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Clinical Trial Details — Status: Active, not recruiting

Administrative data

NCT number NCT03779334
Other study ID # BN40703
Secondary ID 2018-002087-1220
Status Active, not recruiting
Phase Phase 2
First received
Last updated
Start date August 7, 2019
Est. completion date March 31, 2027

Study information

Verified date June 2024
Source Hoffmann-La Roche
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

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


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.


Recruitment information / eligibility

Status Active, not recruiting
Enrollment 26
Est. completion date March 31, 2027
Est. primary completion date February 20, 2023
Accepts healthy volunteers No
Gender All
Age group 1 Day to 6 Weeks
Eligibility 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 Design


Related Conditions & MeSH terms


Intervention

Drug:
Risdiplam
Risdiplam will be administered orally.

Locations

Country Name City State
Australia Sydney Children's Hospital; CENTRE FOR CHILD HEALTH RESEARCH & INNOVATION (CHeRI) Randwick New South Wales
Belgium Chr de La Citadelle Liège
Brazil Hospital das Clinicas - FMUSP_X; Neurologia Sao Paulo SP
Poland Szpital Gdanskiego Uniwersytetu Medycznego; Clinic of developmental neurology Gda?sk
Russian Federation Russian Children Neuromuscular Center of Veltischev Moscow Moskovskaja Oblast
Taiwan Kaohsiung Medical University Chung-Ho Hospital; Pediatric Neurology Kaohsiung
United States Nemours Children's Hospital Orlando Florida

Sponsors (1)

Lead Sponsor Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Brazil,  Poland,  Russian Federation,  Taiwan, 

Outcome

Type Measure Description Time frame Safety issue
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. At Month 12
Secondary Percentage of Participants Developing Clinically Manifested SMA At Month 12 and 24
Secondary Time to Permanent Ventilation and/or Death Up to 7 years
Secondary Percentage of Participants Who Are Alive Without Permanent Ventilation At Month 12 and 24
Secondary Percentage of Participants Alive At Month 12 and 24
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 At Month 12 and 24
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. At Month 12
Secondary Percentage of Participants Sitting Without Support for 5 Seconds Assessed with BSID-III Gross Motor Scale At Month 24
Secondary Percentage of Participants Sitting Without Support for 30 Seconds Assessed with BSID-III Gross Motor Scale At Month 12 and 24
Secondary Percentage of Participants Standing for at Least 3 Seconds Assessed with BSID-III Gross Motor Scale At Month 24
Secondary Percentage of Participants Walking (Takes at Least 3 Steps) Assessed with BSID-III Gross Motor Scale At Month 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 At Month 24 and 42
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. Baseline, Month 12
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. At Month 12
Secondary Percentage of Participants Who Meet CHOP INTEND Stopping Criteria at Any Point Up to Month 24
Secondary Change From Baseline in the Hammersmith Functional Motor Scale Expanded (HFMSE) Score At Month 60
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) At Month 12, 24, 36, 48 and 60
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) At Month 12 and 24
Secondary 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
Secondary Change From Baseline Percentiles for Head Circumference- For-age At Month 12 and 24
Secondary Change From Baseline in Chest Circumference At Month 12 and 24
Secondary Ratio Between Chest and Head Circumferences At Month 12 and 24
Secondary Percentage of Participants With the Ability to Swallow and to Feed Orally At Month 12, 24, 36, 48 and 60
Secondary Change From Baseline in Compound Muscle Action Potential (CMAP) Amplitude Measured by CMAP At Month 12 and 24
Secondary Measurement of Pharmacodynamic Marker Levels in Blood Day 1, 56, 196, 364, 728 and at early withdrawal
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 Up to 7 years
Secondary Ophthalmological Examination as Appropriate for Age Up to 7 years
Secondary Plasma Concentration of Risdiplam and Its Metabolites to Characterize the PK Profile Up to 7 years
See also
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