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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03779334
Recruitment Status : Active, not recruiting
First Posted : December 19, 2018
Last Update Posted : April 4, 2022
Information provided by (Responsible Party):
Hoffmann-La Roche

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

Condition or disease Intervention/treatment Phase
Muscular Atrophy, Spinal Drug: Risdiplam Phase 2

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, for a total treatment duration of at least 5 years for each participant enrolled.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Open-label, single arm
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label Study of Risdiplam in Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy
Actual Study Start Date : August 7, 2019
Estimated Primary Completion Date : June 21, 2023
Estimated Study Completion Date : January 21, 2029

Arm Intervention/treatment
Experimental: Open-label Arm
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.

Primary Outcome Measures :
  1. 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 [ Time Frame: At Month 12 ]
    Sitting is defined as "sits without support for 5 seconds" as assessed in Item 22 of the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) Gross Motor Scale

Secondary Outcome Measures :
  1. Percentage of participants developing clinically manifested SMA [ Time Frame: At Month 12 and 24 ]
  2. Time to permanent ventilation and/or death [ Time Frame: Up to 7 years ]
  3. Percentage of participants who are alive without permanent ventilation [ Time Frame: At Month 12 and 24 ]
  4. Percentage of participants alive [ Time Frame: At Month 12 and 24 ]
  5. Percentage of participants who achieve the attainment level of the motor milestones as assessed in the Hammersmith Infant Neurological Examination-2 (HINE-2) [ Time Frame: At Month 12 and 24 ]
    HINE-2 assessment includes head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking

  6. Percentage of participants with two copies of the SMN2 gene sitting without support for 5 seconds (independent of the CMAP value at baseline). [ Time Frame: At Month 12 ]
    Assessed with BSID-III Gross Motor Scale.

  7. Percentage of participants sitting without support for 5 seconds [ Time Frame: At Month 24 ]
    Assessed with BSID-III Gross Motor Scale

  8. Percentage of participants sitting without support for 30 seconds [ Time Frame: At Month 12 and 24 ]
    Assessed with BSID-III Gross Motor Scale

  9. Percentage of participants standing for at least 3 seconds [ Time Frame: At Month 24 ]
    Assessed with BSID-III Gross Motor Scale

  10. Percentage of participants walking (takes at least 3 steps) [ Time Frame: At Month 24 ]
    Assessed with BSID-III Gross Motor Scale

  11. 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 [ Time Frame: At Month 24 and 42 ]
    Assessed through BSID-III Gross Motor Scale

  12. Change from baseline score in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) motor function scale [ Time Frame: At Month 12 ]
  13. 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 [ Time Frame: At Month 12 ]
  14. Percentage of participants who meet CHOP INTEND stopping criteria at any point [ Time Frame: Up to Month 24 ]
  15. Change from baseline in the Hammersmith Functional Motor Scale Expanded (HFMSE) score [ Time Frame: At Month 60 ]
  16. Number and percentage of participants within 3rd percentile of normal range for weight-for-age, length/height-for-age and weight-for-length/height [ Time Frame: At Month 12, 24, 36, 48 and 60 ]
    Based on the WHO Child Growth Standards (WHO 2019)

  17. Number and percentage of participants within 3rd percentile of normal range for head circumference-for-age [ Time Frame: At Month 12 and 24 ]
    Based on the WHO Child Growth Standards (WHO 2019)

  18. 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 ]
  19. Change from baseline percentiles for head circumference- for-age [ Time Frame: At Month 12 and 24 ]
  20. Change from baseline in chest circumference [ Time Frame: At Month 12 and 24 ]
  21. Ratio between chest and head circumferences [ Time Frame: At Month 12 and 24 ]
  22. Percentage of participants with the ability to swallow and to feed orally [ Time Frame: At Month 12, 24, 36, 48 and 60 ]
  23. Change from baseline in compound muscle action potential (CMAP) amplitude [ Time Frame: At Month 12 and 24 ]
    Measured by CMAP

  24. Measurement of pharmacodynamic marker levels in blood [ Time Frame: Day 1, 56, 196, 364, 728 and at early withdrawal ]
  25. Percentage of participants with adverse events [ Time Frame: 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

  26. Ophthalmological examination as appropriate for age [ Time Frame: Up to 7 years ]
  27. Plasma concentration of risdiplam and its metabolites to characterize the PK profile [ Time Frame: Up to 7 years ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   up to 6 Weeks   (Child)
Sexes Eligible for Study:   All
Accepts 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03779334

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United States, Florida
Nemours Children's Hospital
Orlando, Florida, United States, 32827
United States, New York
Columbia University Medical Center
New York, New York, United States, 10032
United States, Tennessee
St. Jude Children'S Research Hospital
Memphis, Tennessee, United States, 38105
Australia, New South Wales
Randwick, New South Wales, Australia, 2031
Chr de La Citadelle
Liege, Belgium, 3500
Hospital das Clinicas - UFMG; Pediatria
Belo Horizonte, MG, Brazil, 30130-100
Hospital das Clinicas - FMUSP_X; Neurologia
Sao Paulo, SP, Brazil, 05403-000
Canada, Ontario
London Health Sciences Centre; Children's Hospital; Pediatrics
London, Ontario, Canada, N6A 5W9
Children's Hospital of Fudan University
Shanghai, China, 201102
IRCCS Ospedale Pediatrico Bambino Gesù; U.O. Malattie Neuromuscolari e Neurodegenerative
Roma, Lazio, Italy, 00165
Szpital Gdanskiego Uniwersytetu Medycznego; Clinic of developmental neurology
Gdańsk, Poland, 80-952
The Children's Memorial Health Institute Department of Neurology and Epileptology
Warszawa, Poland, 04-730
Russian Federation
Russian Children Neuromuscular Center of Veltischev
Moscow, Moskovskaja Oblast, Russian Federation, 125412
Saudi Arabia
King Faisal Specialist Hospital and Research Centre Building
Riyadh, Saudi Arabia, 11211
Kaohsiung Medical University Chung-Ho Hospital; Pediatric Neurology
Kaohsiung, Taiwan, 807
Sponsors and Collaborators
Hoffmann-La Roche
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Study Director: Clinical Trials Hoffmann-La Roche
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Responsible Party: Hoffmann-La Roche Identifier: NCT03779334    
Other Study ID Numbers: BN40703
2018-002087-12 ( EudraCT Number )
First Posted: December 19, 2018    Key Record Dates
Last Update Posted: April 4, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform ( Further details on Roche's criteria for eligible studies are available here ( For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Muscular Atrophy
Muscular Atrophy, Spinal
Spinal Cord Diseases
Pathological Conditions, Anatomical
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Central Nervous System Diseases
Motor Neuron Disease
Neurodegenerative Diseases
Neuromuscular Diseases
Neuromuscular Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs