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

Brief Title

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

Official Title

Assessing Clinical Endpoint and Biomarkers in Myotonic Dystrophy Type-1 and Type-2

Brief Summary


      Myotonic dystrophy is a long-term genetic disorder that affects muscle function. Symptoms
      include gradually worsening muscle loss and weakness. Muscles often contract and cannot
      relax. Researchers want to find out how various tests for DM1 or DM2 change over 2 years, to
      help them develop better tests for people with these diseases. Data and samples from this
      study will be shared with the Myotonic Dystrophy Clinical Research Network (DMCRN)
      investigators participating in the ongoing Establishing Biomarkers and Clinical Endpoints in
      Myotonic Dystrophy Type 1 (ENDDM1) study


      To find better ways to assess how myotonic dystrophy type 1 or type 2 affects people.


      People ages 11 70 with DM1 or DM2


      Participants will have 3 study visits over 2 years. Participants may be admitted to the
      clinic. Each visit may last up to a week and will include:

      Medical history and physical exam

      Blood, heart, and pregnancy tests

      Questions about their disease

      Breathing and muscle tests, including tests of movement, grip, and hand opening

      Speech and swallowing exam

      Magnetic resonance imaging (MRI). Participants will lie on a table that slides into a

      A magnetic field and radio waves will take pictures of the body. They may do a task during
      the scan. They may have a dye injected.

      Pictures of chemicals in the brain or muscle taken in an MRI scanner

      Thinking and memory tests

      Sleep studies. Electrodes placed on the scalp will record the electrical activity of the

      Other devices on the body will measure heartbeat, breathing, movement, and oxygen.

      Tests of electrical activity of muscles. Participants move their arms and legs with disks
      stuck on their skin.

      Visits may also include:

      Exam by a physician expert in stomach and bowel disorders

      A piece of muscle and/or spinal fluid removed by needle

      Sponsoring Institute: National Institute of Neurological Disorders and Stroke


Detailed Description

      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). To reduce fatigue and impact on results, each study visit be split into more than
      one trip to the NIH within a 30 day window) and may require the patient to be admitted to the
      clinical center. Each trip to the NIH for a study visit may last up to seven days. 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.

Study Type


Primary Outcome

to characterize baseline status and disease progression over two years in the handgrip strength by dynamometry of DM1 and DM2 patients.

Secondary Outcome

 CSF RNA biomarkers, genetic modifiers of disease severity


Myotonic Dystrophy Type-1

Study Arms / Comparison Groups

 Individuals with DM1
Description:  Individuals with myotonic dystrophy type 1 (DM1)


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Estimated Enrollment


Start Date

February 24, 2020

Completion Date

July 31, 2027

Primary Completion Date

July 31, 2026

Eligibility 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


          -  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.

        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.




11 Years - 70 Years

Accepts Healthy Volunteers



Ami K Mankodi, M.D., (301) 435-9319, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Secondary IDs


Responsible Party


Study Sponsor

National Institute of Neurological Disorders and Stroke (NINDS)

Study Sponsor

Ami K Mankodi, M.D., Principal Investigator, National Institute of Neurological Disorders and Stroke (NINDS)

Verification Date

January 21, 2021