Characterization of New Phenotypes of Patients with Spinal Muscular Atrophy Treated with SMN Restoring Therapy

Not Applicable

Recruiting

• Conditions: Spinal Muscular Atrophy
• Interventions: Other: evaluation of muscle function; Other: First-line cognitive assessment; Other: second-line cognitive assessment; Other: Cardiac evaluation; Radiation: MRI; Other: Assessment of activity and muscle fatigue; Other: Assessment of bulbar function; Other: Evaluation of body composition and metabolism; Other: Questionnaires; Biological: Biocollection; Other: Skinfold measurement

• Registration Number: NCT06321965
• Lead Sponsor: Hospices Civils de Lyon

Brief Summary

With the advent of new treatments for ASI, new phenotypes are emerging. The investigators propose to describe these new phenotypes by prospectively following children with ASI of all types treated with TRS and aged under 16 for 2 years.

The investigators also propose to evaluate potential assessment tools to determine whether they are relevant for monitoring this population, either routinely or for future clinical trials. The investigators also aim to collect the total costs associated with ASI in order to propose a first prospective medico-economic study in France.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2024-02-06
• Study First Submitted QC: 2024-03-14
• Study First Posted: 2024-03-20
• Study Start: 2024-07-24
• Status Verified: 2025-01
• Last Update Submitted: 2025-01-09
• Last Update Posted: 2025-01-13
• Primary Completion: 2028-01-24
• Study Completion: 2028-01-24

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

• Genetically confirmed infantile or juvenile spinal muscular atrophy
• Treated with a therapy that restores SMN protein expression (e.g. nusinersen, risdiplam, onasemnogene abeparvovec)
• Aged 0 to 15 years inclusive
• Informed consent signed by both parent(s)/legal guardian(s) and patient's assent
• Affiliated or beneficiary of a health insurance plan*. * for inclusion in France

Exclusion Criteria

• Other condition likely to interfere significantly with ASI assessment and clearly unrelated to the disease
• Other associated neurological disease
• Current pregnancy or breast-feeding (a pregnancy test will also be performed at inclusion).

Please note that patients with a specific contraindication to MRI (i.e. metallic foreign body, claustrophobia and other reasons determined by the investigators) will be allowed to participate in the study, but MRI will not be performed.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
SMA patient treated with SRT	Assessment of activity and muscle fatigue	Patients aged 0-15 with SMA type 1, 2 or 3, treated with TRS (nusinersen/risdiplam/onasemnogene abeparvovec/other).
SMA patient treated with SRT	Evaluation of body composition and metabolism	Patients aged 0-15 with SMA type 1, 2 or 3, treated with TRS (nusinersen/risdiplam/onasemnogene abeparvovec/other).
SMA patient treated with SRT	Questionnaires	Patients aged 0-15 with SMA type 1, 2 or 3, treated with TRS (nusinersen/risdiplam/onasemnogene abeparvovec/other).
SMA patient treated with SRT	second-line cognitive assessment	Patients aged 0-15 with SMA type 1, 2 or 3, treated with TRS (nusinersen/risdiplam/onasemnogene abeparvovec/other).
SMA patient treated with SRT	First-line cognitive assessment	Patients aged 0-15 with SMA type 1, 2 or 3, treated with TRS (nusinersen/risdiplam/onasemnogene abeparvovec/other).
SMA patient treated with SRT	MRI	Patients aged 0-15 with SMA type 1, 2 or 3, treated with TRS (nusinersen/risdiplam/onasemnogene abeparvovec/other).
SMA patient treated with SRT	Biocollection	Patients aged 0-15 with SMA type 1, 2 or 3, treated with TRS (nusinersen/risdiplam/onasemnogene abeparvovec/other).
SMA patient treated with SRT	evaluation of muscle function	Patients aged 0-15 with SMA type 1, 2 or 3, treated with TRS (nusinersen/risdiplam/onasemnogene abeparvovec/other).
SMA patient treated with SRT	Skinfold measurement	Patients aged 0-15 with SMA type 1, 2 or 3, treated with TRS (nusinersen/risdiplam/onasemnogene abeparvovec/other).
SMA patient treated with SRT	Cardiac evaluation	Patients aged 0-15 with SMA type 1, 2 or 3, treated with TRS (nusinersen/risdiplam/onasemnogene abeparvovec/other).
SMA patient treated with SRT	Assessment of bulbar function	Patients aged 0-15 with SMA type 1, 2 or 3, treated with TRS (nusinersen/risdiplam/onasemnogene abeparvovec/other).

Primary Outcome Measures

Name	Time	Method
Markers of disease progression and description of different phenotypes, at : muscular and functional	Every 6 months from inclusion (Day 0, Month 6, Month 12, Month 18, Month 24)	Motor function and muscle strength: Trajectory of mean score between inclusion and M24: Myogrip (≥ 6 years), Myopinch (≥ 6 years)
Markers of disease progression and description of different phenotypes, at Orthopaedic level	at Day 0, Month 24+/- Month 6, Month 12, Month 18	Clinical and pelvic radiography: Proportion of patients with hip eccentricity (\>10% on Reimers index) at Day 0 and Month 24
Markers of disease progression and description of different phenotypes, at the cognitive level: SRS-2 (Social Responsiveness Scale, Second Edition)	At Day 0 and Month 18	SRS measures social ability of children from 2 years to 18 years old. It is used primarily with individuals with Autism Spectrum Disorder (ASD), family members of individuals with ASD, and others who have social impairments. Parent or teacher questionnaire (65 items on a 4-point Likert scale). High scores are associated with more severe social impairments.; Raw total scores are converted to gender-normed T scores; SRS-2 total T-scoring: * Less than or equal to 59 = Within normal limits (generally not associated with ASD); * Between 60-65 = Mild range; * Between 66-75 = Moderate range; * Greater than or equal to 76 = Severe range (strongly associated with clinical diagnosis of ASD)
Markers of disease progression and description of different phenotypes, at the brain level	At Day 0	Cerebral MRI : Proportion of patients with : * Posterior fossa anomaly; * Midline anomaly; * White matter anomaly; * Cortical anomaly; * Basal ganglia anomaly; * Ventricular system anomaly; * Pericerebral space abnormality; * Brain MRI abnormality (including above variables)
Markers of disease progression and description of different phenotypes, at : Fatigue	at Day 0, Month 12 and Month 24	Pediatric Quality of Life Inventory (PedsQL) Fatigue Total Score Minimum Value: 0 Maximum Value: 24 Interpretation: A higher score within the range indicates increased fatigue, while a lower score suggests less fatigue.
Markers of disease progression and description of different phenotypes, at the cognitive level: Bayley-4	At Day 0 and Month 18	Bayley-4 Scales of Infant and Toddler Development is standardized developmental assessment tool for determining a child's developmental status at a given age (up to 42 months) BAYLEY-4 assess development in children of 1-42 months old in 5 domains: cognition, motor, language, socio-emotional, and adaptive behavior.; The Bayley-4 raw scores from 0-84 for the receptive communication subtest, 0-74 for the expressive communication subtest a higher score denotes a better outcome. The Bayley-4 standard score norms are converted to percentiles from \<0.1 to \>99.9 for the language
Markers of disease progression and description of different phenotypes, at the cognitive level: Conners-3	At Day 0 and Month 18	- CONNERS-3 : 108-item hetero-questionnaire to assess the presence of symptoms of inattention, hyperactivity, impulsivity and other frequently associated disorders in children and adolescents aged 6 to 18. Symptoms are rated on a Likert scale with severity ratings from 0 (not at all/never) to 3 (very much/ very frequently). The Conners t-score range from 0 - 100. The higher the number, the worse the outcome
Markers of disease progression and description of different phenotypes, at the cognitive level: M-CHAT-R (Modified Checklist for Autism in Toddlers)	At Day 0 and Month 18	The Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R) is a screener that will ask a series of 20 questions about the child's behavior.; To score the M-CHAT-R, we add up the number of at-risk responses, and follow the algorithm below: LOW RISK: Total score between 0 and 2; MEDIUM RISK: Total score between 3 and 7; HIGH RISK: Total score between 8 and 20
Markers of disease progression and description of different phenotypes, at the cognitive level: Vineland-II	At Month 1	Vineland II Adaptive Behaviour scales (VABS) total mean score and subscale mean scores.; Standardized questionnaire filled by the Neupsy during an interview with the parents or the patient himself if possible. 5 domains. Maximum score 160, minimum score 20, mean score 100, standard deviation 15
Markers of disease progression and description of different phenotypes, at the cognitive level: BRIEF (Behavioral Rating Inventory of Executive Function)	At Day 0 and Month 18	BRIEF provides scores that are used to evaluate different aspects of executive function. The scores are typically presented in various subscales, each focusing on a specific domain of executive function.; composite T-score for overall developmental function equal to or greater than 65 (-1.5 SD); The " composite T-score for overall developmental function equal to or greater than 65 (-1.5 SD)" indicates that a T-score composite for the overall developmental function is considered elevated or clinically significant if it equals or exceeds 65, which is 1.5 standard deviations above the mean in a standardized population. Higher scores on the BRIEF suggest greater difficulties in executive functioning, with a T-score of 65 or above indicating a higher level of impairment or challenges in this domain.
Markers of disease progression and description of different phenotypes, at respiratory level: Respiratory function tests (≥ 6 years)	at Day 0, Month 12, Month 24	Evolutionary trajectory: Evolution of Inspiratory Vital Capacity in Different Positions (% of Theoretical). This measure assesses changes over time in the percentage of theoretical inspiratory vital capacity achieved while standing or sitting and while lying down. This outcome provides valuable information about respiratory muscle function and potential changes in the ability to generate inspiratory volumes in different body positions.
Markers of disease progression and description of different phenotypes, at the cognitive level: CELF-5 (Language and communication assessment battery)	At Day 0 and Month 18	Standard Score: This score are derived from the total raw scores for each test and are on a normalized score scale that has a mean of 10 and a standard deviation (SD) of 3; The mean score is 100, with a standard deviation of 15, meaning: that standard scores between 85-115 are within the normal range. Score Mild: 70-85, Moderate: 55-70, Severe: 55 and lower
Markers of disease progression and description of different phenotypes, at the cognitive level: PVSE (Basic visuo-spatial perception)	At Day 0 and Month 18	- Proportion of patients with overall score: * \< OL_inf; * OL_inf ≤ x \< Q1; * Q1 ≤ x \< M; * M ≤ x \< Q3; * Q3 ≤ x \< Q3; * ≥ OL sup
Markers of disease progression and description of different phenotypes, at metabolic level :	Food survey at Month 6, Month 24	Food survey: average food intake
Markers of disease progression and description of different phenotypes, at In terms of quality of life and autonomy	HUI-2, generic PedsQL and neuromuscular module at Day 0, Month 6, Month 12, Month 18 and Month 24	HUI2 classification system consists of attributes (domains) of health to 6 levels of functional ability/disability within each attribute. For each attribute, singleattribute utility functions range from 0.00 for highly disabled (deaf) to 1.00 Score total : 0 - 1
Markers of disease progression and description of different phenotypes, at respiratory level : Chest/head circumference ratio (PT/PC ratio) (up to 3 years)	at Day 0, Month 6, Month 12, Month 18 and Month 24	Outcome measure related to hospitalizations in the context is "Proportion of Patients with Escalation of Respiratory Assistance." This measure assesses the percentage of patients who experienced an escalation in respiratory support during their hospital stay, encompassing variables such as increased settings on home machines, use of resuscitative NIV, or intubation. This outcome provides critical insights into the respiratory management and support needs of patients during their hospitalizations.
Markers of disease progression and description of different phenotypes, at respiratory level : O2 saturation and nocturnal TcPCO2	at Day 0, Month 12, Month 24	Evolution trajectory: This measure focuses on the percentage of children experiencing elevated levels of transcutaneous carbon dioxide (TcPCO2), specifically defined as time spent with TcPCO2 levels exceeding 50mmHg. This outcome is crucial in assessing the severity of respiratory compromise and may guide interventions to address and manage hypercapnia in the pediatric population.
Markers of disease progression and description of different phenotypes, at bulbar level (Evaluation of dysphagia and dysarthria): NdSSS (Neuromuscular Disease Swallowing Status Scale).	At Day 0, Month 6, Month 12, Month 18, Month 24	An 8-stage Neuromuscular Disease Swallowing Status Scale (NdSSS) Positive if the level on the NdSSS scale is less than or equal to 7
Markers of disease progression and description of different phenotypes, at the cognitive level: EQ (Empathy quotient), AQ (Autism Quotient)	At Day 0 and Month 18	Evaluation of the French Version of Screening Questionnaires for Autism and Asperger Syndrome: Autism Spectrum Quotient (AQ) Empathy Quotient (EQ) EQ is a 40-item questionnaire designed to measure empathy for patients aged 11 and above. The maximum score for this questionnaire is 80.; Threshold score: ↓30 . Scores of 30 or less indicate a lack of empathy common in people with Autism.; AQ comprises 50 questions, with 5 groups of 10 questions assessing imagination, social skills, attention switching, attention to detail and communication skills. Each of these items scores 1 point if the respondent records abnormal or autistic like behaviour. The minimum score on the AQ is 0 and the maximum 50 with high scores indicating high autistic traits.
Markers of disease progression and description of different phenotypes, at metabolic level : fractures	at Day 0, Month 6, Month 12, Month 18, Month 24	Number of fractures by location and mechanism
Markers of disease progression at respiratory level	points (Day 0, between Day 0-Month 12, between Month 12 and Month 24)	Evolutionary trajectory : Proportion of patients with central sleep apnea syndrome Proportion of patients with obstructive sleep apnea syndrome Proportion of patients with alveolar hypoventilation syndrome
Markers of disease progression and description of different phenotypes, at the level of Characteristics at inclusion : patient gender	At Day 0	Proportion of male patients
Markers of disease progression and description of different phenotypes, at the level of Characteristics at inclusion: SMA TYPE	At Day 0	Proportion of patients by type of SMA (1, 2, 3) and by treatment
Markers of disease progression and description of different phenotypes, at Cardiology level	At Day 0 +/- Month 12, Month 24	Electrocardiogram (ECG): An abnormal ECG, with proportion for each type of abnormality Holter-ECG: An abnormal Holter-ECG, with proportion for each type of abnormality Echocardiography (only if troponin anomaly): Abnormal echocardiography, with proportions for each type of abnormality
Markers of disease progression and description of different phenotypes, at metabolic level : Anthropometric measurement trends	Anthropometric measurements at Day 0, Month 6, Month 12, Month 18, Month 24	Anthropometric measurements may be used to monitor growth and nutritional status.; Outcome of tracking these measurements could be the identification of trends related to weight gain and muscle mass development. Assessing changes in weight and body composition over time can provide valuable insights into the impact of SMA on physical development, guide nutritional interventions, and help healthcare providers tailor supportive care to address the unique needs of children with SMA
Markers of disease progression and description of different phenotypes, at metabolic level : renal ultrasound	at Month 6	Proportion of patients with abnormal renal ultrasound
Markers of disease progression and description of different phenotypes, at metabolic level : Absorptiometry (DXA)	at Month 6	DXA measurement will be performed to assess patient's body composition.; Average values + SD (Standard Deviation): Lean mass and fat mass (kg) with deficit or excess of lean mass and fat mass (%) Total bone mineral content (g) Bone mineral density (z-score) at the spine, femoral neck, and distal femur
Markers of disease progression and description of different phenotypes, at metabolic level: Calorimetry	at Month 6	Potential outcome of using this device is the accurate measurement of Resting Energy Expenditure (REE). This information can be particularly important in managing the nutritional needs of individuals with SMA, helping healthcare providers optimize dietary plans to meet the specific energy requirements of patients dealing with this neuromuscular disorder. Resting Energy Expenditure (REE).
Markers of disease progression and description of different phenotypes, at metabolic level : Impedancemetry	at Month 6 and Month 24	Average +SD values of Impedancemetry results
Markers of disease progression and description of different phenotypes, at biological analysis	At Day 0, Month 6, Month 12, Month 18, Month 24	Proportion of patients with biological abnormalities for each parameter: Blood/platelet count: Hb, leukocytes, platelets, ASAT, ALAT, GGT, PAL, TP, Sodium, potassium, bicarbonates, calcium, phosphorus, creatinine, glucose, proteins, urea, cystatin C, Troponin, BNP, NT-pro-BNP, Iron, Ferritin, copper, zinc, selenium, magnesium, Vitamins A,C,D,E, B12, Folates, Albumin, prealbumin, retinol-binding protein, ultra-sensitive C-reactive protein (CRP), FibroTest, PTH (parathormone) For these patients : % above normal; * above; * or below
Markers of disease progression and description of different phenotypes, at metabolic level : Fibroscan	At Month 6 and Month 24	The FibroScan result is reported in kilopascals (kPa), representing the liver stiffness. The numerical value indicates the degree of stiffness, which correlates with the extent of liver fibrosis. The interpretation of the FibroScan score is as follows: Low Stiffness (Low kPa): Indicates a healthier, less fibrotic liver.; Intermediate Stiffness: May suggest some degree of fibrosis, and further evaluation may be needed to determine the extent.; High Stiffness (High kPa): Indicates more advanced liver fibrosis or cirrhosis.
Markers of disease progression and description of different phenotypes, at respiratory level : Chest/head circumference ratio (PT/PC ratio)	at Day 0, Month 6, Month 12, Month 18 and Month 24	Evolution of the PT/PC ratio trajectory
Markers of disease progression and description of different phenotypes, at the level of Characteristics at inclusion: age of patient	At Day 0	+ SD: Age, age of onset of symptoms, age at start of treatment
Markers of disease progression and description of different phenotypes, at bulbar level (Evaluation of dysphagia and dysarthria): DDD-pNMD (Diagnostic list for Dysphagia and Dysarthria in pediatric NeuroMuscular Disorders)	At Day 0, Month 6, Month 12, Month 18, Month 24	The DDD-pNMD is a scale where items are scored by a Speech-Language Therapist (SLT) on a 4-point scale, ranging from 0 (normal) to 3 (severe problems/impossible). The scale is designed to assess various aspects of swallowing and speech in children with neurological conditions.; The DDD-pNMD screening is positive if score greater than or equal to 1.
Markers of disease progression and description of different phenotypes, at the level of Characteristics at inclusion: number of copy	At Day 0	SMN2 copy number distribution
Markers of disease progression and description of different phenotypes, at the level of Characteristics at inclusion: treatment	At Day 0	Calculate the proportion of patients who underwent treatment changes, expressed as a percentage of the total study population.This measure provides insights into the adaptability and potential issues with the current therapeutic approach or side effects.; A higher proportion of treatment changes may prompt further investigation and adjustments in treatment protocols, aiming to enhance overall patient outcomes.; This focused outcome measure aims to capture the essence of treatment dynamics within the SMA patient population.

Trial Locations

Locations (8)

Pediatric Rehabilitation Service - L'Escale Mother and Child Hospital; 🇫🇷 Bron, Rhone, France

CHRU of Brest; 🇫🇷 Brest, France

Pediatric Neurology and Resuscitation Raymond-Poincare Hospital; 🇫🇷 Garche, France

Pediatric Neurology Swynghedauw Hospital; 🇫🇷 Lille, France

Marseille University Hospital - Timone Hospital Department of Pediatric Neurology - Specialized Pediatrics and Child Medicine; 🇫🇷 Marseille, France

I-Motion Pediatric Clinical Trial Platform Armand Trousseau Hospital; 🇫🇷 Paris, France

Hautepierre Hospital - Mother and Child Hospital; 🇫🇷 Strasbourg, France

Department of Pediatrics - Neurology and Infectious Diseases Toulouse University Hospital - Children's Hospital; 🇫🇷 Toulouse, France