Variability of Molecular Biomarkers and Clinical Measures in People With Myotonic Dystrophy Type 1

Objective: Myotonic dystrophy type 1 (DM1) is one of the most prevalent inherited
neuromuscular disorders that leads to severe disability and premature death. DM1 is caused
by toxic effects of mutant RNA, which involve sequestration of splicing factors and
consequent abnormal splicing of genes expressed in skeletal muscle. There is no effective
therapy for DM1. However, recent studies suggest that DM1 may respond to RNA targeted
therapies. With the promise of new therapies in DM1, there is a need for natural history
data, clinical endpoints, and biomarkers to support the design and implementation of
clinical trials. The goal of the current study is to prospectively assess the variability of
clinical measures and molecular biomarkers of DM1 disease severity in multicenter studies.

Study population: We aim to screen up to 29 adult DM1 patients (18 to 70 years old,
inclusive) at the NIH for enrollment in the study. Approximately 100 adult patients with DM1
will be enrolled at 6 study sites.

Design: Patients will report to the NIH study site for 3 visits: screening/baseline (Visit
1), 3 months plus or less 2 weeks (Visit 2), and 12 months plus or less 4 weeks (Visit 3).
No treatment will be administered as part of this study. Patients will receive standard care
as determined by their treating physician.

Outcome measures: The primary outcome measures are the mean and variance of the biomarker
values, i.e., ratio of 2 alternative splice products from the same gene, in skeletal muscle
at baseline and 3 months and the change from baseline (see Appendix B). The secondary
outcome measures are the mean and variance at baseline, 3 months, and 12 months for (1)
myotonia, (2) muscle strength and (3) patient perception of disease burden. Exploratory
outcome measures include assessment of mean and variance of the following measures at
baseline, 3 months and 12 months: (1) muscle function (2) whole body muscle mass by
dual-energy X-ray absorptiometry (DEXA) scan, (3) quality of life, (4) the following
measures of cognitive function: (i) Detection task (processing speed), (ii) Groton Maze
Learning Test (executive function), (iii) One Back task (working memory), (iv)
Identification task (visual attention), and (5) correlation analysis between the RNA
biomarkers of aberrant splicing and the strength of the tibialis anterior (TA) muscle as
measured by manual and quantitative muscle testing as well as ankle intellistretch device.
In addition, serum and plasma may be analyzed for exploratory RNA and protein biomarkers.

- INCLUSION CRITERIA:

To be eligible to participate in this study, candidates must meet the following
eligibility criteria at Visit 1:

- Ability to understand the purpose and risks of the study and provide signed and dated
informed consent and authorization to use protected health information in accordance
with national and local patient privacy regulations.

- Men and women, 18 to 70 years old, inclusive; body mass index less than or equal to
33.

- Onset of DM1 after age 10.

- Clinical diagnosis of DM1 based on research criteria or prior genetic testing with
confirmation of DMPK CTG repeat length greater than or equal to 70. Note that the
number of patients with repeat lengths of 70 to 100 will be limited to 3 per site. A
genetic test confirming DM1 is not required for entry. As discussed below, many
individuals with DM1 who are followed in neuromuscular clinics have never had a
genetic test, and genetic testing confirms DM1 in > 99% of individuals who meet
clinical criteria. A DNA sample will be obtained from all subjects during the first
study visit for DM1 mutation analysis. CTG repeat testing will be run even if
subjects have previously had this tested. If this test does not show an expanded
repeat in DMPK the subject will be withdrawn from the study.

- Ability to complete a 6 minute walk test (ankle foot orthoses allowed, but cane and
walker are not).

EXCLUSION CRITERIA:

Candidates will be excluded from study entry if any of the following exclusion criteria
exist at Visit 1 or at the time point specified in the individual criterion listed:

- Clinically significant infections or medical illness from 30 days prior to Visit 1.

- History of, or abnormal laboratory values indicative of, significant medical,
neurologic (other than DM1), or psychiatric disorders that might preclude
participation in the study in the opinion of the Investigator.

- A recent history 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 the prior 5 years, multiple
sclerosis, or other serious medical illness.

- Myotonic dystrophy type 2 or other diseases that mimic the signs or symptoms of DM1.
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).

- 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 Visit 1.

- Women who are pregnant or breastfeeding or who plan to become pregnant during the
study s duration.

- 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.

- History of bleeding tendency or ongoing oral anticoagulation.

- Hypersensitivity to local anesthetics or components thereof to be used in the biopsy
procedure.

- Participation in any investigational treatment study within 6 months prior to Visit
1.

- Inability or unwillingness to undergo any of the study-specific procedures or
assessments, including needle muscle biopsies.

- Medical or other unspecified reasons that in the opinion of the Investigator makes
the patient unsuitable for enrollment.

- Treatment with any of the following anti-myotonia medications within 8 weeks prior to
the study entry and 1 year thereafter:

- phenytoin

- carbamazepine

- procainamide

- disopyramide

- nifedipine

- acetazolamide

- clomipramine

- imipramine

- mexiletine

- Treatment with corticosteroids within 8 weeks prior to Visit 1.