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Establishing biomarkers and clinical endpoints in myotonic dystrophy type 1 (END-DM1): Protocol of an international
Karlien Mul1, Kate Eichinger2, Man Hung3
1Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Background:
Myotonic dystrophy type 1 (DM1) is an autosomal dominant inherited multi-system disorder that affects skeletal muscles but also many other organ systems. Molecular targets have been identified and targeted therapies are being developed and tested in first-in-human clinical trials. However, insufficient knowledge of the phenotypic heterogeneity and natural course of the disease, together with a lack of reliable biomarkers, complicate the design of clinical trials.
Methods:
The main objectives of this study are to 1) characterize the phenotypic heterogeneity and disease progression of DM1 in a large cohort; 2) identify baseline characteristics that predict subsequent progression; 3) validate RNA biomarkers of disease severity. This is a prospective, multi-site observational study with a follow-up period of 24 months including approximately 700 adult DM1 patients. Visits will occur at baseline, and months 12 and 24. All patients will undergo strength testing, myotonia assessment, a battery of functional outcome assessments, spirometry, and complete various questionnaires and cognitive tests. Blood and urine samples will be taken at each visit for biomarker studies. A subset of 60 patients will undergo a muscle biopsy at baseline and at an additional 3-month visit. The sensitivity to disease progression and minimally clinically important differences will be determined for the various clinical outcome measures. Associations between baseline patient characteristics and the rate of disease progression will be evaluated.
Discussion:
The results of this large international study on DM1 will contribute to optimizing clinical trial design. Both data and biological samples will be collected for future research as well.
Trial Registration:
Clinicaltrials.gov NCT03981575.
Insights
This study characterizes the phenotypic heterogeneity and disease progression in Myotonic Dystrophy type 1 (DM1) patients. Findings will optimize clinical trial design and validate RNA biomarkers for disease severity.
Area of Science:
- Neurology
- Genetics
- Clinical Research
Background:
- Myotonic Dystrophy type 1 (DM1) is a multi-system disorder with significant phenotypic heterogeneity.
- Developing targeted therapies for DM1 is challenging due to limited understanding of disease progression and lack of reliable biomarkers.
Purpose of the Study:
- To characterize DM1 phenotypic heterogeneity and disease progression in a large cohort.
- To identify baseline predictors of disease progression.
- To validate RNA biomarkers for DM1 severity.
Main Methods:
- Prospective, multi-site observational study of approximately 700 adult DM1 patients over 24 months.
- Comprehensive assessments including strength testing, myotonia, functional outcomes, spirometry, questionnaires, and cognitive tests.
- Collection of blood, urine, and muscle biopsy samples for biomarker analysis; evaluation of clinical outcome measure sensitivity and minimally clinically important differences.
Main Results:
- Analysis of phenotypic heterogeneity and disease progression in a large DM1 cohort.
- Identification of baseline characteristics that predict disease progression.
- Validation of RNA biomarkers for DM1 severity.
Conclusions:
- Results will aid in optimizing clinical trial design for Myotonic Dystrophy type 1.
- Collected data and biological samples will support future DM1 research.
