Design and Rationale of an Adaptive Multisite Randomized Crossover Trial in Wagner Grade 1 Diabetic Foot Ulcers

Abstract

Background: Randomized controlled trials in wound care are frequently challenged by heterogeneous patient populations, variability in background standard of care, and ethical concerns related to prolonged exposure to ineffective therapy. These issues are particularly pronounced in diabetic foot ulcer research, where ischemia, neuropathy, infection, and biofilm may independently influence healing outcomes and confound interpretation of treatment effects.

Aims: To describe the design and methodological rationale of a multisite, adaptive randomized controlled trial evaluating a three-dimensional acellular collagen matrix (3D-ACM) used in conjunction with standardized care compared with standardized care alone in Wagner grade 1 diabetic foot ulcers and surgical wound dehiscence below the malleolus.

Methods: Adults enter a standardized two-week run-in period with protocolized standard of care prior to randomization. Participants are then randomized 1:1 to receive 3D-ACM plus standardized care or standardized care alone. The primary endpoint is complete re-epithelialization of the index wound by week 12, confirmed at two consecutive visits. Achievement of >=50% percentage area reduction at week 4 is assessed as a key secondary endpoint and informs adaptive trial features. Participants assigned to standardized care alone undergo a mandatory futility assessment at week 8; those with <=50% percentage area reduction may cross over to investigational treatment at the subsequent visit. A Bayesian assurance-based framework supports adaptive sample size planning and interim evaluation. In parallel, a prospective registry captures non-randomized patients to generate real-world data. Exploratory endpoints include tissue oximetry, thermography, and bacterial fluorescence imaging to evaluate mechanistic contributors to healing.

Results: Enrollment and follow-up are ongoing. This manuscript focuses on trial design and analytical framework rather than treatment efficacy.

Conclusion: This adaptive crossover trial integrates methodological rigor with ethical responsiveness and may serve as a model for evaluating advanced biologic therapies in complex wound populations.