Magnetic Resonance Imaging and Biomarkers for Muscular Dystrophy

Обзор

The purpose of this research study is to determine the potential of magnetic resonance imaging, spectroscopy, and whole body imaging to monitor disease progression and to serve as an objective outcome measure for clinical trials in Muscular Dystrophy (MD). The investigators will compare the muscles of ambulatory or non-ambulatory boys/men with DMD with muscles of healthy individuals of the same age and monitor disease progression in those with DMD over a 5-10 year period. The amount of muscle damage and fat that the investigators measure will also be related to performance in daily activities, such as walking and the loss of muscle strength. In a small group of subjects the investigators will also assess the effect of corticosteroid drugs on the muscle measurements. Additionally, the investigators will map the progression of Becker MD following adults with this rare disease. The primary objective is to conduct a multi-centered study to validate the potential of non-invasive magnetic resonance imaging and magnetic resonance spectroscopy to monitor disease progression and to serve as a noninvasive surrogate outcome measure for clinical trials in DMD and BMD. The secondary objective is to characterize the progressive involvement of the lower extremity, upper extremity, trunk/respiratory muscles in boys/men with DMD and BMD guiding clinical trials.

Подробное описание

The overall objective of this proposal is to validate the potential of noninvasive magnetic resonance imaging (MRI) and spectroscopy (MRS) to monitor disease progression and to serve as an outcome measure for clinical trials in muscular dystrophies. Duchenne muscular dystrophy (DMD) is one of the most devastating genetically linked neuromuscular diseases and is characterized by the absence of dystrophin, resulting in progressive muscle weakness, loss of walking ability and premature death. Despite the poor prognosis therapeutic interventions have been lacking, and outcome measures for clinical trials have been limited to measures of muscle function, quality of life, serum biomarkers of muscle breakdown and invasive muscle biopsies. Closely related to DMD, Becker muscular dystrophy (BMD) has also been largely neglected in therapeutic development, due to its heterogeneity, small patient population, lack of outcome measures and uncertainty surrounding the patterns of disease progression, which may be mutation-dependent. Additional quantitative outcome measures that are noninvasive and sensitive to changes in muscle structure and composition are needed to facilitate the rapid translation of promising new interventions from preclinical studies to clinical trials in both forms of muscular dystrophy. As such, this project targets the development and validation of magnetic resonance as a noninvasive biomarker of disease progression in muscular dystrophy. Using a multi-site research design this study will characterize the intramuscular lipid content, cellular muscle damage and contractile area in the lower and/or upper extremity muscles of 200 ambulatory or non-ambulatory boys/men with DMD, 105 ambulatory or non-ambulatory men with BMD, and 110 healthy age matched boys/men using a combination of sophisticated MRI and MRS technologies. The trunk and respiratory muscles will be characterized in a subgroup of subjects (80 DMD, 20 BMD and 10 controls). In order to assess the sensitivity of each MR measure individually as well as composite MR measures (combination of muscles) to disease progression, all boys/men with DMD or BMD will be re-evaluated in yearly or 6 month intervals. The predictive outcome value of MRI/MRS will be further evaluated by determining the relationship between changes in MR measures and loss in muscle strength and/or functional ability. Using MRI/MRS we will also examine the effect of initiating corticosteroid treatment on skeletal muscle characteristics and composition. Examination of muscles in BMD patients will allow us to increase our understanding of how much dystrophin is needed to protect the muscle. To this end we will specifically examine the relationship between the MR phenotype (e.g. fast or slow increases in fat fraction) and dystrophin mutations, dystrophin expression and other histological markers. Finally, to ensure the rigor of this study we will examine the day-day reproducibility, inter MR system reproducibility and inter-validate the MR measures using localized MRS (golden standard). We anticipate that the MR techniques developed and validated in this study will be suitable for clinical trials in a wide range of muscular dystrophies and other neuromuscular diseases. In addition, MR characterization may serve as a powerful tool to further advance our understanding of the pathogenesis of muscular dystrophy and help guide the design of future trials.

Первичные конечные точки

• Change from baseline in intramuscular lipid up to 3-10 years [Срок оценки: Change in baseline up to 3-10 years]
• Change from baseline in muscle T2 up to 3 months in DMD [Срок оценки: Change in baseline up to 3 months]
• Correlation between MR measures of intramuscular lipid, functional endpoints and histological markers. [Срок оценки: Through study completion, an average of 1 year]

Вторичные конечные точки (3)

• Change from baseline in muscle T2 up to 5-10 years [Срок оценки: Change in baseline up to 5-10 years]
• Change from baseline in muscle contractile area up to 5-10 years [Срок оценки: change in baseline up to 5-10 years]
• Change from baseline in muscle T2 at 6 months [Срок оценки: Change in baseline up to 6 months]

Критерии участия

Inclusion Criteria for boys with DMD:

1\. Ambulatory and non-ambulatory males (ages 5-30 at baseline testing) previously diagnosed with DMD based on:

• clinical features with onset of symptoms before age five
• elevated serum creatine kinase level or
• absence of dystrophin expression, as determined by immunostain or western blot (<2%) and/or DNA confirmation of a dystrophin mutation \*Subjects will not be excluded based on corticosteroid treatment or other clinical trials

Inclusion Criteria for adults with Becker MD:

• Ambulatory males (ages 18-62) without disease or injury to the lower extremities
• Specific recruitment of a subset of individuals with deletion mutations in the dystrophin gene involving either exon 51 or exon 45.

Inclusion Criteria for age matched controls for Becker MD subjects:

1\. Ambulatory males (ages 18-62) without disease or injury to the lower and/or upper extremities will be eligible to participate in this study

Критерии исключения

• Males with a contraindication to an MR examination
• Males with unstable medical problems
• Males who are not able to cooperate during testing
• Males with a secondary condition that may impact muscle metabolism, muscle function or functional ability (i.e. cerebral palsy, endocrine disorders, mitochondrial disease)
• Daytime ventilation
• Implantable Cardioverter Defibrillator- (ICD) or pace maker
• Healthy boys/men who participate in competitive sports specific training in excess of 8 hours per week

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Модель наблюдения

Случай-контроль

Центры проведения

США · 3 центра

• University of Florida — Gainesville
• Oregon Health and Science University — Portland
• Children's Hospital of Philadelphia — Philadelphia

Публикации

• Willis AB, Zelikovich AS, Sufit R, Ajroud-Driss S, Vandenborne K, Demonbreun AR, Batra A, Walter GA, McNally EM. Serum protein and imaging biomarkers after intermittent steroid treatment in muscular dystrophy. medRxiv [Preprint]. 2024 Jun 16:2024.06.14.24308858. doi: 10.1101/2024.06.14.24308858. PMID 38947030
• Muntoni F, Signorovitch J, Sajeev G, Done N, Yao Z, Goemans N, McDonald C, Mercuri E, Niks EH, Wong B, Vandenborne K, Straub V, de Groot IJM, Tian C, Manzur A, Dieye I, Lane H, Ward SJ, Servais L; PRO-DMD-01 study investigators; Association Francaise contre les Myopathies; UK NorthStar Clinical Network; ImagingDMD investigators; cTAP. Meaningful changes in motor function in Duchenne muscular dystr PMID 38985784
• Ikelaar NA, Barnard AM, Eng SWM, Hosseini Vajargah S, Ha KCH, Kan HE, Vandenborne K, Niks EH, Walter GA, Spitali P. Large scale serum proteomics identifies proteins associated with performance decline and clinical milestones in Duchenne muscular dystrophy. medRxiv [Preprint]. 2024 Aug 7:2024.08.05.24311516. doi: 10.1101/2024.08.05.24311516. PMID 39148831
• Kim J, Morales JF, Kang S, Klose M, Willcocks RJ, Daniels MJ, Belfiore-Oshan R, Walter GA, Rooney WD, Vandenborne K, Kim S. A model-informed clinical trial simulation tool with a graphical user interface for Duchenne muscular dystrophy. CPT Pharmacometrics Syst Pharmacol. 2025 Nov;14(11):1765-1774. doi: 10.1002/psp4.13246. Epub 2024 Oct 3. PMID 39360574
• Jenkins BM, Dixon LD, Kokesh KJ, Zingariello CD, Vandenborne K, Walter GA, Barnard AM. Skeletal muscle symptoms and quantitative MRI in females with dystrophinopathy. Muscle Nerve. 2024 Nov;70(5):988-999. doi: 10.1002/mus.28235. Epub 2024 Sep 2. PMID 39221574
• Akima H, Lott D, Senesac C, Deol J, Germain S, Arpan I, Bendixen R, Lee Sweeney H, Walter G, Vandenborne K. Relationships of thigh muscle contractile and non-contractile tissue with function, strength, and age in boys with Duchenne muscular dystrophy. Neuromuscul Disord. 2012 Jan;22(1):16-25. doi: 10.1016/j.nmd.2011.06.750. Epub 2011 Jul 31. PMID 21807516
• Forbes SC, Walter GA, Rooney WD, Wang DJ, DeVos S, Pollaro J, Triplett W, Lott DJ, Willcocks RJ, Senesac C, Daniels MJ, Byrne BJ, Russman B, Finkel RS, Meyer JS, Sweeney HL, Vandenborne K. Skeletal muscles of ambulant children with Duchenne muscular dystrophy: validation of multicenter study of evaluation with MR imaging and MR spectroscopy. Radiology. 2013 Oct;269(1):198-207. doi: 10.1148/radiol. PMID 23696684
• Triplett WT, Baligand C, Forbes SC, Willcocks RJ, Lott DJ, DeVos S, Pollaro J, Rooney WD, Sweeney HL, Bonnemann CG, Wang DJ, Vandenborne K, Walter GA. Chemical shift-based MRI to measure fat fractions in dystrophic skeletal muscle. Magn Reson Med. 2014 Jul;72(1):8-19. doi: 10.1002/mrm.24917. Epub 2013 Sep 4. PMID 24006208

Идентификаторы

NCT: NCT01484678 · IRB201700056-N · R01AR056973 · 176-2010 · OCR16243

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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