A Study of Risdiplam in Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy (Rainbowfish)

An Open-Label Study of Risdiplam in Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy

A global study of oral risdiplam in pre-symptomatic participants with spinal muscular atrophy (SMA).

Study Overview

• Status: Active, not recruiting
• Conditions: Muscular Atrophy, Spinal
• Intervention / Treatment: Drug: Risdiplam

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.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Randwick, New South Wales, Australia, 2031
      • Sydney Children's Hospital
• Belgium
  • Liège, Belgium, 4000
    • CHR de la Citadelle
• Brazil
  • São Paulo
    • São Paulo, São Paulo, Brazil, 05403-000
      • Hospital das Clinicas - FMUSP_X
• Poland
  • Gda?sk, Poland, 80-952
    • Szpital Gdanskiego Uniwersytetu Medycznego
• Russia
  • Moscow Oblast
    • Moscow, Moscow Oblast, Russia, 125412
      • Russian Children Neuromuscular Center of Veltischev
• Taiwan
  • Kaohsiung City, Taiwan, 807
    • Kaohsiung Medical University Chung-Ho Hospital
• United States
  • Florida
    • Orlando, Florida, United States, 32837
      • Nemours Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 1 month (Child)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Open-label Risdiplam; Participants will be enrolled to receive risdiplam orally once daily at a dose selected to achieve the targeted exposure range.	Drug: Risdiplam; Risdiplam will be administered orally.; Other Names: Evrysdi

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	At Month 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	HINE-2 assessment includes head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking	At Month 12 and 24
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.	At Month 12
Percentage of Participants Sitting Without Support for 5 Seconds	Assessed with BSID-III Gross Motor Scale	At Month 24
Percentage of Participants Sitting Without Support for 30 Seconds	Assessed with BSID-III Gross Motor Scale	At Month 12 and 24
Percentage of Participants Standing for at Least 3 Seconds	Assessed with BSID-III Gross Motor Scale	At Month 24
Percentage of Participants Walking (Takes at Least 3 Steps)	Assessed with BSID-III Gross Motor Scale	At Month 24
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	At Month 24 and 42
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.	Baseline, Month 12
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.	At Month 12
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	Based on the WHO Child Growth Standards (WHO 2019)	At Month 12, 24, 36, 48 and 60
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)	At Month 12 and 24
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	Measured by CMAP	At Month 12 and 24
Measurement of Pharmacodynamic Marker Levels in Blood		Day 1, 56, 196, 364, 728 and at early withdrawal
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	Up to 7 years
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

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Investigators: Study Director: Clinical Trials, Hoffmann-La Roche

Publications and helpful links

General Publications

• Finkel RS, Servais L, Vlodavets D, Zanoteli E, Mazurkiewicz-Beldzinska M, Jong YJ, Navas-Nazario A, Al-Muhaizea M, Araujo APQC, Nelson L, Wang Y, Jaber B, Gorni K, Kletzl H, Palfreeman L, Rabbia M, Summers D, Gaki E, Wagner KR, Fontoura P, Farrar MA, Bertini E; RAINBOWFISH Study Group. Risdiplam in Presymptomatic Spinal Muscular Atrophy. N Engl J Med. 2025 Aug 14;393(7):671-682. doi: 10.1056/NEJMoa2410120.

Study record dates

Study Major Dates

• Study Start (Actual): August 7, 2019
• Primary Completion (Actual): February 20, 2023
• Study Completion (Estimated): February 28, 2027

Study Registration Dates

• First Submitted: December 17, 2018
• First Submitted That Met QC Criteria: December 17, 2018
• First Posted (Actual): December 19, 2018

Study Record Updates

• Last Update Posted (Actual): April 8, 2026
• Last Update Submitted That Met QC Criteria: April 7, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; Motor Neuron Disease; Muscular Atrophy, Spinal; Physiological Effects of Drugs; Peripheral Nervous System Agents; Neuromuscular Agents; Risdiplam
• Other Study ID Numbers: BN40703; 2018-002087-12 (EudraCT Number); 2023-506009-20-00 (Ctis: EU CT number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: For eligible studies, qualified researchers may request access to individual patient level clinical data. See Roche's commitment to transparency of clinical study information here: https://go.roche.com/data_sharing

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No