 40 / 41 |
| serious Total, serious adverse events | 4 / 4 | 13 / 17 | 34 / 41 |
Outcome results
Primary
Part 1: Selected Part 2 Dose of Risdiplam
All safety, tolerability, PK and PD data available up to the clinical cut-off date of 5 January 2018, plus data that became available prior to the database snapshot on 6 February 2018 were included in the Internal Monitoring Committee (IMC) review. The 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: Minimum of 2 weeks at steady state exposure
Population: All participants in Part 1 who received at least one dose of risdiplam and had available data at the time of the data snapshot for selecting the Part 2 dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 1: Selected Part 2 Dose of Risdiplam | 0.2 mg/kg |
Primary
Part 2: Percentage of Infants Who Are Sitting Without Support for at Least 5 Seconds as Assessed by Item 22 of the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development Third Edition (BSID-III) at Month 12
The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 22 is not considered achieved if the infant sits alone for less than 5 seconds before losing balance and falling over, or if the infant uses his or her arms to prop him- or herself up. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.
Time frame: Month 12
Population: The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Are Sitting Without Support for at Least 5 Seconds as Assessed by Item 22 of the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development Third Edition (BSID-III) at Month 12 | 29.3 Percentage of Participants |
p-value: <0.0001One-sided Exact Binomial Test
Secondary
Part 1 and Part 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
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: From first dose up to 30 days after last dose of risdiplam (up to 60 months)
Population: All infants who received at least one dose of study medication (risdiplam) were included in the safety population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 1 and Part 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | With at least one AE | 4 Participants |
| Exploratory Part 1 - Risdiplam | Part 1 and Part 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | With at least one SAE | 4 Participants |
| Exploratory Part 1 - Cohort 2 | Part 1 and Part 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | With at least one AE | 17 Participants |
| Exploratory Part 1 - Cohort 2 | Part 1 and Part 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | With at least one SAE | 13 Participants |
| Confirmatory Part 2 - Risdiplam | Part 1 and Part 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | With at least one AE | 41 Participants |
| Confirmatory Part 2 - Risdiplam | Part 1 and Part 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | With at least one SAE | 34 Participants |
Secondary
Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeters
Anthropometric examination included weight, height, head circumference and chest circumference.
Time frame: Month 12, Month 24
Population: All infants who received at least one dose of study medication (risdiplam) were included in the safety population. Only participants for whom data were collected are included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeters | Height at Month 12 | 80.47 centimeter (cm) | Standard Deviation 4 |
| Exploratory Part 1 - Risdiplam | Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeters | Height at Month 24 | 89.13 centimeter (cm) | Standard Deviation 5.12 |
| Exploratory Part 1 - Risdiplam | Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeters | Head Circumference at Month 12 | 47.09 centimeter (cm) | Standard Deviation 1.72 |
| Exploratory Part 1 - Risdiplam | Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeters | Head Circumference at Month 24 | 49.28 centimeter (cm) | Standard Deviation 2.13 |
| Exploratory Part 1 - Risdiplam | Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeters | Chest Circumference at Month 12 | 45.77 centimeter (cm) | Standard Deviation 2.31 |
| Exploratory Part 1 - Risdiplam | Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeters | Chest Circumference at Month 24 | 48.35 centimeter (cm) | Standard Deviation 3.1 |
Secondary
Part 2: Anthropometric Examination of Weight Measured in Kilograms
Anthropometric examination included weight, height, head circumference and chest circumference.
Time frame: Month 12, Month 24
Population: All infants who received at least one dose of study medication (risdiplam) were included in the safety population. Only participants for whom data were collected are included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Anthropometric Examination of Weight Measured in Kilograms | Month 12 | 9.59 kilogram (kg) | Standard Deviation 1.4 |
| Exploratory Part 1 - Risdiplam | Part 2: Anthropometric Examination of Weight Measured in Kilograms | Month 24 | 11.28 kilogram (kg) | Standard Deviation 1.91 |
Secondary
Part 2: Area Under the Curve (AUC) From 0 to 24 Hours of Risdiplam at Year 5 Visit
The AUC was derived by modelling & simulation via the population pharmacokinetics (PPK) method based on the Year 5 pre-dose concentration measurement only. Hence, no other timepoints have been reported.
Time frame: Year 5 visit: pre-dose
Population: All participants with at least one time point with a risdiplam concentration measurement were included in the PK analysis data set. Only participants for whom data were collected are included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Area Under the Curve (AUC) From 0 to 24 Hours of Risdiplam at Year 5 Visit | 2560 ng*h/mL |
Secondary
Part 2: Change From Baseline in the Total Raw Score of the BSID-III Gross Motor Scale at Months 12 and 24
The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). In this study the gross motor scale was assessed in a modified way compared with the standard administration. A total raw score was calculated by summing the item scores to give a maximum possible score of 72.
Time frame: Baseline, Month 12, Month 24
Population: The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not. Only participants for whom data were collected are included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Change From Baseline in the Total Raw Score of the BSID-III Gross Motor Scale at Months 12 and 24 | Baseline | 1.85 Scores on a Scale | Standard Deviation 1.61 |
| Exploratory Part 1 - Risdiplam | Part 2: Change From Baseline in the Total Raw Score of the BSID-III Gross Motor Scale at Months 12 and 24 | Change from Baseline at Month 12 | 7.21 Scores on a Scale | Standard Deviation 5.71 |
| Exploratory Part 1 - Risdiplam | Part 2: Change From Baseline in the Total Raw Score of the BSID-III Gross Motor Scale at Months 12 and 24 | Change from Baseline at Month 24 | 12.89 Scores on a Scale | Standard Deviation 6.89 |
Secondary
Part 2: Concentration at the End of a Dosing Interval (Ctrough) of Risdiplam at Year 5
Ctrough at Year 5 was the last predose sample collected from each participant who had at least 1400 days of risdiplam treatment duration.
Time frame: Predose at Year 5
Population: All participants with at least one time point with a risdiplam concentration measurement were included in the PK analysis data set. Only participants for whom data were collected are included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Concentration at the End of a Dosing Interval (Ctrough) of Risdiplam at Year 5 | 63.1 ng/mL |
Secondary
Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24
The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). This specific measure included 6 milestones: Item 9 'Controls head while upright for 15 seconds', Item 14 'Rolls from side to back', Item 22 'Sits without support for 5 seconds', Item 30 'Crawls on stomach', Item 40 'Stands alone' and Item 42 'Walks alone'. Reported here is the percentage of participants for whom the reported item was the highest item achieved out of these six items by Months 12 and 24.
Time frame: Month 12, Month 24
Population: The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 | Item 42: Walks Alone at Month 12 | 0 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 | Item 9: Controls Head While Upright for 15 sec at Month 12 | 0 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 | Item 14: Rolls from Side to Back at Month 12 | 56.1 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 | Item 22: Sits Without Support for 5 sec at Month 12 | 29.3 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 | Item 30: Crawls on Stomach at Month 12 | 0 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 | Item 40: Stands Alone at Month 12 | 0 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 | Item 9: Controls Head While Upright for 15 sec at Month 24 | 0 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 | Item 14: Rolls from Side to Back at Month 24 | 29.3 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 | Item 22: Sits Without Support for 5 sec at Month 24 | 61.0 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 | Item 30: Crawls on Stomach at Month 24 | 0 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 | Item 40: Stands Alone at Month 24 | 0 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 | Item 42: Walks Alone at Month 24 | 0 Percentage of Participants |
Secondary
Part 2: Maximum Plasma Concentration (Cmax) of Risdiplam
Reported here is the maximum observed concentration throughout the observation period.
Time frame: Day 1: 2, 4, 6, 24 hours post dose; Days 14, 119, 245, 364, 427, 490, 609, 728: predose ; Days 28, 56, 182, 301, 546, 672: predose, 2, 4, 6 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) |
|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Maximum Plasma Concentration (Cmax) of Risdiplam | 195 nanograms/milliliter (ng/mL) |
Secondary
Part 2: Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood
Time frame: Days 1, 28, 119, 245, 364, 609, 728, 819 and 1820
Population: All participants with at least one time point with a protein measurement were included in the pharmacodynamic (PD) analysis data set. Only participants for whom data were collected are included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood | Day 1 | 1.00 ng/mL |
| Exploratory Part 1 - Risdiplam | Part 2: Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood | Day 28 | 2.13 ng/mL |
| Exploratory Part 1 - Risdiplam | Part 2: Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood | Day 119 | 2.21 ng/mL |
| Exploratory Part 1 - Risdiplam | Part 2: Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood | Day 245 | 2.26 ng/mL |
| Exploratory Part 1 - Risdiplam | Part 2: Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood | Day 364 | 1.99 ng/mL |
| Exploratory Part 1 - Risdiplam | Part 2: Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood | Day 609 | 1.69 ng/mL |
| Exploratory Part 1 - Risdiplam | Part 2: Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood | Day 728 | 1.84 ng/mL |
| Exploratory Part 1 - Risdiplam | Part 2: Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood | Day 819 | 2.05 ng/mL |
| Exploratory Part 1 - Risdiplam | Part 2: Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood | Day 1820 | 1.69 ng/mL |
Secondary
Part 2: Number of Participants With AEs and SAEs Leading to Treatment Discontinuation
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: From first dose up to 30 days after last dose of risdiplam (up to 60 months)
Population: All infants who received at least one dose of study medication (risdiplam) were included in the safety population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Number of Participants With AEs and SAEs Leading to Treatment Discontinuation | Due to AE | 0 Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Number of Participants With AEs and SAEs Leading to Treatment Discontinuation | Due to SAE | 0 Participants |
Secondary
Part 2: Number of Participants With AEs and SAEs Leading to Treatment Modification/Interruption
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: From first dose up to 30 days after last dose of risdiplam (up to 60 months)
Population: All infants who received at least one dose of study medication (risdiplam) were included in the safety population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Number of Participants With AEs and SAEs Leading to Treatment Modification/Interruption | Due to AE | 4 Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Number of Participants With AEs and SAEs Leading to Treatment Modification/Interruption | Due to SAE | 2 Participants |
Secondary
Part 2: Percentage of Infants Able to Feed Orally at Months 12 and 24
Able to feed orally includes participants fed orally and participants fed via a combination of oral and tube feeding. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.
Time frame: Month 12, Month 24
Population: The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Able to Feed Orally at Months 12 and 24 | Month 12 | 82.9 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Able to Feed Orally at Months 12 and 24 | Month 24 | 85.4 Percentage of Participants |
Secondary
Part 2: Percentage of Infants Achieving an Increase of >/= 4 Points in Their CHOP-INTEND Score From Baseline at Months 8 and 12
The CHOP-INTEND instrument was developed to evaluate motor function in infants with SMA from the ages of 1.4 to 37.9 months. It consists of 16 items, where each item assesses a specific motor task graded on a scale of 0 to 4, where zero is no response and 4 is a complete response. The total score ranges from 0 to 64, with higher scores consistent with better motor function. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.
Time frame: Month 8, Month 12
Population: The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Achieving an Increase of >/= 4 Points in Their CHOP-INTEND Score From Baseline at Months 8 and 12 | Month 8 | 87.8 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Achieving an Increase of >/= 4 Points in Their CHOP-INTEND Score From Baseline at Months 8 and 12 | Month 12 | 90.2 Percentage of Participants |
p-value: <0.0001One-sided Exact Binomial Test
Secondary
Part 2: Percentage of Infants Achieving Head Control (Defined as a Score of >/= 3 for CHOP-INTEND Item 12) at Months 8, 12 and 24
The CHOP-INTEND instrument was developed to evaluate motor function in infants with SMA from the ages of 1.4 to 37.9 months. It consists of 16 items, where each item assesses a specific motor task graded on a scale of 0 to 4, where zero is no response and 4 is a complete response. The total score ranges from 0 to 64, with higher scores consistent with better motor function. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.
Time frame: Month 8, Month 12, Month 24
Population: The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Achieving Head Control (Defined as a Score of >/= 3 for CHOP-INTEND Item 12) at Months 8, 12 and 24 | Month 12 | 53.7 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Achieving Head Control (Defined as a Score of >/= 3 for CHOP-INTEND Item 12) at Months 8, 12 and 24 | Month 8 | 46.3 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Achieving Head Control (Defined as a Score of >/= 3 for CHOP-INTEND Item 12) at Months 8, 12 and 24 | Month 24 | 70.7 Percentage of Participants |
Secondary
Part 2: Percentage of Infants Not Requiring Respiratory Support (Invasive or Non-Invasive) at Months 12 and 24
90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.
Time frame: Month 12, Month 24
Population: The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Not Requiring Respiratory Support (Invasive or Non-Invasive) at Months 12 and 24 | Month 12 | 24.4 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Not Requiring Respiratory Support (Invasive or Non-Invasive) at Months 12 and 24 | Month 24 | 19.5 Percentage of Participants |
Secondary
Part 2: Percentage of Infants Who Achieve a Reduction of At Least 30 Degrees in Phase Angle From Baseline, as Measured by Respiratory Plethysmography (RP) at Month 12
RP measures the degree of synchrony between abdominal and thoracic cage-driven breathing. The weakness of intercostal muscles leads to asynchrony of the thorax with the diaphragm, resulting in inefficient and paradoxical breathing patterns. The degree of synchrony between the movement of the chest wall and abdomen during the respiratory cycle can be expressed as the phase angle between the two compartments and measured by placing two RP bands around the thorax and abdomen. In paradoxical breathing, the phase angle is reversed compared with the normal ventilation cycle. A phase angle of 0° indicates perfect in-phase movement, while a value of 180° indicates completely out-of-phase movement between the two compartments. In this measure, 8 or more valid breaths were used to determine the phase angle at each visit; the calculation was not performed if fewer than 8 valid breaths had been measured. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.
Time frame: Month 12
Population: The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve a Reduction of At Least 30 Degrees in Phase Angle From Baseline, as Measured by Respiratory Plethysmography (RP) at Month 12 | 34.1 Percentage of Participants |
Secondary
Part 2: Percentage of Infants Who Achieve a Score of 40 or Higher in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) at Month 12
The CHOP-INTEND instrument was developed to evaluate motor function in infants with SMA from the ages of 1.4 to 37.9 months. It consists of 16 items, where each item assesses a specific motor task graded on a scale of 0 to 4, where zero is no response and 4 is a complete response. The total score ranges from 0 to 64, with higher scores consistent with better motor function. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.
Time frame: Month 12
Population: The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve a Score of 40 or Higher in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) at Month 12 | 56.1 Percentage of Participants |
p-value: <0.0001One-sided Exact Binomial Test
Secondary
Part 2: Percentage of Infants Who Achieve the Attainment Levels of a Subset of Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 8
The HINE was designed to evaluate infants between 2 months and 24 months of age. It is a simple and standardized instrument that includes 26 items assessing different aspects of neurological examinations, such as cranial nerves, posture, movements, tone, and reflexes. In this study, Module 2 of the HINE (HINE-2) was assessed. The HINE-2 evaluates 8 developmental milestones (head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking) scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform a task and a score of 2, 3, or 4 (depending on the task) indicating full milestone development. The total score is calculated by summing the item scores to give a maximum possible score of 26. This measure represents subset numbers at Month 8 for head control, ability to kick and rolling milestones only.
Time frame: Month 8
Population: The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of a Subset of Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 8 | Unable to maintain head upright (Head Control) at Month 8 | 36.6 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of a Subset of Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 8 | Wobbles (Head Control) at Month 8 | 14.6 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of a Subset of Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 8 | All the time maintained upright (Head Control) at Month 8 | 39.0 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of a Subset of Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 8 | No kicking (Ability to Kick [supine]) at Month 8 | 24.4 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of a Subset of Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 8 | Kicks horizontally; legs do not lift (Ability to Kick [supine]) at Month 8 | 58.5 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of a Subset of Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 8 | Upward (vertically) (Ability to Kick [supine]) at Month 8 | 7.3 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of a Subset of Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 8 | Touches leg (Ability to Kick [supine]) at Month 8 | 0 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of a Subset of Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 8 | Touches toes (Ability to Kick [supine]) at Month 8 | 0 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of a Subset of Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 8 | No rolling (Rolling) at Month 8 | 56.1 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of a Subset of Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 8 | Rolling to side (Rolling) at Month 8 | 29.3 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of a Subset of Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 8 | Prone to supine (Rolling) at Month 8 | 2.4 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of a Subset of Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 8 | Supine to prone (Rolling) at Month 8 | 2.4 Percentage of Participants |
Secondary
Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12
The HINE was designed to evaluate infants between 2 months and 24 months of age. It is a simple and standardized instrument that includes 26 items assessing different aspects of neurological examinations, such as cranial nerves, posture, movements, tone, and reflexes. In this study, Module 2 of the HINE (HINE-2) was assessed. The HINE-2 evaluates 8 developmental milestones (head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking) scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform a task and a score of 2, 3, or 4 (depending on the task) indicating full milestone development. The total score is calculated by summing the item scores to give a maximum possible score of 26.
Time frame: Month 12
Population: The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Pincer grasp (Voluntary Grasp) at Month 12 | 12.2 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Unable to maintain head upright (Head Control) at Month 12 | 17.1 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Wobbles (Head Control) at Month 12 | 31.7 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | All the time maintained upright (Head Control) at Month 12 | 43.9 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Cannot sit (Sitting) at Month 12 | 31.7 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Sits with support at hips (Sitting) at Month 12 | 17.1 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Props (Sitting) at Month 12 | 19.5 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Stable sit (Sitting) at Month 12 | 14.6 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Pivots (rotates) (Sitting) at Month 12 | 9.8 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | No grasp (Voluntary Grasp) at Month 12 | 2.4 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Uses whole hand (Voluntary Grasp) at Month 12 | 29.3 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Index finger and thumb but immature grasp (Voluntary Grasp) at Month 12 | 48.8 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | No kicking (Ability to Kick [supine]) at Month 12 | 12.2 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Kicks horizontally; legs do not lift (Ability to Kick [supine]) at Month 12 | 58.5 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Upward (vertically) (Ability to Kick [supine]) at Month 12 | 7.3 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Touches leg (Ability to Kick [supine]) at Month 12 | 4.9 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Touches toes (Ability to Kick [supine]) at Month 12 | 9.8 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | No rolling (Rolling) at Month 12 | 36.6 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Rolling to side (Rolling) at Month 12 | 31.7 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Prone to supine (Rolling) at Month 12 | 14.6 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Supine to prone (Rolling) at Month 12 | 9.8 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Does not lift head (Crawling) at Month 12 | 85.4 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | On elbow (Crawling) at Month 12 | 2.4 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | On outstretched hand (Crawling) at Month 12 | 2.4 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Crawling flat on abdomen (Crawling) at Month 12 | 0 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Crawling on hands and knees (Crawling) at Month 12 | 0 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Cannot test (Crawling) at Month 12 | 2.4 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Does not support weight (Standing) at Month 12 | 61.0 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Supports weight (Standing) at Month 12 | 17.1 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Stands with support (Standing) at Month 12 | 4.9 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Stands unaided (Standing) at Month 12 | 0 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Cannot test (Standing) at Month 12 | 4.9 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Not done (Standing) at Month 12 | 4.9 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Bouncing (Walking) at Month 12 | 2.4 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Cruising (walks holding on) (Walking) at Month 12 | 0 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Walking independently (Walking) at Month 12 | 0 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Cannot test (Walking) at Month 12 | 82.9 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 | Not Done (Walking) at Month 12 | 7.3 Percentage of Participants |
Secondary
Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24
The HINE was designed to evaluate infants between 2 months and 24 months of age. It is a simple and standardized instrument that includes 26 items assessing different aspects of neurological examinations, such as cranial nerves, posture, movements, tone, and reflexes. In this study, Module 2 of the HINE (HINE-2) was assessed. The HINE-2 evaluates 8 developmental milestones (head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking) scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform a task and a score of 2, 3, or 4 (depending on the task) indicating full milestone development. The total score is calculated by summing the item scores to give a maximum possible score of 26.
Time frame: Month 24
Population: The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Unable to maintain head upright (Head Control) at Month 24 | 7.3 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Wobbles (Head Control) at Month 24 | 19.5 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | All the time maintained upright (Head Control) at Month 24 | 63.4 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Not done (Head Control) at Month 24 | 2.4 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Cannot sit (Sitting) at Month 24 | 19.5 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Sits with support at hips (Sitting) at Month 24 | 7.3 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Props (Sitting) at Month 24 | 9.8 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Stable sit (Sitting) at Month 24 | 24.4 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Pivots (rotates) (Sitting) at Month 24 | 29.3 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Not done (Sitting) at Month 24 | 2.4 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | No grasp (Voluntary Grasp) at Month 24 | 2.4 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Uses whole hand (Voluntary Grasp) at Month 24 | 4.9 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Index finger and thumb but immature grasp (Voluntary Grasp) at Month 24 | 39.0 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Pincer grasp (Voluntary Grasp) at Month 24 | 41.5 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Not done (Voluntary Grasp) at Month 24 | 4.9 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | No kicking (Ability to Kick [supine]) at Month 24 | 7.3 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Kicks horizontally; legs do not lift (Ability to Kick [supine]) at Month 24 | 31.7 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Upward (vertically) (Ability to Kick [supine]) at Month 24 | 9.8 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Touches leg (Ability to Kick [supine]) at Month 24 | 9.8 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Touches toes (Ability to Kick [supine]) at Month 24 | 31.7 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Not Done (Ability to Kick [supine]) at Month 24 | 2.4 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | No rolling (Rolling) at Month 24 | 9.8 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Rolling to side (Rolling) at Month 24 | 29.3 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Prone to supine (Rolling) at Month 24 | 7.3 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Supine to prone (Rolling) at Month 24 | 43.9 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Not Done (Rolling) at Month 24 | 2.4 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Does not lift head (Crawling) at Month 24 | 75.6 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | On elbow (Crawling) at Month 24 | 7.3 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | On outstretched hand (Crawling) at Month 24 | 2.4 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Crawling flat on abdomen (Crawling) at Month 24 | 0 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Crawling on hands and knees (Crawling) at Month 24 | 4.9 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Not done (Crawling) at Month 24 | 2.4 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Does not support weight (Standing) at Month 24 | 63.4 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Supports weight (Standing) at Month 24 | 12.2 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Stands with support (Standing) at Month 24 | 14.6 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Stands unaided (Standing) at Month 24 | 0 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Not done (Standing) at Month 24 | 2.4 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Bouncing (Walking) at Month 24 | 2.4 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Cruising (walks holding on) (Walking) at Month 24 | 2.4 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Walking independently (Walking) at Month 24 | 0 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Cannot test (Walking) at Month 24 | 75.6 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 | Not Done (Walking) at Month 24 | 12.2 Percentage of Participants |
Secondary
Part 2: Percentage of Infants Who Are Alive at Months 12 and 24
Kaplan-Meier methodology was used to estimate the percentages. 90% CI was computed using the complementary log-log transformation.
Time frame: Month 12, Month 24
Population: The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Are Alive at Months 12 and 24 | Month 12 | 92.68 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Are Alive at Months 12 and 24 | Month 24 | 92.68 Percentage of Participants |
p-value: 0.0005One-sided Z-test
Secondary
Part 2: Percentage of Infants Who Are Alive Without Permanent Ventilation at Months 12 and 24
Permanent ventilation is defined as \>/=16 hours of non-invasive ventilation per day or intubation for \>21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. Kaplan-Meier methodology was used to estimate the percentages. 90% CI was computed using the complementary log-log transformation.
Time frame: Month 12, Month 24
Population: The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Are Alive Without Permanent Ventilation at Months 12 and 24 | Month 12 | 85.37 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Are Alive Without Permanent Ventilation at Months 12 and 24 | Month 24 | 82.93 Percentage of Participants |
p-value: <0.0001One-sided Z-test
Secondary
Part 2: Percentage of Infants Who Are Sitting Without Support for at Least 30 Seconds as Assessed by Item 26 of the BSID-III Gross Motor Scale at Month 24
The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 26 is not considered achieved if the infant sits alone for less than 30 seconds before losing balance and falling over, or if the infant uses his or her arms to prop him- or herself up. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.
Time frame: Month 24
Population: The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Are Sitting Without Support for at Least 30 Seconds as Assessed by Item 26 of the BSID-III Gross Motor Scale at Month 24 | 43.9 Percentage of Participants |
p-value: <0.0001One-sided Exact Binomial Test
Secondary
Part 2: Percentage of Infants Who Are Sitting Without Support for at Least 5 Seconds as Assessed by Item 22 of the BSID-III Gross Motor Scale at Month 24
The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 22 is not considered achieved if the infant sits alone for less than 5 seconds before losing balance and falling over, or if the infant uses his or her arms to prop him- or herself up. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.
Time frame: Month 24
Population: The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Are Sitting Without Support for at Least 5 Seconds as Assessed by Item 22 of the BSID-III Gross Motor Scale at Month 24 | 61.0 Percentage of Participants |
p-value: <0.0001One-sided Exact Binomial Test
Secondary
Part 2: Percentage of Infants Who Are Standing Alone as Assessed by Item 40 of the BSID-III Gross Motor Scale at Month 24
The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Reported here is the percentage of participants who achieved item 40 'Stands alone' at Month 24. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.
Time frame: Month 24
Population: The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Are Standing Alone as Assessed by Item 40 of the BSID-III Gross Motor Scale at Month 24 | 0 Percentage of Participants |
p-value: 1One-sided Exact Binomial Test
Secondary
Part 2: Percentage of Infants Who Are Walking Alone as Assessed by Item 42 of the BSID-III Gross Motor Scale at Month 24
The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Reported here is the percentage of participants who achieved item 42 'Walks alone' at Month 24. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.
Time frame: Month 24
Population: The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Are Walking Alone as Assessed by Item 42 of the BSID-III Gross Motor Scale at Month 24 | 0 Percentage of Participants |
p-value: 1One-sided Exact Binomial Test
Secondary
Part 2: Percentage of Infants Who Are Without Permanent Ventilation at Months 12 and 24
Permanent ventilation is defined as \>/=16 hours of non-invasive ventilation per day or intubation for \>21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. Kaplan-Meier methodology was used to estimate the percentages. 90% CI was computed using the complementary log-log transformation.
Time frame: Month 12, Month 24
Population: The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Are Without Permanent Ventilation at Months 12 and 24 | Month 12 | 92.29 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Infants Who Are Without Permanent Ventilation at Months 12 and 24 | Month 24 | 89.65 Percentage of Participants |
p-value: 0.2595One-sided Z-test
Secondary
Part 2: Percentage of Motor Milestone Responders as Assessed by HINE-2 at Months 12 and 24
The HINE-2 evaluates 8 developmental milestones scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform a task and a score of 2, 3, or 4 (depending on the task) indicating full milestone development. The total score is calculated by summing the item scores to give a maximum possible score of 26. For the motor milestone responder definition, an improvement in a motor milestone is defined as at least a 2-point increase in ability to kick (or maximal score) or a 1-point increase in head control, rolling, sitting, crawling, standing, or walking. Worsening is similarly defined as a 2-point decrease in ability to kick (or lowest score) or a 1-point decrease in head control, rolling, sitting, crawling, standing, or walking. Voluntary grasp is excluded from the definition. An infant is classified as a responder if more motor milestones show improvement than show worsening. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.
Time frame: Month 12, Month 24
Population: The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Motor Milestone Responders as Assessed by HINE-2 at Months 12 and 24 | Month 12 | 78.0 Percentage of Participants |
| Exploratory Part 1 - Risdiplam | Part 2: Percentage of Motor Milestone Responders as Assessed by HINE-2 at Months 12 and 24 | Month 24 | 85.4 Percentage of Participants |
p-value: <0.0001One-sided Exact Binomial Test
Secondary
Part 2: Time to Death
The median time to event was estimated using Kaplan-Meier methodology. 90% CI was estimated using the method of Brookmeyer and Crowley.
Time frame: Up to 24 months
Population: The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Time to Death | NA Months |
Secondary
Part 2: Time to Death or Permanent Ventilation
Permanent ventilation is defined as \>/=16 hours of non-invasive ventilation per day or intubation for \>21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. The median time to event was estimated using Kaplan-Meier methodology. 90% CI was estimated using the method of Brookmeyer and Crowley.
Time frame: Up to 24 months
Population: The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Time to Death or Permanent Ventilation | NA Months |
Secondary
Part 2: Time to Permanent Ventilation
Permanent ventilation is defined as \>/=16 hours of non-invasive ventilation per day or intubation for \>21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. The median time to event was estimated using Kaplan-Meier methodology. 90% CI was estimated using the method of Brookmeyer and Crowley.
Time frame: Up to 24 months
Population: The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Exploratory Part 1 - Risdiplam | Part 2: Time to Permanent Ventilation | NA Months |