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

Phase 2Active Not RecruitingNCT03779334

Hoffmann-La Roche26 enrolled

Overview

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

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

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Muscular Atrophy, Spinal

Interventions

RisdiplamDRUG

Risdiplam will be administered orally.

Eligibility

Sex: ALLMin age: 1 DayMax age: 6 Weeks

Medical Language ↔ Plain English

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

Locations (7)

Nemours Children's Hospital

Orlando, Florida, United States

Sydney Children's Hospital

Randwick, New South Wales, Australia

Chr de La Citadelle

Liège, Belgium

Hospital das Clinicas - FMUSP_X

São Paulo, São Paulo, Brazil

Outcomes

Primary Outcomes

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.

Time frame: At Month 12

Secondary Outcomes

Percentage of Participants Developing Clinically Manifested SMA

Time frame: At Month 12 and 24

Time to Permanent Ventilation and/or Death

Time frame: Up to 7 years

Percentage of Participants Who Are Alive Without Permanent Ventilation

Time frame: At Month 12 and 24

Percentage of Participants Alive

Time frame: 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

Data from ClinicalTrials.gov

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Szpital Gdanskiego Uniwersytetu Medycznego

Gda?sk, Poland

Russian Children Neuromuscular Center of Veltischev

Moscow, Moscow Oblast, Russia

Kaohsiung Medical University Chung-Ho Hospital

Kaohsiung City, Taiwan

Time frame: 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.

Time frame: At Month 12

Percentage of Participants Sitting Without Support for 5 Seconds

Assessed with BSID-III Gross Motor Scale

Time frame: At Month 24

Percentage of Participants Sitting Without Support for 30 Seconds

Assessed with BSID-III Gross Motor Scale

Time frame: At Month 12 and 24

Percentage of Participants Standing for at Least 3 Seconds

Assessed with BSID-III Gross Motor Scale

Time frame: At Month 24

Percentage of Participants Walking (Takes at Least 3 Steps)

Assessed with BSID-III Gross Motor Scale

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: At Month 12

Percentage of Participants Who Meet CHOP INTEND Stopping Criteria at Any Point

Time frame: Up to Month 24

Change From Baseline in the Hammersmith Functional Motor Scale Expanded (HFMSE) Score

Time frame: 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)

Time frame: 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)

Time frame: At Month 12 and 24

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

Change From Baseline Percentiles for Head Circumference- For-age

Time frame: At Month 12 and 24

Change From Baseline in Chest Circumference

Time frame: At Month 12 and 24

Ratio Between Chest and Head Circumferences

Time frame: At Month 12 and 24

Percentage of Participants With the Ability to Swallow and to Feed Orally

Time frame: At Month 12, 24, 36, 48 and 60

Change From Baseline in Compound Muscle Action Potential (CMAP) Amplitude

Measured by CMAP

Time frame: At Month 12 and 24

Measurement of Pharmacodynamic Marker Levels in Blood

Time frame: 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

Time frame: Up to 7 years

Ophthalmological Examination as Appropriate for Age

Time frame: Up to 7 years

Plasma Concentration of Risdiplam and Its Metabolites to Characterize the PK Profile

Time frame: Up to 7 years