Clinical trial NCT06157268: The Natural History and Muscle Fatigability of Patients With Congenital Myopathies.
Official title: Trial Readiness and Trial Fitness for Congenital Myopathies: a 2-year Prospective Natural History Study Including a Cross-sectional Study on Muscle Fatigability
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Central Core Disease
Multi-Minicore Disease
Nemaline Myopathy
Centronuclear Myopathy
Keywords: Natural history study
Outcome measures
Congenital myopathy
Muscle disease
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: UMC Utrecht
First posted: 2023-12-05
Enrollment: 100
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: 45 patients will be included in the natural history study and 75 patients in the fatigability study, with some patients in both studies. The participants will be equally divided over three groups (CCD/MmD, NEM, CNM). Patients will be identified through patient databases of the Radboudumc and UMC Utrecht and patient groups. If more than 15/25 patients per group are willing to participate, we will select patients based on age and severity to have a good representation of the entire/complete disease spectrum.

Brief summary: Core myopathies (CCD/MmD), nemaline myopathies (NEM) and centronuclear myopathies (CNM) are three types of rare congenital myopathies. Not much is known about the natural history and no curative treatment is available for these groups. Also patients report fatigability as one of their symptoms. The goal of this observational study is to study the natural history during 24 months to achieve trial readiness and to study the muscle fatigability in CCD/MmD, NEM and CNM.

Detailed description: Rationale: Patients with CCD/MmD, NEM and CNM report symptoms of weakness in the arms and legs. Other symptoms include weakness of the respiratory, facial and swallowing muscles. No treatments are available for congenital myopathies (CM) to slow down or cure the disease. A few type I-II trials have taken place and more are expected. Therefore it is important to reach trial readiness. To create trial readiness, there is a need for natural history study to create a detailed report of the disease course and a selection of the most sensitive clinical and functional outcome measures and biomarkers. Besides muscle weakness, several patients report muscle fatigability. This has not been investigated systematically in CM. The lack of evidence calls for a cross-sectional study assessing muscle fatigability and neuromuscular transmission in CM.

Objectives: i) To assess the natural disease course of CCD/MmD, NEM and CNM during 24 months. ii) To select relevant and sensitive clinical and functional outcome measures and biomarkers. iii) To assess the severity of muscle fatigability in CCD/MmD, NEM and CNM.

Study design: Patients with a genetically confirmed CCD/MmD, NEM or CNM will be able to participate in this study. The study consist of 2 parts. Part 1: a prospective cohort study with 5 visits every 6 months, for a total of 2 years. 45 patients will be included for this part. Part 2: an observational study with 2 visits. For this part 75 patients will be included. There will be an overlap in patients for the two parts. So a total of approximately 100 patients will be included. A large set of tests will be performed to assess the full capabilities of the patient, e.g. muscle strength/endurance, muscle imaging (MRI/ultrasound), activities, walking ability, quality of life, muscle fatigability and the feeling of fatigue.

Eligibility criteria: Inclusion Criteria for the natural history:

* 2 years or older
* Willing and able to complete the measurement protocol
* Willing and able to travel to Nijmegen and Utrecht
* Dutch-speaking
* Genetically-confirmed congenital myopathy (CCD/MmD, NEM, and CNM)

Inclusion Criteria for the fatigability study:

* 8-60 years old
* Willing and able to complete the measurement protocol
* Willing and able to travel to Nijmegen and Utrecht
* Dutch-speaking
* Genetically-confirmed congenital myopathy (CCD/MmD, NEM, and CNM)
* Willing to stop taking pyridostigmine and/or salbutamol 24 hours before the visit.

Exclusion Criteria for both parts:

Other neuromuscular, psychiatric or neurological disorders.

Primary outcomes:
measure: Change of Motor Function Measure (MFM)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: Endurance shuttle test - fatigability part
timeFrame: At assessment 1 or 2 of the fatigability part of the study. Which day is dependent on the preference of the patient and planning possibilities.
Secondary outcomes:
measure: Change of 6-minute walk test (6MWT) (5 years and older)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: Accelerometry - change of extent and intensity of physical activity in daily life (all ages)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: Change of bone density (DEXA scan) (6 years and older)
timeFrame: Change from baseline at 24 months
measure: Change of graded and timed rise from floor (5 years and older)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: Handheld dynamometry (5 years and older)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: Creatine Kinase
timeFrame: At baseline
measure: Vitamin D3
timeFrame: At baseline
measure: Calcium
timeFrame: At baseline
measure: Liver function panel
timeFrame: At baseline
measure: Manual muscle testing (MMT) (5 years and older)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: Change in muscle fattening by quantitative lower extremity muscle MRI (10 years and older)
timeFrame: Change from baseline at 24 months
measure: Change of muscle atrophy by quantitative lower extremity muscle MRI (10 years and older)
timeFrame: Change from baseline at 24 months
measure: Change in muscle atrophy (cm) assessed by muscle ultrasound (all ages)
timeFrame: Change from baseline at 24 months
measure: Change in muscle fattening (echo-intensity) assessed by muscle ultrasound (all ages)
timeFrame: Change from baseline at 24 months
measure: Range of motion (all ages)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: Pulmonary function - change of forced vital capacity (percentage predicted) (5 years and older)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: Pulmonary function - change of forced expiratory volume in the first second (5 years and older)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: Pulmonary function - change of maximal expiratory pressure (cmH2O) (5 years and older)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: Pulmonary function - change of maximal inspiratory pressure (cmH2O) (5 years and older)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: Pulmonary function - change of sniff nasal inspiratory pressure (5 years and older)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: Vignos and Brooke scale (all ages)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: Isokinetic dynamometry (quadriceps and hamstrings or biceps and triceps) (8-60 years old) - fatigability part
timeFrame: At assessment 1 or 2 of the fatigability part of the study. Which day is dependent on the preference of the patient and planning possibilities.
measure: Change in surface electromyography (EMG) amplitude and median frequency during isokinetic dynamometry with surface EMG (quadriceps and hamstrings or biceps and triceps) (8-60 years old) - fatigability part
timeFrame: At assessment 1 or 2 of the fatigability part of the study. Which day is dependent on the preference of the patient and planning possibilities.
measure: Repetitive nerve stimulation (RNS) (8-60 years old) - fatigability part
timeFrame: At assessment 1 or 2 of the fatigability part of the study. Which day is dependent on the preference of the patient and planning possibilities.
measure: Checklist individual strength (CIS) questionnaire fatigue subscale (18 years and older)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: Fatigue severity scale questionnaire (12 years and older)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: PedsQL multidimensional fatigue scale (MFS) (2-17 years old)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: PROMIS Fatigue Short Form questionnaire (all ages)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: McGill pain questionnaire (MPQ) (12 years and older)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: Wong-Baker Faces Pain Scale (2-11 years old)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: PedsQL generic quality of life (2-17 years old)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: Short Form 36 (SF36) quality of life scale (18 years and older)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: Activlim questionnaire (7-17 years old)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: Impact on participation and autonomy (18 years and older)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: Utrecht Scale for Evaluation of Rehabilitation-Participation (USER-P) (18 years and older)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: Borg rating scale of perceived exertion (5 years and older)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: Hospital anxiety and depression scale (18 years and older)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: PedsQL neuromuscular module (NMM) (2-17 years old)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: Resilience evaluation scale (18 years and older)
timeFrame: Change from baseline at 6, 12, 18 and 24 months
measure: Effects of pyridostigmine and/or salbutamol (8-60 years old) - fatigability part
timeFrame: At baseline of the fatigability part of the study
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboudumc
state: Gelderland
city: Utrecht
country: Netherlands
facility: UMC Utrecht
Study officials:
affiliation: Radboud University Medical Center
name: Nicol Voermans, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: