Assessing Clinical Endpoints and Biomarkers in Myotonic Dystrophy Type-1 and Type 2 (ASCEND-DM)

Objective: Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are the most common inherited
skeletal myopathies in adults. RNA toxicity is the core disease mechanism, good molecular
targets have been identified and there has been rapid progress in developing targeted
therapies. However, incomplete characterization and limited biologic understanding of
phenotypic heterogeneity, and lack of reliable clinical endpoints and biomarkers remain major
obstacle in the road to therapeutic success in these diseases. The present study seeks to
overcome these roadblocks building on previous work of the Myotonic Dystrophy Clinical
Research Network (DMCRN) (14-N-0132 study) with the following added features: 1) larger DM1
cohort including 11 70 year old individuals; 2) including DM2 individuals, 3) longer study
duration; 4) allowing validation of NIH custombuilt devices for longitudinal measurements;
and 5) including non-muscle endpoints and biomarkers specifically respiratory and central
nervous system (CNS) function, which are important for survival and quality of life. The goal
of the current study is to prospectively assess the disease progression over 2 years in
individuals with DM1 and DM2. Selected tests, imaging and patient-reported outcomes will be
assessed for ability to quantify disease burden, detect disease progression and predict
changes. Additionally, we will examine muscle and cerebrospinal fluid (CSF) RNA alternative
splice events as biomarkers of DM1 and DM2 severity and explore genetic modifiers of DM1 and
DM2 severity by genome wide association (GWA) study.

Study population: This study plans to enroll up to 180 participants: 120 individuals with DM1
and 60 individuals with DM2 (open to both juvenile and adult individuals (11 to 70 years old,
inclusive)) at the NIH Clinical Center.

Study Design: This will be a prospective observational study. No treatment will be
administered as part of this study. Participants will receive standard of care as determined
by their treating physician. Participants will report to the NIH Clinical Center for 3 visits
each: at baseline (Visit 1), at 1-year from baseline (Visit 2), and at 2-years from baseline
(Visit 3). Each visit may last up to seven days and may require the patient to be admitted to
the clinical center. Study procedures for each visit are outlined in Section 4 and Appendix
A. Data and samples will be shared with DMCRN investigators participating in Establishing
Biomarkers and Clinical Endpoints in Myotonic Dystrophy Type 1 (ENDDM1) study as indicated in
Appendix B.

Outcome measures: No specific primary and secondary outcomes will be specified; however, the
change in the following measures from baseline may be used to characterize the baseline
status and disease progression over the course of the study: 1) muscle strength; 2) myotonia;
3) hand and upper arm functional tests; 4) measures of gait, balance and mobility; 5)
skeletal muscle MRI measures of muscle mass and fatty degeneration; 6) skeletal muscle RNA
biomarkers from biopsied tissue; 7) cognitive function; 8) brain MRI measures of gray matter
volume, white matter hyperintensity volume, whole brain volume, integrity of white matter
tracts measured as mean diffusivity and fractional anisotropy and resting state functional
connectivity by functional MRI; 9) pulmonary function tests; 10) MRI measures of the
diaphragm motion and contractility, myocardial function as well as myocardial fat and water
composition and fibrosis; 11) clinical assessments of sleep, speech and swallow and
gastrointestinal motility impairment; and 12) CSF RNA biomarkers and genetic modifiers of DM1
and DM2 severity from a GWA study in collaboration with other DMCRN researchers.

- INCLUSION CRITERIA:

- Age 11 to 70 inclusive

- Competent to provide informed consent and assent (consent of a parent or guardian will
be required for pediatric participants)

- Positive genetic test for DM1 or DM2 (Genetic testing for DM1 or DM2 may be determined
after enrollment

EXCLUSION CRITERIA:

- Concurrent enrollment in a clinical trial or participation in an investigative drug
trial within 6 months of study 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:

- Clinically significant infections or medical illness within 30 days from study entry.

- History of, or abnormal laboratory values indicative of, significant medical,
neurologic (other than DM1 or DM2), or psychiatric disorders.

- A recent history (30 days prior to study entry) of any of the following conditions on
routine blood screening: white blood cells < 3000, platelets < 100,000, hematocrit <
30%, symptomatic liver disease with serum albumin < 3 g/L, or creatinine > 1.5 mg%.

- Any of the following medical conditions: uncontrolled or insulin-dependent diabetes
mellitus, congestive heart failure, symptomatic cardiomyopathy, symptomatic coronary
artery disease, cancer (other than skin cancer) within 5 years from study entry,
multiple sclerosis, or other serious medical illness.

- Other diseases that mimic the signs or symptoms of DM1 or DM2. Coexistence of other
neuromuscular disease.

- Thyroid dysfunction that is untreated (if on thyroid hormone replacement therapy, need
to have adequate and stable replacement over the previous 6 months from study entry).

- Second or third degree heart block, atrial flutter, atrial fibrillation, ventricular
tachycardia, or is receiving medication for the treatment of cardiac arrhythmia.

- Liver or kidney disease requiring ongoing treatment.

- Have a seizure disorder.

- Drug or alcohol abuse within 3 months of study entry (DSM-V criteria will be used for
the diagnosis and level of a substance use disorder:

- Treatment with supplemental anabolic hormones (including testosterone, human
recombinant growth hormone, human recombinant insulin like growth factor-1, other
anabolic drug mixtures) during the previous 12 months from study entry.

- History of bleeding tendency or ongoing oral anticoagulation.

Note: non-ambulatory participants are not excluded but are limited to <15% of enrollment.
Individuals using a cane or walker will not be examined for gait, balance and mobility.