Establishing Biomarkers and Clinical Endpoints in Myotonic Dystrophy Type 1 (END-DM1)

Study Overview
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Brief Summary
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Building on previous work of the Myotonic Dystrophy Clinical Research Network (DMCRN), the present study seeks to overcome insufficient data on natural history; lack of reliable biomarkers; and incomplete characterization and limited biological understanding of the phenotypic heterogeneity of Myotonic Dystrophy 1 by examining strategies to improve the reliability by making further refinements in our sample collection and analysis procedures by developing strategies for managing patient heterogeneity going forward. Funding Source- FDA OOPD

Detailed Description
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Approximately 700 adult participants (18 to 70 years old, inclusive) with DM1 will be enrolled at 15 centers (up to 70 patients will be recruited at each site). No treatment will be administered as part of this study. Participants will receive standard of care as determined by the investigators. Study visits occur at baseline/0 months, 12 months, and 24 months. Few restrictions are placed on participation in the study because the investigators aim to capture the full spectrum of disease severity. Studies of splicing biomarkers in muscle biopsy samples will be conducted on a subset of 95 participants. These participants will have an additional study visit at 3 months.

Official Title
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Establishing Biomarkers and Clinical Endpoints in Myotonic Dystrophy Type 1 (END-DM1)

Conditions
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Myotonic Dystrophy 1

Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Age 18 to 70 (inclusive) Competent to provide informed consent Clinical diagnosis of DM1 based on research criteria1 or positive genetic test Comment: The clinical research criteria require myotonia, muscle weakness in a characteristic distribution, and history of similar findings in a first degree relative. Genetic testing confirmed the diagnosis of DM1 in > 99% of individuals who satisfied these criteria.2 Exclusion criteria: Symptomatic renal or liver disease, uncontrolled diabetes or thyroid disorder, or active malignancy other than skin cancer. Current alcohol or substance abuse Concurrent enrollment in clinical trial for DM1, or participation in trial within 6 months of entry. Concurrent pregnancy or planned pregnancy during the course of the study. Concurrent medical condition that would, in the opinion of the investigator or clinical evaluator, compromise performance on study measures. Note: non-ambulatory participants are not excluded, but are limited to <15% of enrollment. Inclusion criteria for participants in the muscle biopsy sub-study: • Of the 95 patients undergoing the tibialis anterior muscle biopsy, at least half will have at least moderate weakness of ankle dorsiflexion, defined as MRC score ≤ 4+. This is in order to obtain a muscle tissue sample in a person more severely affected with myotonic dystrophy. Approximately 10 patients at each site will undergo the muscle biopsy. Exclusion criteria for 95 participants in the muscle biopsy sub-study: Known CTG repeat expansion size less than 100 repeats, unless there are clear cut signs of limb weakness and muscle wasting. This is in order to obtain a muscle tissue sample in a person more severely affected with myotonic dystrophy. Use of anticoagulant such as warfarin or a direct oral anticoagulant (e.g. dabigatran) due to the increased risk of bleeding. Use of aspirin or non-steroidal anti-inflammatory agents should be discontinued 3 days prior to the biopsy procedure, if possible. Platelet count <50,000 (if known) due to the increased risk of bleeding. History of a bleeding disorder due to the increased risk of bleeding. Advanced wasting of tibialis anterior (TA) muscle that precludes needle muscle biopsy in order to ensure that a sample taken would be of muscle and not just fat and fascia. Previous muscle biopsy of either TA in order to provide muscle tissue samples of non-biopsied muscles.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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 |
| --- | --- |
| Study Visits<br>Patients will receive standard of care as determined by their treating physician. Study visits occur at baseline/0 months, 12 months, and 24 months | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in ambulation over 24 months as measured by the 10 meter walk (m/s). | 10 meter walk will be measured (m/s) | 12 and 24 months | 
| Change in respiratory function over 24 months as measured by spirometry, specifically the supine forced vital capacity (FVC). | Supine forced vital capacity (% predicted) | 12 and 24 months | 
| Percent splicing of DM1-affected splice events | RNA sequenced of muscle biopsy samples collected at two different times will be combined and used to calculate a percent splicing index (PMI) | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myotonic Dystrophy, END DM-1, Muscular Dystophy, DMCRN