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

• ClinicalTrials.gov Identifier: NCT03779334
• Recruitment Status: Active, not recruiting
• First Posted: December 19, 2018
• Results First Posted: March 5, 2024
• Last Update Posted: March 15, 2024
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Study Description

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 (if applicable), for a total treatment duration of at least 5 years for each participant enrolled.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 26 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
• Actual Primary Completion Date: February 20, 2023
• Estimated Study Completion Date: March 31, 2027

Arms and Interventions

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 Name: Evrysdi

Outcome Measures

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 ]
   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 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 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.
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 at Month 12 [ Time Frame: 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.
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 at Month 12 [ Time Frame: 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.
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 ]

Eligibility Criteria

• Ages Eligible for Study: 1 Day to 6 Weeks (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Florida

Nemours Children's Hospital

Orlando, Florida, United States, 32827

Australia, New South Wales

Sydney Children's Hospital; CENTRE FOR CHILD HEALTH RESEARCH & INNOVATION (CHeRI)

Randwick, New South Wales, Australia, 2031

Belgium

Chr de La Citadelle

Liège, Belgium, 4000

Brazil

Hospital das Clinicas - FMUSP_X; Neurologia

Sao Paulo, SP, Brazil, 05403-000

Poland

Szpital Gdanskiego Uniwersytetu Medycznego; Clinic of developmental neurology

Gda?sk, Poland, 80-952

Russian Federation

Russian Children Neuromuscular Center of Veltischev

Moscow, Moskovskaja Oblast, Russian Federation, 125412

Taiwan

Kaohsiung Medical University Chung-Ho Hospital; Pediatric Neurology

Kaohsiung, Taiwan, 807

Sponsors and Collaborators

Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

  Study Documents (Full-Text)

Documents provided by Hoffmann-La Roche:

Study Protocol  [PDF] March 30, 2021

Statistical Analysis Plan  [PDF] May 12, 2021

More Information

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT03779334
• Other Study ID Numbers: BN40703; 2018-002087-12 ( EudraCT Number )
• First Posted: December 19, 2018
• Results First Posted: March 5, 2024
• Last Update Posted: March 15, 2024
• Last Verified: March 2024

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 (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). 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 (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Muscular Atrophy; Muscular Atrophy, Spinal; Atrophy; Pathological Conditions, Anatomical; Neuromuscular Manifestations; Neurologic Manifestations; Nervous System Diseases; Spinal Cord Diseases; Central Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; Neuromuscular Diseases; Risdiplam; Neuromuscular Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs