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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT03779334
Registration number
NCT03779334
Ethics application status
Date submitted
17/12/2018
Date registered
19/12/2018
Date last updated
10/06/2024
Titles & IDs
Public title
A Study of Risdiplam in Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy
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Scientific title
An Open-Label Study of Risdiplam in Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy
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Secondary ID [1]
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2018-002087-12
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Secondary ID [2]
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BN40703
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Universal Trial Number (UTN)
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Trial acronym
Rainbowfish
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Muscular Atrophy, Spinal
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Condition category
Condition code
Musculoskeletal
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Other muscular and skeletal disorders
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Neurological
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Other neurological disorders
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Other
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Research that is not of generic health relevance and not applicable to specific health categories listed above
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Risdiplam
Experimental: Open-label Risdiplam - Participants will be enrolled to receive risdiplam orally once daily at a dose selected to achieve the targeted exposure range.
Treatment: Drugs: Risdiplam
Risdiplam will be administered orally.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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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
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Assessment method [1]
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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.
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Timepoint [1]
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At Month 12
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Secondary outcome [1]
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Percentage of Participants Developing Clinically Manifested SMA
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Assessment method [1]
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Timepoint [1]
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At Month 12 and 24
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Secondary outcome [2]
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Time to Permanent Ventilation and/or Death
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Assessment method [2]
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Timepoint [2]
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Up to 7 years
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Secondary outcome [3]
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Percentage of Participants Who Are Alive Without Permanent Ventilation
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Assessment method [3]
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Timepoint [3]
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At Month 12 and 24
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Secondary outcome [4]
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Percentage of Participants Alive
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Assessment method [4]
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Timepoint [4]
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At Month 12 and 24
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Secondary outcome [5]
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Percentage of Participants Who Achieve the Attainment Level of the Motor Milestones as Assessed in the Hammersmith Infant Neurological Examination-2 (HINE-2)
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Assessment method [5]
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HINE-2 assessment includes head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking
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Timepoint [5]
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At Month 12 and 24
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Secondary outcome [6]
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Percentage of Participants With Two Copies of the SMN2 Gene Sitting Without Support for 5 Seconds (Independent of the CMAP Value at Baseline).
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Assessment method [6]
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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.
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Timepoint [6]
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At Month 12
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Secondary outcome [7]
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Percentage of Participants Sitting Without Support for 5 Seconds
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Assessment method [7]
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Assessed with BSID-III Gross Motor Scale
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Timepoint [7]
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At Month 24
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Secondary outcome [8]
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Percentage of Participants Sitting Without Support for 30 Seconds
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Assessment method [8]
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Assessed with BSID-III Gross Motor Scale
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Timepoint [8]
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At Month 12 and 24
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Secondary outcome [9]
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Percentage of Participants Standing for at Least 3 Seconds
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Assessment method [9]
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Assessed with BSID-III Gross Motor Scale
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Timepoint [9]
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At Month 24
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Secondary outcome [10]
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Percentage of Participants Walking (Takes at Least 3 Steps)
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Assessment method [10]
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Assessed with BSID-III Gross Motor Scale
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Timepoint [10]
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At Month 24
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Secondary outcome [11]
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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
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Assessment method [11]
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Assessed through BSID-III Gross Motor Scale
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Timepoint [11]
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At Month 24 and 42
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Secondary outcome [12]
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Change From Baseline Score in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Motor Function Scale at Month 12
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Assessment method [12]
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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.
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Timepoint [12]
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Baseline, Month 12
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Secondary outcome [13]
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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
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Assessment method [13]
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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.
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Timepoint [13]
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At Month 12
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Secondary outcome [14]
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Percentage of Participants Who Meet CHOP INTEND Stopping Criteria at Any Point
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Assessment method [14]
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Timepoint [14]
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Up to Month 24
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Secondary outcome [15]
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Change From Baseline in the Hammersmith Functional Motor Scale Expanded (HFMSE) Score
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Assessment method [15]
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Timepoint [15]
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At Month 60
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Secondary outcome [16]
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Number and Percentage of Participants Within 3rd Percentile of Normal Range for Weight-for-Age, Length/Height-for-Age and Weight-for-Length/Height
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Assessment method [16]
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Based on the WHO Child Growth Standards (WHO 2019)
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Timepoint [16]
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At Month 12, 24, 36, 48 and 60
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Secondary outcome [17]
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Number and Percentage of Participants Within 3rd Percentile of Normal Range for Head Circumference-for-age
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Assessment method [17]
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Based on the WHO Child Growth Standards (WHO 2019)
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Timepoint [17]
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At Month 12 and 24
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Secondary outcome [18]
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Change From Baseline Percentiles for Weight-for-age, Length/Height-for-age, and weight-for- Length/Height
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Assessment method [18]
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Timepoint [18]
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At Month 12, 24, 36, 48 and 60
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Secondary outcome [19]
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Change From Baseline Percentiles for Head Circumference- For-age
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Assessment method [19]
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Timepoint [19]
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At Month 12 and 24
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Secondary outcome [20]
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Change From Baseline in Chest Circumference
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Assessment method [20]
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Timepoint [20]
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At Month 12 and 24
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Secondary outcome [21]
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Ratio Between Chest and Head Circumferences
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Assessment method [21]
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Timepoint [21]
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At Month 12 and 24
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Secondary outcome [22]
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Percentage of Participants With the Ability to Swallow and to Feed Orally
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Assessment method [22]
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Timepoint [22]
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At Month 12, 24, 36, 48 and 60
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Secondary outcome [23]
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Change From Baseline in Compound Muscle Action Potential (CMAP) Amplitude
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Assessment method [23]
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Measured by CMAP
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Timepoint [23]
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At Month 12 and 24
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Secondary outcome [24]
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Measurement of Pharmacodynamic Marker Levels in Blood
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Assessment method [24]
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Timepoint [24]
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Day 1, 56, 196, 364, 728 and at early withdrawal
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Secondary outcome [25]
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Percentage of Participants With Adverse Events
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Assessment method [25]
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Adverse event severity is determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5 (NCI CTCAE) v5
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Timepoint [25]
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Up to 7 years
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Secondary outcome [26]
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Ophthalmological Examination as Appropriate for Age
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Assessment method [26]
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Timepoint [26]
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Up to 7 years
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Secondary outcome [27]
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Plasma Concentration of Risdiplam and Its Metabolites to Characterize the PK Profile
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Assessment method [27]
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Timepoint [27]
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Up to 7 years
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Eligibility
Key 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
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Minimum age
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Maximum age
6
Weeks
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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
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Study design
Purpose of the study
Treatment
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Allocation to intervention
N/A
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Active, not recruiting
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
7/08/2019
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
31/03/2027
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Actual
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Sample size
Target
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Accrual to date
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Final
26
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Recruitment in Australia
Recruitment state(s)
NSW
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Recruitment hospital [1]
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Sydney Children's Hospital; CENTRE FOR CHILD HEALTH RESEARCH & INNOVATION (CHeRI) - Randwick
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Recruitment postcode(s) [1]
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2031 - Randwick
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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Florida
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Country [2]
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Belgium
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State/province [2]
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Liège
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Country [3]
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Brazil
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State/province [3]
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SP
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Country [4]
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Poland
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State/province [4]
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Gda?sk
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Country [5]
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Russian Federation
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State/province [5]
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Moskovskaja Oblast
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Country [6]
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Taiwan
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State/province [6]
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Kaohsiung
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Hoffmann-La Roche
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
A global study of oral risdiplam in pre-symptomatic participants with spinal muscular atrophy
(SMA).
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Trial website
https://clinicaltrials.gov/ct2/show/NCT03779334
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Clinical Trials
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Address
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Hoffmann-La Roche
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT03779334
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