New study may help more DMD patients be included in clinical trials
Problems with arm, lung function seen even before children lose ability to walk
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Most children with Duchenne muscular dystrophy (DMD) start experiencing notable issues with arm function and breathing ability before they lose the ability to walk, a new study reports.
The findings have major implications for clinical trials testing treatments that aim to boost arm and/or lung function in DMD. Traditionally, such studies have enrolled only patients who are nonambulatory (unable to walk), based off the assumption that patients who can still walk won’t have notable problems with arm or lung function. However, the new data indicate that assumption doesn’t actually hold water, meaning many ambulatory patients may be able to be included in such trials in the future.
“These findings should help drug developers include more patients in clinical trials that test for upper-limb or pulmonary function benefits, rather than limiting to patients who cannot walk,” James Signorovitch, PhD, co-author of the study and co-founder of the Collaborative Trajectory Analysis Project, a group that helped lead the study, said in a press release.
The study, “Functional trajectories before and after loss of ambulation in Duchenne muscular dystrophy and implications for clinical trials,” was published in PLOS One. The work was funded in part by CureDuchenne.
‘We cannot leave older patients and young adults behind’
“There is an urgent need for treatments for individuals of all ages and abilities facing this devastating disease,” said Debra Miller, founder and CEO of CureDuchenne. “Research is progressing, but many trials focus on younger and ambulatory populations. We cannot leave older patients and young adults behind. This study demonstrates our need to continuously improve clinical trials in order to best serve our community.”
DMD is characterized by symptoms such as muscle weakness that progressively worsen over time. The disease is highly variable, however, and specific patterns of DMD progression can be very different from person to person. This can make it hard to run clinical trials, since those studies usually try to enroll many patients with similar features to get reliable data.
To better understand the variety of experiences among people with DMD, a team of researchers analyzed data from 51 children with DMD who took part in a natural history study. All of these children had lost the ability to walk during the study, so the researchers were able to compare outcomes from before and after the children hit this DMD progression milestone.
“This study characterized the transition phase between ambulatory and non-ambulatory DMD to better understand how these ‘patients in transition’ can be included in clinical trials of new therapeutics,” the researchers wrote.
They specifically assessed scores on the performance of upper limb 1.2 (PUL), which is a standardized measure of arm function, and forced vital capacity (FVC), which is a standard measure of lung function. A PUL score lower than 6 suggests clinically meaningful problems with arm function, while FVC lower than 80% predicted indicates notable issues with breathing.
Most had problems with arm, lung function by time they lost walking ability
Results showed that, at the time when patients lost the ability to walk, about three-quarters had a PUL score lower than 6, and half had a FVC lower than 80%. In other words, most patients were already experiencing clinically meaningful problems with arm and/or lung function by the time they had lost the ability to walk.
Average scores tended to decline faster after loss of ambulation, but nonetheless showed steady declines even before loss of ambulation. Specifically, average PUL scores worsened by 2.3 points per year before loss of ambulation and by 3.8 points per year after the loss, while average FVC decreased by 5.6% and 10.1% per year, respectively, before and after the loss of ambulation.
More detailed analyses showed losing the ability to walk wasn’t always linked with PUL or FVC scores. Some patients lost the ability to walk but still had good arm and lung function, and others had notable issues with arm or lung function even when they were still able to walk.
Data show inability to walk not useful metric for predicting arm, lung function
Collectively, the data show that whether or not a patient is able to walk isn’t a particularly useful metric for predicting their arm or lung function. As such, clinical trials aiming to boost arm or lung function shouldn’t restrict entry based on walking ability, the researchers wrote.
“Enriching trials for patients with declining pulmonary or upper limb function is achievable without restricting eligibility to non-ambulatory patients; this is particularly important when outcomes of interest evaluate parameters unrelated to lower extremity function such as pulmonary and upper limb function endpoints,” the team wrote.
“The sequencing of [loss of ambulation] and initial deficits in pulmonary and upper limb function varied across patients and highlights the potential for composite outcomes or multi-outcome trial designs to assess disease-modifying therapies more comprehensively,” the scientists added.
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