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

Overview

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.

Interventions

• Other evaluation of muscle function
  Myogrip (≥ 6 years): precise dynamometric measurement of gripping force, measuring force in Newton up to 90kg with 0.01kg resolution. It's evaluated at D0, M6, M12, M18, and M24 Myopinch (≥ 6 years) : measure thumb-index force up to 15 kg with a resolution of 0.001 kg using a precision sensor equipped with two steel distance blades. It's evaluated at D0, M6, M12, M18, and M24
• Other First-line cognitive assessment
  Vineland-II (All patients) : is a scale for assessing adaptive behaviors. will be carried out during the telephone call at M1/V2. All tests are evaluated at D0, and M18 : Bayley-4 language part (\< 42 months) PVSE (≥ 4 years) CELF-5 (≥ 5 years) Conners-3 (≥ 6 years) AQ (≥ 4 years), EQ (≥ 11 years) M-CHAT-R (\< 4 years) : SRS-2 (≥ 2 years)
• Other second-line cognitive assessment
  In the event of positive cognitive screening at D0 or M18, a second-line cognitive assessment will be carried out at a subsequent visit. A list of tests is proposed below, but will be adapted according to the tests available at each center. * EVALO BB (0-2 years) or EVALO (2-6 years) or full CELF-5 (5-18 years) following positive screening in the communication domain of first-line tests (Vineland II communication domain, Bayley 4, CELF-5 pragmatic profile) * FEE and DSM-5 diagnostic criteria fo
• Other Cardiac evaluation
  All tests are evaluated at D0, M12, and M24 : Electrocardiogram (ECG) : This examination will be carried out in accordance with the 12 leads recording the following parameters: verification of sinus rhythm, P wave, PR interval, QRS complex (interval), ST segment, T wave, QT complex, heart rate. Cardiac ultrasound: Non-invasive ultrasound will focus on the following parameters measured from 2-dimensional images, to look for cardiomyopathy and/or structural abnormality: * end-diastolic/end-syst
• Radiation MRI
  Cerebral MRI : Performed at D0, only for patients with ASI type 1 ≥ 6 years, or younger patients for whom the investigator considers that the examination can be performed without sedation or general anesthesia. It will include sequences: * 3D T1, gradient echo, 1.1 mm voxel, sagittal acquisition * axial T2, spin-echo, slice thickness 4 mm * 3D FLAIR, spin-echo, 1 mm voxel, sagittal acquisition Muscular MRI: performed at V1/J0, and V6/M24. The examination will include water-fat imaging (Dixon) i
• Other Assessment of activity and muscle fatigue
  Syde® : evaluated at D0, M6, M12, M24. Patients aged 2 and over will receive the Syde® wearable device to collect their daily activities. Muscular endurance tests (≥ 6 years) : evaluated at D0, M12, M24 ( only one of 3 tests based on motor function level) oESNHPT : In this test, patients are asked to walk a 10-meter path. oESBBT : In this test, patients have to move 10 blocks over a partition. oESWT: In this test, patients must repeatedly place and remove 9 sticks in 9 holes. PedsQL Fatigue (≥
• Other Assessment of bulbar function
  DDD-pNMD (≥ 2 years) : evaluated at D0, M6, M12, M18, and M24, is a list of 9 questions used by doctors to screen for dysphagia and dysarthria. NdSSS (All Patients) : evaluated at D0, M6, M12, M18, and M24, is an 8-level scale for assessing swallowing. TOMASS-c : (≥ 4 years of age, in patients able to eat solids safely, after assessment of the risk of a false route by the speech therapist): this is a score designed to assess mastication when eating a cracker. Age-dependent standards exist for
• Other Evaluation of body composition and metabolism
  Food survey : The dietary survey questionnaire will be sent to parents at D0 and M18. Parents will be asked to complete it for 3 days before the M6 and M24. Bioelectrical impedancemetry: Evaluated at M6 and M24. Renal ultrasound: Evaluated at M6, is a non-invasive examination that analyzes the appearance of the kidney and urinary tract. Dual-energy X-ray absorptiometry (DXA) : Evaluated at M6, it measures body composition using spectral imaging, including fat mass, lean mass and bone mineral d
• Other Questionnaires
  SMAIS : The questionnaire has been developed specifically for ASI. At D0, M6, M12, M18 and M24. HUI2 : specializes in preference-based measures of health-related quality of life. At D0, M6, M12, M18 and M24. Peds QL : is a modular instrument designed to measure health-related quality of life and disease-specific symptoms. At D0, M6, M12, M18 and M24. Neuromuscular module : 17 disease-related items. It is evaluated at D0, M6, M12, M18 and M24. Family impact module : It measures parents' repor
• Biological Biocollection
  A blood bio collection (optional) will be offered to patients at D0, M6 , M12, M18, M24. Patients receiving intrathecal injections will also be offered the opportunity to participate in a CSF (cerebrospinal fluid) biocollection (optional).

Primary outcome measures

• Markers of disease progression and description of different phenotypes, at : muscular and functional [Time frame: Every 6 months from inclusion (Day 0, Month6, Month12, Month18, Month24)]
• Markers of disease progression and description of different phenotypes, at : muscular and functional [Time frame: Every 6 months from inclusion (Day 0, Month 6, Month 12, Month 18, Month 24)]
• Markers of disease progression and description of different phenotypes, at : muscular and functional [Time frame: Every 6 months from inclusion (Day 0, Month 6, Month 12, Month 18, Month 24)]
• Markers of disease progression and description of different phenotypes, at : muscular and functional [Time frame: Every 6 months from inclusion (Day 0, Month 6, Month 12, Month 18, Month 24)]
• Markers of disease progression and description of different phenotypes, at : muscular and functional [Time frame: Every 6 months from inclusion (Day 0, Month 6, Month 12, Month 18, Month 24)]
• Markers of disease progression and description of different phenotypes, at : Fatigue [Time frame: Syde: At Day 0, Month 6, Month 12 and Month 24]
• Markers of disease progression and description of different phenotypes, at : Fatigue [Time frame: Endurance test (≥ 6 years)]
• Markers of disease progression and description of different phenotypes, at : Fatigue [Time frame: at Day 0, Month 12 and Month 24]
• Markers of disease progression and description of different phenotypes, at Orthopaedic level [Time frame: Joint amplitudes at Day 0, Month 6, Month 12 and Month 24]
• Markers of disease progression and description of different phenotypes, at Orthopaedic level [Time frame: Clinic and spinal radiography at Day 0, Month 12,Month 18, Month 24]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Other

Study locations

France · 8 centers

• Pediatric Rehabilitation Service - L'Escale Mother and Child Hospital — Bron
• CHRU of Brest — Brest
• Pediatric Neurology and Resuscitation Raymond-Poincare Hospital — Garche
• Pediatric Neurology Swynghedauw Hospital — Lille
• Marseille University Hospital - Timone Hospital Department of Pediatric Neurology - Specia — Marseille
• I-Motion Pediatric Clinical Trial Platform Armand Trousseau Hospital — Paris
• Hautepierre Hospital - Mother and Child Hospital — Strasbourg
• Department of Pediatrics - Neurology and Infectious Diseases Toulouse University Hospital — Toulouse

Identifiers

NCT: NCT06321965 · 69HCL22_0599

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗