Clinical trial NCT03779334: A Study of Risdiplam in Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy
Official title: An Open-Label Study of Risdiplam in Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Muscular Atrophy, Spinal
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2018-12-19
Enrollment: 26
Sex: ALL
Minimum age (years): 1
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Open-label, single arm
Primary purpose: TREATMENT

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

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.

Eligibility 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

Primary outcomes:
measure: 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
timeFrame: At Month 12
Secondary outcomes:
measure: Percentage of Participants Developing Clinically Manifested SMA
timeFrame: At Month 12 and 24
measure: Time to Permanent Ventilation and/or Death
timeFrame: Up to 7 years
measure: Percentage of Participants Who Are Alive Without Permanent Ventilation
timeFrame: At Month 12 and 24
measure: Percentage of Participants Alive
timeFrame: At Month 12 and 24
measure: Percentage of Participants Who Achieve the Attainment Level of the Motor Milestones as Assessed in the Hammersmith Infant Neurological Examination-2 (HINE-2)
timeFrame: At Month 12 and 24
measure: Percentage of Participants With Two Copies of the SMN2 Gene Sitting Without Support for 5 Seconds (Independent of the CMAP Value at Baseline).
timeFrame: At Month 12
measure: Percentage of Participants Sitting Without Support for 5 Seconds
timeFrame: At Month 24
measure: Percentage of Participants Sitting Without Support for 30 Seconds
timeFrame: At Month 12 and 24
measure: Percentage of Participants Standing for at Least 3 Seconds
timeFrame: At Month 24
measure: Percentage of Participants Walking (Takes at Least 3 Steps)
timeFrame: At Month 24
measure: 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
timeFrame: At Month 24 and 42
measure: Change From Baseline Score in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Motor Function Scale at Month 12
timeFrame: Baseline, Month 12
measure: 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
timeFrame: At Month 12
measure: Percentage of Participants Who Meet CHOP INTEND Stopping Criteria at Any Point
timeFrame: Up to Month 24
measure: Change From Baseline in the Hammersmith Functional Motor Scale Expanded (HFMSE) Score
timeFrame: At Month 60
measure: Number and Percentage of Participants Within 3rd Percentile of Normal Range for Weight-for-Age, Length/Height-for-Age and Weight-for-Length/Height
timeFrame: At Month 12, 24, 36, 48 and 60
measure: Number and Percentage of Participants Within 3rd Percentile of Normal Range for Head Circumference-for-age
timeFrame: At Month 12 and 24
measure: Change From Baseline Percentiles for Weight-for-age, Length/Height-for-age, and weight-for- Length/Height
timeFrame: At Month 12, 24, 36, 48 and 60
measure: Change From Baseline Percentiles for Head Circumference- For-age
timeFrame: At Month 12 and 24
measure: Change From Baseline in Chest Circumference
timeFrame: At Month 12 and 24
measure: Ratio Between Chest and Head Circumferences
timeFrame: At Month 12 and 24
measure: Percentage of Participants With the Ability to Swallow and to Feed Orally
timeFrame: At Month 12, 24, 36, 48 and 60
measure: Change From Baseline in Compound Muscle Action Potential (CMAP) Amplitude
timeFrame: At Month 12 and 24
measure: Measurement of Pharmacodynamic Marker Levels in Blood
timeFrame: Day 1, 56, 196, 364, 728 and at early withdrawal
measure: Percentage of Participants With Adverse Events
timeFrame: Up to 7 years
measure: Ophthalmological Examination as Appropriate for Age
timeFrame: Up to 7 years
measure: Plasma Concentration of Risdiplam and Its Metabolites to Characterize the PK Profile
timeFrame: Up to 7 years
Other outcomes:
Locations:
city: Orlando
country: United States
facility: Nemours Children's Hospital
state: Florida
city: Randwick
country: Australia
facility: Sydney Children's Hospital
state: New South Wales
city: Liège
country: Belgium
facility: Chr de La Citadelle
city: Sao Paulo
country: Brazil
facility: Hospital das Clinicas - FMUSP_X
state: São Paulo
city: Gda?sk
country: Poland
facility: Szpital Gdanskiego Uniwersytetu Medycznego
city: Moscow
country: Russian Federation
facility: Russian Children Neuromuscular Center of Veltischev
state: Moskovskaja Oblast
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: