Outcome
| Type |
Measure |
Description |
Time frame |
Safety issue |
| 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. |
Minimum of 2 weeks at steady state exposure |
|
| 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. |
Month 12 |
|
| 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. |
Month 12 |
|
| 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. |
Month 8, Month 12 |
|
| 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. |
Month 8, Month 12, Month 24 |
|
| 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. |
Baseline, Month 12, Month 24 |
|
| 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. |
Month 8 |
|
| 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. |
Month 12 |
|
| 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. |
Month 24 |
|
| 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. |
Month 12, Month 24 |
|
| 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. |
Month 12, Month 24 |
|
| 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. |
Month 24 |
|
| 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. |
Month 24 |
|
| 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. |
Month 24 |
|
| 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. |
Month 24 |
|
| 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. |
Up to 24 months (up to the Clinical Cut-off Date [CCOD] of 12 November 2020) |
|
| 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. |
Up to 24 months (up to the CCOD of 12 November 2020) |
|
| 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. |
Up to 24 months (up to the CCOD of 12 November 2020) |
|
| 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. |
Month 12, Month 24 |
|
| 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. |
Month 12, Month 24 |
|
| 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. |
Month 12, Month 24 |
|
| 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. |
Month 12 |
|
| 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. |
Month 12, Month 24 |
|
| 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. |
Month 12, Month 24 |
|
| 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. |
From first dose of risdiplam up to a minimum of 24 months (CCOD of 12 November 2020) |
|
| 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. |
From first dose of risdiplam up to a minimum of 24 months (CCOD of 12 November 2020) |
|
| 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. |
From first dose of risdiplam up to a minimum of 24 months (CCOD of 12 November 2020) |
|
| Secondary |
Part 2: Anthropometric Examination of Weight Measured in Kilograms |
Anthropometric examination included weight, height, head circumference and chest circumference. |
Month 12, Month 24 |
|
| 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. |
Month 12, Month 24 |
|
| Secondary |
Part 2: Maximum Plasma Concentration (Cmax) of Risdiplam |
|
Day 1: predose, 2, 4, 6, 24 hours; Days 14, 119, 245, 364, 427, 490, 609, 728: predose, 4 hours; Days 28, 56, 182, 301, 546, 672: predose, 2, 4, 6 hours |
|
| Secondary |
Part 2: Area Under the Curve (AUC) of Risdiplam |
|
Day 1: predose, 2, 4, 6, 24 hours; Days 14, 119, 245, 364, 427, 490, 609, 728: predose, 4 hours; Days 28, 56, 182, 301, 546, 672: predose, 2, 4, 6 hours |
|
| Secondary |
Part 2: Concentration at the End of a Dosing Interval (Ctrough) of Risdiplam |
|
Predose on Days 2, 14, 28, 56, 119, 182, 301, 546, 672 |
|
| Secondary |
Survival Motor Neuron (SMN) Protein Levels in Blood |
|
Days 1, 14 (Part 1 only), 28, 119, 245, 364, 609, 728 |
|
| Secondary |
Survival Motor Neuron (SMN) Messenger Ribonucleic Acid (mRNA) Levels in Blood |
|
Days 1, 14 (Part 1 only), 28, 245, 364, 609, 728 |
|
