The Natural History and Muscle Fatigability of Patients With Congenital Myopathies.

Study Overview
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Brief Summary
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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
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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.

Official Title
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Trial Readiness and Trial Fitness for Congenital Myopathies: a 2-year Prospective Natural History Study Including a Cross-sectional Study on Muscle Fatigability

Conditions
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Central Core Disease, Multi-Minicore Disease, Nemaline Myopathy, Centronuclear Myopathy

Intervention / Treatment
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* Other: Natural history and non therapeutical therapy


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Core myopathies<br>Patients with a genetically confirmed core myopathy | Other: Natural history and non therapeutical therapy<br>* This study concerns a natural history study part and a muscle fatigability part. For the natural history study no interventions will be used. For the muscle fatigability part non therapeutical therapies will be used. This includes endurance tests, isokinetic dynamometry and repetitive nerve stimulation.<br>|
| Nemaline myopathy<br>Patients with a genetically confirmed nemaline myopathy | Other: Natural history and non therapeutical therapy<br>* This study concerns a natural history study part and a muscle fatigability part. For the natural history study no interventions will be used. For the muscle fatigability part non therapeutical therapies will be used. This includes endurance tests, isokinetic dynamometry and repetitive nerve stimulation.<br>|
| Centronuclear myopathy<br>Patients with a genetically confirmed centronuclear myopathy | Other: Natural history and non therapeutical therapy<br>* This study concerns a natural history study part and a muscle fatigability part. For the natural history study no interventions will be used. For the muscle fatigability part non therapeutical therapies will be used. This includes endurance tests, isokinetic dynamometry and repetitive nerve stimulation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of Motor Function Measure (MFM) | 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. | Change from baseline at 6, 12, 18 and 24 months | 
| Endurance shuttle test - fatigability part | 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. | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of 6-minute walk test (6MWT) (5 years and older) | How far the patient can walk in 6 minutes. The first and last minute will be compared to each other. | Change from baseline at 6, 12, 18 and 24 months | 
| Accelerometry - change of extent and intensity of physical activity in daily life (all ages) | Physical activity in daily life will be assessed by wearing an wrist worn accelerometer (GENEActiv original devices) for 7 days. | Change from baseline at 6, 12, 18 and 24 months | 
| Change of bone density (DEXA scan) (6 years and older) | The bone density of the spine and hip will be measured by a DEXA scan. | Change from baseline at 24 months | 
| Change of graded and timed rise from floor (5 years and older) | The time it takes to rise from the floor | Change from baseline at 6, 12, 18 and 24 months | 
| Handheld dynamometry (5 years and older) | Maximal voluntary isometric contraction will be measured by handheld dynamometry (m. biceps brachii, m. quadriceps, grip strength, all bilaterally) | Change from baseline at 6, 12, 18 and 24 months | 
| Creatine Kinase | Blood level of Creatine Kinase | At baseline | 
| Vitamin D3 | Blood level of Vitamin D3 | At baseline | 
| Calcium | Blood level of calcium | At baseline | 
| Liver function panel | Blood level of bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyltransferase GGT, albumin, bile acids and full blood count. | At baseline | 
| Manual muscle testing (MMT) (5 years and older) | 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 from baseline at 6, 12, 18 and 24 months | 
| Change in muscle fattening by quantitative lower extremity muscle MRI (10 years and older) | 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). | Change from baseline at 24 months | 
| Change of muscle atrophy by quantitative lower extremity muscle MRI (10 years and older) | 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). | Change from baseline at 24 months | 
| Change in muscle atrophy (cm) assessed by muscle ultrasound (all ages) | Muscle atrophy of the leg, arm, back, abdominal muscles and diaphragm will be assessed by muscle ultrasound. | Change from baseline at 24 months | 
| Change in muscle fattening (echo-intensity) assessed by muscle ultrasound (all ages) | Muscle fattening of the leg, arm, back, abdominal muscles and diaphragm will be assessed by muscle ultrasound. | Change from baseline at 24 months | 
| Range of motion (all ages) | The range of motion of the elbows, fingers, knees and ankles is noted bilaterally by goniometry. | Change from baseline at 6, 12, 18 and 24 months | 
| Pulmonary function - change of forced vital capacity (percentage predicted) (5 years and older) | Obtained with handheld spirometry in sit and supine. | Change from baseline at 6, 12, 18 and 24 months | 
| Pulmonary function - change of forced expiratory volume in the first second (5 years and older) | Obtained with handheld spirometry in sit and supine. | Change from baseline at 6, 12, 18 and 24 months | 
| Pulmonary function - change of maximal expiratory pressure (cmH2O) (5 years and older) | Obtained with handheld device. | Change from baseline at 6, 12, 18 and 24 months | 
| Pulmonary function - change of maximal inspiratory pressure (cmH2O) (5 years and older) | Obtained with handheld device. | Change from baseline at 6, 12, 18 and 24 months | 
| Pulmonary function - change of sniff nasal inspiratory pressure (5 years and older) | Obtained with handheld device. | Change from baseline at 6, 12, 18 and 24 months | 
| Vignos and Brooke scale (all ages) | 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. | Change from baseline at 6, 12, 18 and 24 months | 
| Isokinetic dynamometry (quadriceps and hamstrings or biceps and triceps) (8-60 years old) - fatigability part | 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. | 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. | 
| 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 | On the quadriceps/hamstrings or biceps/triceps surface EMG amplitude and median frequency will be measured. | 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. | 
| Repetitive nerve stimulation (RNS) (8-60 years old) - fatigability part | 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. | 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. | 
| Checklist individual strength (CIS) questionnaire fatigue subscale (18 years and older) | 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. | Change from baseline at 6, 12, 18 and 24 months | 
| Fatigue severity scale questionnaire (12 years and older) | 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. | Change from baseline at 6, 12, 18 and 24 months | 
| PedsQL multidimensional fatigue scale (MFS) (2-17 years old) | 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. | Change from baseline at 6, 12, 18 and 24 months | 
| PROMIS Fatigue Short Form questionnaire (all ages) | 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. | Change from baseline at 6, 12, 18 and 24 months | 
| McGill pain questionnaire (MPQ) (12 years and older) | 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. | Change from baseline at 6, 12, 18 and 24 months | 
| Wong-Baker Faces Pain Scale (2-11 years old) | 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). | Change from baseline at 6, 12, 18 and 24 months | 
| PedsQL generic quality of life (2-17 years old) | 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. | Change from baseline at 6, 12, 18 and 24 months | 
| Short Form 36 (SF36) quality of life scale (18 years and older) | 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. | Change from baseline at 6, 12, 18 and 24 months | 
| Activlim questionnaire (7-17 years old) | 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. | Change from baseline at 6, 12, 18 and 24 months | 
| Impact on participation and autonomy (18 years and older) | 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. | Change from baseline at 6, 12, 18 and 24 months | 
| Utrecht Scale for Evaluation of Rehabilitation-Participation (USER-P) (18 years and older) | 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. | Change from baseline at 6, 12, 18 and 24 months | 
| Borg rating scale of perceived exertion (5 years and older) | 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. | Change from baseline at 6, 12, 18 and 24 months | 
| Hospital anxiety and depression scale (18 years and older) | 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. | Change from baseline at 6, 12, 18 and 24 months | 
| PedsQL neuromuscular module (NMM) (2-17 years old) | 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. | Change from baseline at 6, 12, 18 and 24 months | 
| Resilience evaluation scale (18 years and older) | 9-Item questionnaire on psychological resilience with each item being scored from 0-4, higher scores indicating greater resilience. | Change from baseline at 6, 12, 18 and 24 months | 
| Effects of pyridostigmine and/or salbutamol (8-60 years old) - fatigability part | 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. | At baseline of the fatigability part of the study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Natural history study, Outcome measures, Congenital myopathy, Muscle disease