The Natural History and Muscle Fatigability of Patients With Congenital Myopathies.
- Conditions
- Centronuclear MyopathyCentral Core DiseaseNemaline MyopathyMulti-Minicore Disease
- Interventions
- Other: Natural history and non therapeutical therapy
- Registration Number
- NCT06157268
- Lead Sponsor
- Radboud University Medical Center
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 100
Not provided
Not provided
Study & Design
- Study Type
- OBSERVATIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description Centronuclear myopathy Natural history and non therapeutical therapy Patients with a genetically confirmed centronuclear myopathy Nemaline myopathy Natural history and non therapeutical therapy Patients with a genetically confirmed nemaline myopathy Core myopathies Natural history and non therapeutical therapy Patients with a genetically confirmed core myopathy
- Primary Outcome Measures
Name Time Method Change of Motor Function Measure (MFM) Change from baseline at 6, 12, 18 and 24 months Global motor functioning. The main outcome is the change in MFM score over a period of 2 years. The scores of the patients will also be compared to reference values.
Endurance shuttle test - fatigability part 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. Patients walk/move blocks/move pegs at a personalised set speed. The main outcome is if the patient drops out due to the speed being too low. If the patient drops out the time until dropout is noted.
- Secondary Outcome Measures
Name Time Method Vitamin D3 At baseline Blood level of Vitamin D3
Change of graded and timed rise from floor (5 years and older) Change from baseline at 6, 12, 18 and 24 months The time it takes to rise from the floor
Change of bone density (DEXA scan) (6 years and older) Change from baseline at 24 months The bone density of the spine and hip will be measured by a DEXA scan.
Accelerometry - change of extent and intensity of physical activity in daily life (all ages) Change from baseline at 6, 12, 18 and 24 months Physical activity in daily life will be assessed by wearing an wrist worn accelerometer (GENEActiv original devices) for 7 days.
Change of 6-minute walk test (6MWT) (5 years and older) Change from baseline at 6, 12, 18 and 24 months How far the patient can walk in 6 minutes. The first and last minute will be compared to each other.
Change of muscle atrophy by quantitative lower extremity muscle MRI (10 years and older) Change from baseline at 24 months A lower extremity muscle MRI will be performed in participants who are able to lie supine and still for 20 minutes and who are not dependent on respiratory equipment. Atrophy will be assessed by muscle volume score (semi-quantitative).
Range of motion (all ages) Change from baseline at 6, 12, 18 and 24 months The range of motion of the elbows, fingers, knees and ankles is noted bilaterally by goniometry.
Pulmonary function - change of forced vital capacity (percentage predicted) (5 years and older) Change from baseline at 6, 12, 18 and 24 months Obtained with handheld spirometry in sit and supine.
Pulmonary function - change of maximal inspiratory pressure (cmH2O) (5 years and older) Change from baseline at 6, 12, 18 and 24 months Obtained with handheld device.
Vignos and Brooke scale (all ages) Change from baseline at 6, 12, 18 and 24 months The Brooke (score 1-6) and Vignos (score 1-10) scales provide ordinal data to assess the upper and lower extremity functions. A lower score indicates more functionality.
Liver function panel At baseline Blood level of bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyltransferase GGT, albumin, bile acids and full blood count.
Change in muscle fattening (echo-intensity) assessed by muscle ultrasound (all ages) Change from baseline at 24 months Muscle fattening of the leg, arm, back, abdominal muscles and diaphragm will be assessed by muscle ultrasound.
Repetitive nerve stimulation (RNS) (8-60 years old) - fatigability part 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. We will stimulate the n. ulnaris, n. accesorius and n. facialis at 3 Hz to measure the m abductor digiti minimi, m. trapezius and m nasalis. The decrement/increment will be determined by the compound muscle action potential amplitude and area.
The RNS will be performed before and after 60 seconds of voluntary contraction.Fatigue severity scale questionnaire (12 years and older) Change from baseline at 6, 12, 18 and 24 months Nine-questions scale about the impact of fatigue on the patient's life. Each item is scored on a 7 point scale. A higher score indicates greater fatigue/greater impact of fatigue on daily life.
PROMIS Fatigue Short Form questionnaire (all ages) Change from baseline at 6, 12, 18 and 24 months Consists of 8 items representing the most informative items from the PROMIS item bank. The PROMIS Fatigue item banks assess a range of self-reported symptoms, from mild subjective feelings of tiredness to an overwhelming, debilitating, and sustained sense of exhaustion that likely decreases one's ability to execute daily activities and function normally in family or social roles. For patients younger than 18 a parent proxy is also available. The items are scored form 1-5 with a higher score indicating more fatigue.
McGill pain questionnaire (MPQ) (12 years and older) Change from baseline at 6, 12, 18 and 24 months The MPQ consists of 4 components: a pain word list to state the type and intensity of the pain, questions about the effect on daily life, a visual-analogue scale for pain intensity and questions about the location and course of the pain.
PedsQL generic quality of life (2-17 years old) Change from baseline at 6, 12, 18 and 24 months The PedsQL generic quality of life questionnaire consists of 8 items on physical functioning, 5 items on emotional functioning, 5 items on social functioning, and 5 items on school functioning. Each item is scored on a 0-4 scale. The items are reversed scored and linearly transformed to a 0-100 scale, so that higher scores indicate a better outcome.
Short Form 36 (SF36) quality of life scale (18 years and older) Change from baseline at 6, 12, 18 and 24 months The adult Quality of Life is measured by the SF36/RAND36 questionnaire. The SF36/RAND36 addresses eight concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. It also includes a single item that provides an indication of perceived change in health. It has a total of 36 items.
Impact on participation and autonomy (18 years and older) Change from baseline at 6, 12, 18 and 24 months Questionnaire about participation and autonomy in daily life with 41 questions on a ordinal 3- or 5-point likert scale. Higher scores indicate more obstacles in participation and autonomy.
Handheld dynamometry (5 years and older) Change from baseline at 6, 12, 18 and 24 months Maximal voluntary isometric contraction will be measured by handheld dynamometry (m. biceps brachii, m. quadriceps, grip strength, all bilaterally)
Creatine Kinase At baseline Blood level of Creatine Kinase
Calcium At baseline Blood level of calcium
Pulmonary function - change of maximal expiratory pressure (cmH2O) (5 years and older) Change from baseline at 6, 12, 18 and 24 months Obtained with handheld device.
Checklist individual strength (CIS) questionnaire fatigue subscale (18 years and older) Change from baseline at 6, 12, 18 and 24 months The CIS is a questionnaire rating four subscales: subjective tiredness, concentration, motivation and physical activity. It consists of 20 items on a 7-point scale. We will use the Fatigue subscale. A CIS fatigue scale ≥ 35 points to severe fatigue.
Utrecht Scale for Evaluation of Rehabilitation-Participation (USER-P) (18 years and older) Change from baseline at 6, 12, 18 and 24 months USER-P Restrictions scale is a patients-reported outcome measures with 32 questions focusing on daily activities including school and work. Each item is scored on a 4-, 5-, and 6-point Likert scale. A higher score indicates more participation.
Borg rating scale of perceived exertion (5 years and older) Change from baseline at 6, 12, 18 and 24 months Borg Rating Scale of Perceived Exertion is a way of measuring physical activity intensity level. Perceived exertion is based on the physical sensations a person experiences during physical activity. It is scored 6-20 with a higher score indicating a greater perceived exertion.
Participants will be asked to score the intensity level at the beginning and at the end of the 6MWT.Hospital anxiety and depression scale (18 years and older) Change from baseline at 6, 12, 18 and 24 months Questionnaire about the main complaints of anxiety and depression with 7 items each on a 4-point Likert scale. A higher score indicates more complaints.
PedsQL neuromuscular module (NMM) (2-17 years old) Change from baseline at 6, 12, 18 and 24 months The PedsQL NMM questionnaire consists of 25 questions in three domains: Neuromuscular disease, communication and family resources. Each item is scored on a 0-4 scale. The items are reversed scored and linearly transformed to a 0-100 scale, so that higher scores indicate a better outcome.
Effects of pyridostigmine and/or salbutamol (8-60 years old) - fatigability part At baseline of the fatigability part of the study We will ask patients if they use pyridostigmine and/or salbutamol. If they use it we will ask how often, what the effects are and how long those effects last.
Manual muscle testing (MMT) (5 years and older) Change from baseline at 6, 12, 18 and 24 months Muscle power of individual muscle groups can be assessed by muscle power measurements and graded in correspondence with the Medical Research Council (MRC) scale.
Change in muscle fattening by quantitative lower extremity muscle MRI (10 years and older) Change from baseline at 24 months A lower extremity muscle MRI will be performed in participants who are able to lie supine and still for 20 minutes and who are not dependent on respiratory equipment. Muscle fattening will be assessed by Regions of Interest (ROIs) (quantitative) and modified Mercuri score (semi-quantitative).
Pulmonary function - change of forced expiratory volume in the first second (5 years and older) Change from baseline at 6, 12, 18 and 24 months Obtained with handheld spirometry in sit and supine.
Pulmonary function - change of sniff nasal inspiratory pressure (5 years and older) Change from baseline at 6, 12, 18 and 24 months Obtained with handheld device.
Isokinetic dynamometry (quadriceps and hamstrings or biceps and triceps) (8-60 years old) - fatigability part 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. Peak torque, time to peak torque, change in torque from first third to last third, acceleration time and deceleration time for 3, 5 and 30 repetitions at a set speed. For the 30 repetitions how many repetitions until failure is also noted.
Wong-Baker Faces Pain Scale (2-11 years old) Change from baseline at 6, 12, 18 and 24 months The Wong-Baker Faces Pain Scale was originally created for children to help them communicate about their pain. It has six types of faces ranging from no hurt (0) tot hurts worst (10).
Resilience evaluation scale (18 years and older) Change from baseline at 6, 12, 18 and 24 months 9-Item questionnaire on psychological resilience with each item being scored from 0-4, higher scores indicating greater resilience.
Change in muscle atrophy (cm) assessed by muscle ultrasound (all ages) Change from baseline at 24 months Muscle atrophy of the leg, arm, back, abdominal muscles and diaphragm will be assessed by muscle ultrasound.
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 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. On the quadriceps/hamstrings or biceps/triceps surface EMG amplitude and median frequency will be measured.
PedsQL multidimensional fatigue scale (MFS) (2-17 years old) Change from baseline at 6, 12, 18 and 24 months The PedsQL MFS assesses subjective fatigue in three domains with 6 items each, namely General Fatigue Scale, Sleep/Rest Fatigue Scale, and Cognitive Fatigue Scale. Each item is scored on a three point scale ranging from not at all to a lot for children aged 5-7 and a five point scale from never to almost always for the others. Higher scores indicates less symptoms.
Activlim questionnaire (7-17 years old) Change from baseline at 6, 12, 18 and 24 months ACTIVLIM assesses the ability to perform 22 activities of daily life on a 3-point scale from impossible to easy. The questionnaires will be answered by the parents of the patient.
Trial Locations
- Locations (2)
Radboudumc
🇳🇱Nijmegen, Gelderland, Netherlands
UMC Utrecht
🇳🇱Utrecht, Netherlands