Clinical trial NCT02780492: Outcome Measures in Duchenne Muscular Dystrophy: A Natural History Study
Official title: Developing Tools for Assessing the Natural History of Ambulant and Non-ambulant DMD Individuals to Assist in Antisense-oligomer Clinical Trials
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Duchenne Muscular Dystrophy
Keywords: Duchenne muscular dystrophy
Natural history
Outcome measures
North Star Ambulatory Assessment (NSAA)
6 minute walk distance (6MWD)
Myoset
Exon skipping
Lead sponsor: University College, London
Sponsor class: OTHER
Collaborators: name: Association Française contre les Myopathies (AFM), Paris
name: University of Newcastle Upon-Tyne
name: Groupe Hospitalier Pitie-Salpetriere
name: Leiden University Medical Center
name: Radboud University Medical Center
First posted: 2016-05-23
Enrollment: 35
Sex: MALE
Minimum age (years): 5
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with Duchenne muscular dystrophy (DMD) recruited across 5 specialised neuromuscular centres (London, Newcastle, Paris, Leiden, Nijmegen)

Brief summary: Novel emerging therapies for Duchenne Muscular Dystrophy (DMD) require a deeper understanding of DMD natural history. This study aim to assess the natural history of DMD through a composite assessment tool capable of capturing disease progression linking ambulant and non-ambulant phases of the disease.

Detailed description: Novel emerging therapies for Duchenne Muscular Dystrophy (DMD) require a deeper understanding of DMD natural history. This study aim to assess the natural history of DMD through a composite assessment tool capable of capturing disease progression linking ambulant and non-ambulant phases of the disease.

With a recruitment target of 80 DMD patients across 5 centres (London, Newcastle, Paris, Leiden, Nijmegen), subjects are assessed 6 monthly according to a shared protocol. Assessments include 6-minute walk distance (6MWD), North Star Ambulatory Assessment (NSAA), Performance of Upper Limb (PUL) and MyoSet (myogrip, myopinch and moviplate). Both ambulant and non-ambulant subjects undergo upper limb evaluation and respiratory function test including forced vital capacity (FVC), maximum inspiratory and expiratory pressures (MIP/MEP). A subgroup of patients performs annual whole body DEXA scan. An imaging sub-study will aim to characterize muscle (upper/lower limb) and brain MRI.

The investigators will analyze the longitudinal data for the different assessment tools and explore correlations among them.

This study will offer a comprehensive natural history of DMD including novel outcome measures, allowing to capture disease progression and explore the relationship between different assessment tools.

Eligibility criteria: Inclusion Criteria:

For non-ambulant patients:

1. Children and teenagers aged between 5 and 18 years with DMD, who have lost the ability to walk 10 meters with no support
2. The diagnosis of DMD must be documented by genetic testing. If a muscle biopsy is available, it should contain less than 10% of revertant fibres
3. Patients should have deletions amenable of skipping of exons 51 or 53 or 45 or 44 or 46 or 50 or 52
4. Patients should be capable of sitting upright in a wheelchair for at least an hour
5. Patients should be stable from a respiratory point of view. Artificial ventilation with either Bipap or tracheostomy is not a contraindication to the study.
6. Informed consent signed by a parent/legal guardian (or by the patient if 16 years of age).
7. In France, a subject will be eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category.

For ambulant patients:

1. Ambulant children from 5 years old and teenagers with DMD, and potential candidates for future genetic therapies with antisense oligomer (AO) exon skipping
2. The diagnosis of DMD must be documented by MLPA or a standard genetic test for the disorder, genotypically confirmed to have an out-of-frame deletion(s) that could be corrected by skipping exon 51 or 53 or 45 or 44 or 46 or 50 or 52
3. If a muscle biopsy is available less than 10% revertant fibres
4. Ability to walk independently for at least 75 meters in 6 minutes at recruitment.
5. Patients should receive the standard of care for DMD as recommended by the NorthStar UK and TREAT-NMD (i.e.: on glucocorticoids treatment)
6. Sufficiently preserved pulmonary function (FVC \>30%) and absence of symptoms of cardiac failure
7. Informed consent signed by a parent/legal guardian (or by the patient if 16 years of age)
8. In France, a subject will be eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category.

For healthy volunteers and disease controls:

1. Participant are able to provide informed consent/assent for taking blood samples and/or performing limb MRI and/or physiotherapy assessment of the upper limb function
2. Participants have a neuromuscular disease that is not Duchenne Muscular Dystrophy or are a healthy volunteer with no neuromuscular disease
3. Able to have a blood sample taken

Exclusion Criteria:

For non-ambulant patients:

1. Patients who are currently involved in interventional clinical trials aimed at restoring dystrophin will be excluded, as their data could not be used to establish natural history of the disease (participation in a previous interventional clinical trial prior to 6 months from being recruited in the study is not an exclusion criterion)
2. Patients with severe intellectual impairment, who would be unable to cooperate with examination
3. Patients/families the investigators anticipate may have emotional/ psychological problems if recruited into a natural history study
4. Symptomatic cardiac failure
5. Recent (\< 6 months) upper limb surgery or trauma
6. Anticipated surgery for anytime during the duration of the study
7. None of the current treatments for DMD are exclusion criteria
8. For the MRI sub-study, patients with metal/metallic surgically inserted equipment incompatible with MRI scan will be excluded as well as patients suffering from claustrophobia.

For ambulant patients:

1. Patients who are currently involved in interventional clinical trials aimed at restoring dystrophin will be excluded, as their data could not be used to establish natural history of the disease (participation in a previous interventional clinical trial prior to 6 months from being recruited in the study is not an exclusion criterion)
2. Patients with severe intellectual impairment, who would be unable to cooperate with examination
3. Patients/families the investigators anticipate may have emotional/ psychological problems if recruited into a natural history study
4. Recent surgery or anticipated for anytime during the duration of the study
5. For the MRI sub-study, patients with metal/metallic surgically inserted equipment incompatible with MRI scan will be excluded as well as patients suffering from claustrophobia.

For healthy volunteers and disease controls

1. Patients who are currently involved in interventional clinical trials aimed at restoring dystrophin will be excluded, as their data could not be used to establish natural history of the disease (participation in a previous interventional clinical trial prior to 6 months from being recruited in the study is not an exclusion criterion)
2. Patients with severe intellectual impairment, who would be unable to cooperate with examination
3. Patients/families the investigators anticipate may have emotional/ psychological problems if recruited into a natural history study
4. For the MRI sub-study, patients with metal/metallic surgically inserted equipment incompatible with MRI scan will be excluded as well as patients suffering from claustrophobia

Primary outcomes:
measure: Disease progression
timeFrame: up to 4 years
Secondary outcomes:
Other outcomes:
Locations:
city: Paris
country: France
facility: Institut de Myologie, Groupe Hospitalier Pitié Salpêtrière
city: Leiden
country: Netherlands
facility: Leiden University Medical Centre
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Centre
city: London
country: United Kingdom
facility: Dubowitz Neuromuscular Centre, UCL-Institute of Child Health
city: Newcastle
country: United Kingdom
facility: John Walton Muscular Dystrophy Research Centre, Newcastle University
Study officials:
affiliation: Dubowitz Neuromuscular Centre, UCL-Institute of Child Health
name: Francesco Muntoni, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Trucco F, Ridout D, Domingos J, Maresh K, Chesshyre M, Munot P, Sarkozy A, Robb S, Quinlivan R, Riley M, Wallis C, Chan E, Abel F, De Lucia S, Hogrel JY, Niks EH, de Groot I, Servais L, Straub V, Ricotti V, Manzur A, Muntoni F; UK NorthStar Clinical Network and AFM Network. Genotype-related respiratory progression in Duchenne muscular dystrophy-A multicenter international study. Muscle Nerve. 2022 Jan;65(1):67-74. doi: 10.1002/mus.27427. Epub 2021 Oct 27.
citation: Catapano F, Scaglioni D, Maresh K, Ala P, Domingos J, Selby V, Ricotti V, Phillips L, Servais L, Seferian A, Groot I, Krom YD, Voit T, Verschuuren JJGM, Niks EH, Straub V, Morgan J, Muntoni F. Novel free-circulating and extracellular vesicle-derived miRNAs dysregulated in Duchenne muscular dystrophy. Epigenomics. 2020 Nov;12(21):1899-1915. doi: 10.2217/epi-2020-0052. Epub 2020 Nov 20.