DM1 Patients Asked to Join Natural History Study Aiming for Better Clinical Trials

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by Forest Ray PhD |

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The Myotonic Dystrophy Clinical Research Network (DMCRN) is asking adults with myotonic dystrophy type 1 (DM1) to participate in a large natural history study aimed at improving clinical trials by better understanding the full spectrum of the disorder.

“Prior drug studies have been limited by a lack of understanding of the disease, preventing the ability to truly test whether these therapies are effective,” Nicholas Johnson, MD, the study’s co-primary investigator and a neurologist at Virginia Commonwealth University (VCU) Health, said in a university news release.

The study, “Establishing Biomarkers and Clinical Endpoints in Myotonic Dystrophy Type 1” (END-DM1, NCT03981575) seeks to enroll about 700 people, ages 18 to 70, with a diagnosis of DM1 based on clinical criteria or a positive genetic test.

Sixteen sites across the U.S. and Europe are participating in the trial. More information on locations is available here, and ways of contacting the team at VCU are listed here. The study’s coordinating center is at VCU, while the University of Rochester is the co-coordinating site and data center.

DM1 is a progressive illness that — depending on its severity — causes skeletal muscle weakness and wasting, and muscle stiffness or tensing (myotonia). Other symptoms can include cataracts, cardiac arrhythmias, breathing difficulties, fatigue and pain, as well as diabetes, thyroid problems, brain problems, and excessive daytime sleepiness.

As a natural history study, END-DM1 aims to observe participants’ disease course over time, rather than test any particular therapy.

Enrolled patients will be given standard care and are required to make three clinical visits over the study period: an initial (baseline) visit, then two more at one and two years.

The trial’s primary outcomes are changes in ambulation as measured by the 10-meter walk and changes in respiratory function as measured by forced vital capacity. A subgroup of 95 volunteers will also undergo a muscle biopsy, whose samples will be used to measure DM1-related splicing markers, and asked to make an additional study visit at three months.

A type of mutation called a trinucleotide repeat expansion in the DMPK gene underlies DM1. Normally, three DNA building blocks, known as nucleotides — CTG in this case — are copied repeatedly in the gene, but people with DM1 have an excessive number of such repeats (hundreds to thousands). A greater number of repeats correlates with an earlier age of onset and more severe disease.

Investigators hope study results will, in addition to a better disease understanding, enable them to optimize biomarkers used in clinical studies of myotonic dystrophy, and to refine trial protocols to better capture patients with more rapid progression. All this, in turn, will support the development of DM1 treatment options.

Johnson said that this information is especially needed to appropriately test potential precision medicine therapies, those tailored to individual patients, that are coming into clinical testing.

The study builds on previous work of the DMCRN, which is headed by Charles Thornton, MD, of the University of Rochester Medical Center and a co-primary investigator of the END-DM1 trial. The network focuses on developing methods to measure disease progression and establish clinical outcome markers to document treatment efficacy.

More contact information for the END-DM1 trial, as well as other DMCRN-sponsored myotonic dystrophy trials that are currently recruiting, can be found here.