Clinical trial NCT03981575: Estab Biomarkers and Clinical Endpoints in Myotonic Dystrophy Type 1 (END-DM1)
Official title: Establishing Biomarkers and Clinical Endpoints in Myotonic Dystrophy Type 1 (END-DM1)
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Myotonic Dystrophy 1
DM1
Keywords: Myotonic Dystrophy
END DM-1
Muscular Dystophy
DMCRN
Lead sponsor: Virginia Commonwealth University
Sponsor class: OTHER
Collaborators: name: University of Rochester
name: Stanford University
name: Ohio State University
name: University of Florida
name: University of Iowa
name: Ludwig-Maximilians - University of Munich
name: Fondazione Serena Onlus - Centro Clinico NeMO Milano
name: The Methodist Hospital Research Institute
name: Radboud University Medical Center
name: University College London Hospitals
name: University of California, Los Angeles
First posted: 2019-06-11
Enrollment: 700
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: DM1 has a prevalence rate of approximately 1 per 2,300. There are no expected gender differences. Both men and women will be selected for this study.

Children with DM1 are not included in this project because the pathophysiological basis of congenital and childhood DM1 appears to be mechanistically distinct.

Brief summary: 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: 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.

Muscle biopsy sub-study: 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.

Longitudinal muscle biopsy sub-study: Up to 30 individuals who have had a prior muscle biopsy as part of a DMCRN study will be asked to undergo another biopsy greater than 24 months after the prior biopsy. These participants will have an additional ad hoc biopsy visit.

COVID-19 sub-study: To evaluate severity of illness and response to COVID-19 vaccination in DM1 patients compared to corresponding data available about the general population, END-DM1 study participants will be asked to complete a one-time survey about COVID-19 experiences. A subset of those participants' blood samples will be analyzed to understand immunoglobulin response to infection and vaccination in DM1 patients.

Actigraphy sub-study: To assess daily physical activity in individuals with DM1 and evaluate physical activity changes over a 12-24 month period related to disease progression, a subset of participants will be asked to wear a small, wireless activity monitor while performing functional assessments described in the main study. Those participants will be asked to wear the activity monitor for 7 days following their research visit. Those participants will be asked to complete additional questionnaires.

Handheld Dynamometry sub-study: To evaluate additional muscle strength methods, a subset of participants will be asked to complete additional strength testing using either the MEDup or MicroFET handheld dynamometry device on the same day as their END-DM1 main study visit. Those participants will be asked to return to the clinic for a second visit within 10 days of the END-DM1 study visit to repeat the handheld dynamometry assessments and complete additional strength measures.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in ambulation over 24 months as measured by the 10 meter walk (m/s).
timeFrame: 12 and 24 months
measure: Change in respiratory function over 24 months as measured by spirometry, specifically the supine forced vital capacity (FVC).
timeFrame: 12 and 24 months
measure: Percent splicing of DM1-affected splice events
timeFrame: 3 months
Secondary outcomes:
Other outcomes:
measure: Longitudinal Muscle Biopsy Sub-study: Characterization of RNA splicing measures over a prolonged period of time (>24 months)
timeFrame: 24 months
measure: Longitudinal Muscle Biopsy Sub-study: Characterization of functional endpoints over a prolonged period of time (>24 months)
timeFrame: 24 months
measure: COVID-19 Sub-study: Data from DM1 patients or caregivers about COVID-19 illness and vaccination experience, severity of illness and response to vaccination in DM1 patients compared to corresponding data available about the general population.
timeFrame: 24 months
measure: COVID-19 Sub-study: Immunoglobulin profile and measles titers, and COVID-19 IgG titers
timeFrame: 24 months
measure: Actigraphy Sub-study: Feasibility of measuring daily physical activity in individuals with DM1 in a multi-site study
timeFrame: 24 months
measure: Actigraphy Sub-study: Objective daily physical activity using wireless accelerometry (ActiGraph), and comparison to normative values and patient reported physical activity.
timeFrame: 24 months
measure: Actigraphy Sub-study: Physical activity changes over a 12-24 month period related to disease progression.
timeFrame: 24 months
measure: Handheld Dynamometry Sub-study: Inter-rater reliability, standard error of measurement, and minimal detectable change of Maximal Isometric Muscle Strength force values obtained with the MEDup and MicroFET handheld dynamometers in adults with DM1
timeFrame: 24 months
measure: Handheld Dynamometry Sub-study: Comparison of quantitative muscle strength testing feasibility and validity between MEDup and MicroFET with the existing Fixed-QMT currently used in the END-DM1 study protocol.
timeFrame: 24 months
Locations:
city: La Jolla
country: United States
facility: University of California, San Diego
state: California
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
city: Denver
country: United States
facility: University of Colorado - Denver
state: Colorado
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Kansas City
country: United States
facility: Kansas University Medical Center
state: Kansas
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Houston
country: United States
facility: Houston Methodist Neurological Institute
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Québec
country: Canada
facility: Université de Sherbrooke
city: München
country: Germany
facility: Friedrich Baur Institute, Ludwig-Maximilians-Universität München
city: Milan
country: Italy
facility: Centro Clinico NeMO
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center
city: Auckland
country: New Zealand
facility: University of Auckland
city: London
country: United Kingdom
facility: St. George's, University of London
city: London
country: United Kingdom
facility: University College London
Study officials:
affiliation: Virginia Commonwealth University
name: Nicholas Johnson, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Rochester
name: Charles Thornton, MD
role: PRINCIPAL_INVESTIGATOR
References: