Dataset Information

Therapeutic opportunities and clinical outcome measures in Duchenne muscular dystrophy.

ABSTRACT:

Introduction

Duchenne muscular dystrophy (DMD) is a devastatingly severe genetic muscle disease characterized by childhood-onset muscle weakness, leading to loss of motor function and premature death due to respiratory and cardiac insufficiency.

Discussion

In the following three and half decades, DMD kept its paradigmatic role in the field of muscle diseases, with first systematic description of disease progression with ad hoc outcome measures and the first attempts at correcting the disease-causing gene defect by several molecular targets. Clinical trials are critical for developing and evaluating new treatments for DMD.

Conclusions

In the last 20 years, research efforts converged in characterization of the disease mechanism and development of therapeutic strategies. Same effort needs to be dedicated to the development of outcome measures able to capture clinical benefit in clinical trials.

SUBMITTER: Ricci G

PROVIDER: S-EPMC9126754 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Publications

Therapeutic opportunities and clinical outcome measures in Duchenne muscular dystrophy.

Ricci Giulia G Bello Luca L Torri Francesca F Schirinzi Erika E Pegoraro Elena E Siciliano Gabriele G

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 20220524 Suppl 2

<h4>Introduction</h4>Duchenne muscular dystrophy (DMD) is a devastatingly severe genetic muscle disease characterized by childhood-onset muscle weakness, leading to loss of motor function and premature death due to respiratory and cardiac insufficiency.<h4>Discussion</h4>In the following three and half decades, DMD kept its paradigmatic role in the field of muscle diseases, with first systematic description of disease progression with ad hoc outcome measures and the first attempts at correcting ...[more]

PMID: 35608735

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Project description:BackgroundDuchenne muscular dystrophy (DMD) is a progressive neuromuscular disease characterized by progressive muscle weakness, multiple system involvement and premature mortality. Effective treatments for DMD through clinical trials and natural history studies are currently underway. Clinical trials in DMD typically include several outcome measures of motor function. Research sites and studies have been found to have slightly different operational definitions for a given functional outcome resulting in different procedures and protocols for these measurements.ObjectiveThe goal of this study is to establish agreement among experts in the field around best practices in collecting functional outcome data in DMD providing researchers and clinicians with guidance on best practices.MethodsA group of 30 experts in Duchenne Muscular Dystrophy (DMD) with experience in the development and/ or execution of lower extremity outcome measures for this population met face to face to identify incongruences in the collection of this data. This effort was based in the United States (US) and sponsored by Parent Project Muscular Dystrophy. Several discrepancies were categorized for each outcome which included: 6-minute walk test, 10-meter walk/run, supine to stand, ascend 4 stairs, sit to stand, and the NorthStar Ambulatory Assessment. Following this meeting an additional 32 experts in DMD (28 from the United States and 11 international participants) consented to participate in a Delphi Survey to reach consensus on the protocols and execution of lower extremity outcomes.ResultsRound one: 70 operationally defined questions were surveyed with 45 (64%) reaching >70% consensus. Round two: 27 questions were operational, with 20 (74%) reaching >70% consensus. Those questions that did not reach consensus appear minor.ConclusionWith minor modifications in the collection of data across sites, outcomes could potentially be normalized across research studies. This would reduce excessive training for evaluators in trials and produce minimal differences between protocols. Consistency in protocols will promote more efficient study start up, less errors between administration of items across studies, and ultimately improve quality and reliability of the functional outcomes. The authors strongly advocate for the establishment of a "research network library" that could be utilized by all those performing clinical assessments and trials in DMD.

Project description:BackgroundOutcome measures for non-ambulant Duchenne muscular dystrophy (DMD) patients are limited, with only the Performance of the Upper Limb (PUL) approved as endpoint for clinical trials.ObjectiveWe assessed four outcome measures based on devices developed for the gaming industry, aiming to overcome disadvantages of observer-dependency and motivation.MethodsTwenty-two non-ambulant DMD patients (range 8.6-24.1 years) and 14 healthy controls (HC; range 9.5-25.4 years) were studied at baseline and 16 patients at 12 months using Leap Motion to quantify wrist/hand active range of motion (aROM) and a Kinect sensor for reached volume with Ability Captured Through Interactive Video Evaluation (ACTIVE), Functional Workspace (FWS) summed distance to seven upper extremity body points, and trunk compensation (KinectTC). PUL 2.0 was performed in patients only. A stepwise approach assessed quality control, construct validity, reliability, concurrent validity, longitudinal change and patient perception.ResultsLeap Motion aROM distinguished patients and HCs for supination, radial deviation and wrist flexion (range p = 0.006 to <0.001). Reliability was low and the manufacturer's hand model did not match the sensor's depth images. ACTIVE differed between patients and HCs (p < 0.001), correlated with PUL (rho = 0.76), and decreased over time (p = 0.030) with a standardized response mean (SRM) of -0.61. It was appraised as fun on a 10-point numeric rating scale (median 9/10). PUL decreased over time (p < 0.001) with an SRM of -1.28, and was appraised as fun (median 7/10). FWS summed distance distinguished patients and HCs (p < 0.001), but reliability in patients was insufficient. KinectTC differed between patients and HCs (p < 0.01), but correlated insufficiently with PUL (rho = -0.69).ConclusionsOnly ACTIVE qualified as potential outcome measure in non-ambulant DMD patients, although the SRM was below the commonly used threshold of 0.8. Lack of insight in technological constraints due to intellectual property and software updates made the technology behind these outcome measures a kind of black box that could jeopardize long-term use in clinical development.

Dataset Information

Therapeutic opportunities and clinical outcome measures in Duchenne muscular dystrophy.

Introduction

Discussion

Conclusions

Publications

Therapeutic opportunities and clinical outcome measures in Duchenne muscular dystrophy.

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