Muscular Atrophy, Spinal
Conditions
Brief summary
A global study of oral risdiplam in pre-symptomatic participants with spinal muscular atrophy (SMA).
Detailed description
The study is an open-label, single-arm, multicenter clinical study to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of risdiplam in infants aged from birth to 6 weeks who have been genetically diagnosed with SMA but are not yet presenting with symptoms. There will be a screening, treatment, open-label extension (OLE) and a follow-up. All participants will receive risdiplam orally once daily for 2 years followed by an OLE phase of at least 3 years and a follow-up (if applicable), for a total treatment duration of at least 5 years for each participant enrolled.
Interventions
DRUGRisdiplam
Risdiplam will be administered orally.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-label, single arm
Eligibility
Sex/Gender
ALL
Age
1 Days to 6 Weeks
Healthy volunteers
No
Inclusion criteria
* Males and females aged from birth (1 day) to 6 weeks (42 days) of age at the time of first dose (Day 1); a minimum age of 7 days at first dose is required for the first infant to be enrolled * Gestational age of 37-42 weeks for singleton births; gestational age of 34-42 weeks for twins * Body weight \>= 3rd percentile for age, using appropriate country-specific guidelines * Genetic diagnosis of 5q-autosomal recessive SMA, including confirmation of homozygous deletion or compound heterozygosity predictive of loss of function of the SMN1 gene * Absence of clinical signs or symptoms at screening (Day -42 to Day -2) or at baseline (Day -1) that are, in the opinion of the investigator, strongly suggestive of SMA * Receiving adequate nutrition and hydration at the time of screening, in the opinion of the investigator * Adequately recovered from any acute illness at baseline and considered well enough to participate in the study, in the opinion of the investigator * Able and expected to be able to safely travel to the study site for the entire duration of the study and in accordance to the frequency of required study visits, in the opinion of the investigator * Able to complete all study procedures, measurements, and visits, and the parent (or caregiver), in the opinion of the investigator, has adequately supportive psychosocial circumstances * Parent (or caregiver) is willing to consider nasogastric, naso-jejunal, or gastrostomy tube placement during the study to maintain safe hydration, nutrition, and treatment delivery, if recommended by the investigator * Parent (or caregiver) is willing to consider the use of non-invasive ventilation during the study, if recommended by the investigator
Exclusion criteria
* Concomitant or previous participation in any investigational drug or device study at any time * Concomitant or previous administration of an SMN2-targeting antisense oligonucleotide, SMN2-splicing modifier, or gene therapy either in a clinical study or as part of medical care * Presence of significant concurrent syndromes or diseases * In the opinion of the investigator, inadequate venous or capillary blood access for the study procedures * Requiring invasive ventilation, tracheostomy or awake non-invasive ventilation * Awake hypoxemia (SaO2 \< 95%) with or without ventilator support * Multiple or fixed contractures and/or hip subluxation or dislocation at birth * Systolic blood pressure or diastolic blood pressure or heart rate considered to be clinically significant by the investigator * Presence of clinically relevant ECG abnormalities before study drug administration; corrected QT interval using Bazett's method \> 460 ms; personal or family history (first degree relatives) of congenital long QT syndrome indicating a safety risk for patients as determined by the investigator. First-degree atrioventricular block or isolated right bundle branch block are allowed * The infant (and the mother, if breastfeeding the infant) taking any inhibitor of CYP3A4 taken within 2 weeks, any inducer of CYP3A4 taken within 4 weeks, any OCT 2 and MATE substrates within 2 weeks and known FMO1 or FMO3 inhibitors or substrates * Clinically significant abnormalities in laboratory test results * Ascertained or presumptive hypersensitivity to risdiplam or to the constituents of its formulation * Treatment with oral salbutamol or another beta-2 adrenergic agonist taken orally for SMA is not allowed. Use of inhaled beta-2 adrenergic agonists is allowed * Infants exposed to drugs with known retinal toxicity given to mothers during pregnancy (and lactation) should not be enrolled. Anticipated need for drugs known to cause retinal toxicity during the study. * Diagnosis of ophthalmic diseases
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Two Copies of the Survival Motor Neuron (SMN) 2 Gene (Excluding the Known SMN2 Gene Modifier Mutation c.859G>C) and Baseline Compound Muscle Action Potential (CMAP) >=1.5 Millivolt (mV) Who Are Sitting Without Support | At Month 12 | The Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) Gross Motor Scale is a commonly used measure of infant and toddler development (0 to 42 months). The normed-scores derived from the BSID-III are used in clinical practice to detect infants with developmental delays, as well as to evaluate developmental progress and the impact of therapeutic interventions. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 22, "sits without support for 5 seconds", 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. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. An exact binomial test was performed. If the lower limit of the two-sided 90% CI was above the 5% threshold, the primary objective of the study was considered achieved. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Developing Clinically Manifested SMA | At Month 12 and 24 | — |
| Time to Permanent Ventilation and/or Death | Up to 7 years | — |
| Percentage of Participants Who Are Alive Without Permanent Ventilation | At Month 12 and 24 | — |
| Percentage of Participants Alive | At Month 12 and 24 | — |
| Percentage of Participants Who Achieve the Attainment Level of the Motor Milestones as Assessed in the Hammersmith Infant Neurological Examination-2 (HINE-2) | At Month 12 and 24 | HINE-2 assessment includes head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking |
| Percentage of Participants With Two Copies of the SMN2 Gene Sitting Without Support for 5 Seconds (Independent of the CMAP Value at Baseline). | At Month 12 | Assessed in Item 22 of the BSID-III Gross Motor Scale. The BSID-III is a commonly used measure of infant and toddler development (0 to 42 months). The normed-scores derived from the BSID-III are used in clinical practice to detect infants with developmental delays, as well as to evaluate developmental progress and the impact of therapeutic interventions. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 22, "sits without support for 5 seconds", 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. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. |
| Percentage of Participants Sitting Without Support for 5 Seconds | At Month 24 | Assessed with BSID-III Gross Motor Scale |
| Percentage of Participants Sitting Without Support for 30 Seconds | At Month 12 and 24 | Assessed with BSID-III Gross Motor Scale |
| Percentage of Participants Standing for at Least 3 Seconds | At Month 24 | Assessed with BSID-III Gross Motor Scale |
| Percentage of Participants Walking (Takes at Least 3 Steps) | At Month 24 | Assessed with BSID-III Gross Motor Scale |
| Percentage of Participants Demonstrating the Ability to Achieve a Scaled Score on BSID-III Gross Motor Subtests Within 1.5 Standard Deviations of Chronological Reference Standard | At Month 24 and 42 | Assessed through BSID-III Gross Motor Scale |
| Change From Baseline Score in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Motor Function Scale at Month 12 | Baseline, Month 12 | The CHOP-INTEND is a measure of motor function that was developed from the Test of Infant Motor Performance specifically for weak infants with neuromuscular disease. It consists of 16 items, where each item assesses a specific motor task (such as spontaneous movement of upper and lower extremity, hand grasping, rolling, head control, and others) graded on a scale of 0 to 4, where zero is no response and 4 is a complete response. A total score is calculated by summing the item scores (range 0 to 64) with lower scores indicating greater severity. A positive change from baseline indicates an improvement. |
| Percentage of Participants Who Achieve a Score of 40 or Higher, 50 or Higher, and 60 or Higher in the CHOP INTEND Motor Function Scale at Month 12 | At Month 12 | The CHOP-INTEND is a measure of motor function that was developed from the Test of Infant Motor Performance specifically for weak infants with neuromuscular disease. It consists of 16 items, where each item assesses a specific motor task (such as spontaneous movement of upper and lower extremity, hand grasping, rolling, head control, and others) graded on a scale of 0 to 4, where zero is no response and 4 is a complete response. A total score is calculated by summing the item scores (range 0 to 64) with lower scores indicating greater severity. Data are presented with a two-sided 90% Clopper-Pearson (exact) CI for the proportion. |
| Percentage of Participants Who Meet CHOP INTEND Stopping Criteria at Any Point | Up to Month 24 | — |
| Change From Baseline in the Hammersmith Functional Motor Scale Expanded (HFMSE) Score | At Month 60 | — |
| Number and Percentage of Participants Within 3rd Percentile of Normal Range for Weight-for-Age, Length/Height-for-Age and Weight-for-Length/Height | At Month 12, 24, 36, 48 and 60 | Based on the WHO Child Growth Standards (WHO 2019) |
| Number and Percentage of Participants Within 3rd Percentile of Normal Range for Head Circumference-for-age | At Month 12 and 24 | Based on the WHO Child Growth Standards (WHO 2019) |
| Change From Baseline Percentiles for Weight-for-age, Length/Height-for-age, and weight-for- Length/Height | At Month 12, 24, 36, 48 and 60 | — |
| Change From Baseline Percentiles for Head Circumference- For-age | At Month 12 and 24 | — |
| Change From Baseline in Chest Circumference | At Month 12 and 24 | — |
| Ratio Between Chest and Head Circumferences | At Month 12 and 24 | — |
| Percentage of Participants With the Ability to Swallow and to Feed Orally | At Month 12, 24, 36, 48 and 60 | — |
| Change From Baseline in Compound Muscle Action Potential (CMAP) Amplitude | At Month 12 and 24 | Measured by CMAP |
| Measurement of Pharmacodynamic Marker Levels in Blood | Day 1, 56, 196, 364, 728 and at early withdrawal | — |
| Percentage of Participants With Adverse Events | Up to 7 years | Adverse event severity is determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5 (NCI CTCAE) v5 |
| Ophthalmological Examination as Appropriate for Age | Up to 7 years | — |
| Plasma Concentration of Risdiplam and Its Metabolites to Characterize the PK Profile | Up to 7 years | — |
Countries
Australia, Belgium, Brazil, Poland, Russia, Taiwan, United States
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Participant flow
Recruitment details
Overall, 26 infants with spinal muscular atrophy (SMA) were enrolled in the study across 7 different sites in 7 countries.
Pre-assignment details
The study enrolled infants aged from birth to 6 weeks who were genetically diagnosed with SMA but were not yet presenting with symptoms. Study arms were based on the number of copies of the SMN2 gene.
Participants by arm
| Arm | Count |
|---|---|
| 2 SMN2 Copies, Risdiplam Infants with 2 copies of SMN2 were enrolled to receive risdiplam orally once daily at a dose selected to achieve the targeted exposure range of close to 2000 ng\*hr/mL. | 8 |
| 3 SMN2 Copies, Risdiplam Infants with 3 copies of SMN2 were enrolled to receive risdiplam orally once daily at a dose selected to achieve the targeted exposure range of close to 2000 ng\*hr/mL. | 13 |
| >/=4 SMN2 Copies, Risdiplam Infants with 4 or more copies of SMN2 were enrolled to receive risdiplam orally once daily at a dose selected to achieve the targeted exposure range of close to 2000 ng\*hr/mL. | 5 |
| Total | 26 |
Baseline characteristics
| Characteristic | 2 SMN2 Copies, Risdiplam | 3 SMN2 Copies, Risdiplam | >/=4 SMN2 Copies, Risdiplam | Total |
|---|---|---|---|---|
| Age, Continuous | 22.8 days STANDARD_DEVIATION 5 | 28.9 days STANDARD_DEVIATION 7.5 | 31.2 days STANDARD_DEVIATION 6.1 | 27.5 days STANDARD_DEVIATION 7.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 12 Participants | 5 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 8 Participants | 11 Participants | 3 Participants | 22 Participants |
| Sex: Female, Male Female | 4 Participants | 9 Participants | 3 Participants | 16 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 2 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 13 | 0 / 5 |
| other Total, other adverse events | 8 / 8 | 12 / 13 | 4 / 5 |
| serious Total, serious adverse events | 3 / 8 | 0 / 13 | 1 / 5 |
Outcome results
Primary
Percentage of Participants With Two Copies of the Survival Motor Neuron (SMN) 2 Gene (Excluding the Known SMN2 Gene Modifier Mutation c.859G>C) and Baseline Compound Muscle Action Potential (CMAP) >=1.5 Millivolt (mV) Who Are Sitting Without Support
The Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) Gross Motor Scale is a commonly used measure of infant and toddler development (0 to 42 months). The normed-scores derived from the BSID-III are used in clinical practice to detect infants with developmental delays, as well as to evaluate developmental progress and the impact of therapeutic interventions. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 22, sits without support for 5 seconds, 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. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. An exact binomial test was performed. If the lower limit of the two-sided 90% CI was above the 5% threshold, the primary objective of the study was considered achieved.
Time frame: At Month 12
Population: Primary efficacy population included all infants in the intent-to-treat (ITT) population with two SMN2 copies (excluding the known SMN2 gene modifier mutation c.859G\>C) and a baseline compound muscle action potential (CMAP) amplitude \>/= 1.5 mV.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 2 SMN2 Copies, Risdiplam | Percentage of Participants With Two Copies of the Survival Motor Neuron (SMN) 2 Gene (Excluding the Known SMN2 Gene Modifier Mutation c.859G>C) and Baseline Compound Muscle Action Potential (CMAP) >=1.5 Millivolt (mV) Who Are Sitting Without Support | 80.0 percentage of participants |
p-value: <0.0001Exact Binomial Test
Secondary
Change From Baseline in Chest Circumference
Time frame: At Month 12 and 24
Secondary
Change From Baseline in Compound Muscle Action Potential (CMAP) Amplitude
Measured by CMAP
Time frame: At Month 12 and 24
Secondary
Change From Baseline in the Hammersmith Functional Motor Scale Expanded (HFMSE) Score
Time frame: At Month 60
Secondary
Change From Baseline Percentiles for Head Circumference- For-age
Time frame: At Month 12 and 24
Secondary
Change From Baseline Percentiles for Weight-for-age, Length/Height-for-age, and weight-for- Length/Height
Time frame: At Month 12, 24, 36, 48 and 60
Secondary
Change From Baseline Score in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Motor Function Scale at Month 12
The CHOP-INTEND is a measure of motor function that was developed from the Test of Infant Motor Performance specifically for weak infants with neuromuscular disease. It consists of 16 items, where each item assesses a specific motor task (such as spontaneous movement of upper and lower extremity, hand grasping, rolling, head control, and others) graded on a scale of 0 to 4, where zero is no response and 4 is a complete response. A total score is calculated by summing the item scores (range 0 to 64) with lower scores indicating greater severity. A positive change from baseline indicates an improvement.
Time frame: Baseline, Month 12
Population: ITT population included all enrolled participants, regardless of whether they received risdiplam or not.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 2 SMN2 Copies, Risdiplam | Change From Baseline Score in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Motor Function Scale at Month 12 | Baseline | 46.50 score on a scale |
| 2 SMN2 Copies, Risdiplam | Change From Baseline Score in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Motor Function Scale at Month 12 | Change from Baseline at Month 12 | 9.50 score on a scale |
| 3 SMN2 Copies, Risdiplam | Change From Baseline Score in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Motor Function Scale at Month 12 | Baseline | 55.00 score on a scale |
| 3 SMN2 Copies, Risdiplam | Change From Baseline Score in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Motor Function Scale at Month 12 | Change from Baseline at Month 12 | 8.00 score on a scale |
| >/=4 SMN2 Copies, Risdiplam | Change From Baseline Score in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Motor Function Scale at Month 12 | Baseline | 50.00 score on a scale |
| >/=4 SMN2 Copies, Risdiplam | Change From Baseline Score in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Motor Function Scale at Month 12 | Change from Baseline at Month 12 | 16.00 score on a scale |
Secondary
Measurement of Pharmacodynamic Marker Levels in Blood
Time frame: Day 1, 56, 196, 364, 728 and at early withdrawal
Secondary
Number and Percentage of Participants Within 3rd Percentile of Normal Range for Head Circumference-for-age
Based on the WHO Child Growth Standards (WHO 2019)
Time frame: At Month 12 and 24
Secondary
Number and Percentage of Participants Within 3rd Percentile of Normal Range for Weight-for-Age, Length/Height-for-Age and Weight-for-Length/Height
Based on the WHO Child Growth Standards (WHO 2019)
Time frame: At Month 12, 24, 36, 48 and 60
Secondary
Ophthalmological Examination as Appropriate for Age
Time frame: Up to 7 years
Secondary
Percentage of Participants Alive
Time frame: At Month 12 and 24
Secondary
Percentage of Participants Demonstrating the Ability to Achieve a Scaled Score on BSID-III Gross Motor Subtests Within 1.5 Standard Deviations of Chronological Reference Standard
Assessed through BSID-III Gross Motor Scale
Time frame: At Month 24 and 42
Secondary
Percentage of Participants Developing Clinically Manifested SMA
Time frame: At Month 12 and 24
Secondary
Percentage of Participants Sitting Without Support for 30 Seconds
Assessed with BSID-III Gross Motor Scale
Time frame: At Month 12 and 24
Secondary
Percentage of Participants Sitting Without Support for 5 Seconds
Assessed with BSID-III Gross Motor Scale
Time frame: At Month 24
Secondary
Percentage of Participants Standing for at Least 3 Seconds
Assessed with BSID-III Gross Motor Scale
Time frame: At Month 24
Secondary
Percentage of Participants Walking (Takes at Least 3 Steps)
Assessed with BSID-III Gross Motor Scale
Time frame: At Month 24
Secondary
Percentage of Participants Who Achieve a Score of 40 or Higher, 50 or Higher, and 60 or Higher in the CHOP INTEND Motor Function Scale at Month 12
The CHOP-INTEND is a measure of motor function that was developed from the Test of Infant Motor Performance specifically for weak infants with neuromuscular disease. It consists of 16 items, where each item assesses a specific motor task (such as spontaneous movement of upper and lower extremity, hand grasping, rolling, head control, and others) graded on a scale of 0 to 4, where zero is no response and 4 is a complete response. A total score is calculated by summing the item scores (range 0 to 64) with lower scores indicating greater severity. Data are presented with a two-sided 90% Clopper-Pearson (exact) CI for the proportion.
Time frame: At Month 12
Population: ITT population included all enrolled participants, regardless of whether they received risdiplam or not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 2 SMN2 Copies, Risdiplam | Percentage of Participants Who Achieve a Score of 40 or Higher, 50 or Higher, and 60 or Higher in the CHOP INTEND Motor Function Scale at Month 12 | Score >=50 | 75.0 percentage of participants |
| 2 SMN2 Copies, Risdiplam | Percentage of Participants Who Achieve a Score of 40 or Higher, 50 or Higher, and 60 or Higher in the CHOP INTEND Motor Function Scale at Month 12 | Score >=40 | 75.0 percentage of participants |
| 2 SMN2 Copies, Risdiplam | Percentage of Participants Who Achieve a Score of 40 or Higher, 50 or Higher, and 60 or Higher in the CHOP INTEND Motor Function Scale at Month 12 | Score >=60 | 37.5 percentage of participants |
| 3 SMN2 Copies, Risdiplam | Percentage of Participants Who Achieve a Score of 40 or Higher, 50 or Higher, and 60 or Higher in the CHOP INTEND Motor Function Scale at Month 12 | Score >=50 | 100 percentage of participants |
| 3 SMN2 Copies, Risdiplam | Percentage of Participants Who Achieve a Score of 40 or Higher, 50 or Higher, and 60 or Higher in the CHOP INTEND Motor Function Scale at Month 12 | Score >=40 | 100 percentage of participants |
| 3 SMN2 Copies, Risdiplam | Percentage of Participants Who Achieve a Score of 40 or Higher, 50 or Higher, and 60 or Higher in the CHOP INTEND Motor Function Scale at Month 12 | Score >=60 | 100 percentage of participants |
| >/=4 SMN2 Copies, Risdiplam | Percentage of Participants Who Achieve a Score of 40 or Higher, 50 or Higher, and 60 or Higher in the CHOP INTEND Motor Function Scale at Month 12 | Score >=40 | 100 percentage of participants |
| >/=4 SMN2 Copies, Risdiplam | Percentage of Participants Who Achieve a Score of 40 or Higher, 50 or Higher, and 60 or Higher in the CHOP INTEND Motor Function Scale at Month 12 | Score >=60 | 100 percentage of participants |
| >/=4 SMN2 Copies, Risdiplam | Percentage of Participants Who Achieve a Score of 40 or Higher, 50 or Higher, and 60 or Higher in the CHOP INTEND Motor Function Scale at Month 12 | Score >=50 | 100 percentage of participants |
Secondary
Percentage of Participants Who Achieve the Attainment Level of the Motor Milestones as Assessed in the Hammersmith Infant Neurological Examination-2 (HINE-2)
HINE-2 assessment includes head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking
Time frame: At Month 12 and 24
Secondary
Percentage of Participants Who Are Alive Without Permanent Ventilation
Time frame: At Month 12 and 24
Secondary
Percentage of Participants Who Meet CHOP INTEND Stopping Criteria at Any Point
Time frame: Up to Month 24
Secondary
Percentage of Participants With Adverse Events
Adverse event severity is determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5 (NCI CTCAE) v5
Time frame: Up to 7 years
Secondary
Percentage of Participants With the Ability to Swallow and to Feed Orally
Time frame: At Month 12, 24, 36, 48 and 60
Secondary
Percentage of Participants With Two Copies of the SMN2 Gene Sitting Without Support for 5 Seconds (Independent of the CMAP Value at Baseline).
Assessed in Item 22 of the BSID-III Gross Motor Scale. The BSID-III is a commonly used measure of infant and toddler development (0 to 42 months). The normed-scores derived from the BSID-III are used in clinical practice to detect infants with developmental delays, as well as to evaluate developmental progress and the impact of therapeutic interventions. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 22, sits without support for 5 seconds, 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. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.
Time frame: At Month 12
Population: Intent-to-treat (ITT) population included all enrolled participants, regardless of whether they received risdiplam or not. Only participants with two copies of the SMN2 gene were included in this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 2 SMN2 Copies, Risdiplam | Percentage of Participants With Two Copies of the SMN2 Gene Sitting Without Support for 5 Seconds (Independent of the CMAP Value at Baseline). | 87.5 percentage of participants |
Secondary
Plasma Concentration of Risdiplam and Its Metabolites to Characterize the PK Profile
Time frame: Up to 7 years
Secondary
Ratio Between Chest and Head Circumferences
Time frame: At Month 12 and 24
Secondary
Time to Permanent Ventilation and/or Death
Time frame: Up to 7 years