ABSTRACT Carpal tunnel syndrome is a commonly diagnosed hand disorder that is routinely treated by surgically transecting the transverse carpal ligament to reduce pressure on the median nerve and to alleviate symptoms. Despite known complications of surgery, including reduced hand function and symptom recurrence, the surgical technique has remained fundamentally unchanged since the early twentieth century. Non-surgical interventions where the wrist is therapeutically manipulated have been developed, but these modalities have not gained widespread acceptance due to a lack of scientific and clinical evidence of efficacy. Our previous investigations have identified a novel mechanism for median nerve decompression, the core concept of which is that radioulnar wrist compression leads to carpal arch space augmentation (CASA) and, subsequently, to median nerve decompression. In contrast to currently available therapeutic methods which aim to increase the width of the carpal arch, our approach narrows the arch width in order to increase the arch height and cross- sectional area. This novel biomechanical intervention is supported by our extensive research including in vitro cadaveric experiments, geometric modeling, finite element analysis, in vivo human experimentation, and preclinical feasibility studies. Building upon these scientific and clinical premises, we plan to carry out a single site, double-blinded, randomized controlled clinical trial pilot study to demonstrate the treatment efficacy of CASA for carpal tunnel syndrome and compare the therapeutic effects with a sham device. The Specific Aims of the project are (1) to demonstrate that non-surgical CASA intervention improves symptoms and hand function in patients with carpal tunnel syndrome; (2) to compare the clinical outcomes of CASA intervention with a sham intervention; and (3) to demonstrate the feasibility and scalability of a multisite, randomized controlled, full-scale clinical trial comparing CASA intervention and sham intervention. We hypothesize that (i) four-weeks of CASA intervention will alleviate carpal tunnel syndrome symptoms and improve hand function and that the beneficial effects will persist beyond the intervention period; (ii) CASA intervention will result in greater improvement of symptoms and function than the sham intervention; and (iii) recruitment will be feasible, retention rates and compliance will be acceptable, and the treatment will be safe. Results of this pilot clinical trial will allow us to understand the expected treatment effects of CASA intervention, refine sample size, set expectations for patient compliance and dropout rates, and inform the design of a larger scale multisite randomized controlled clinical trial of CASA intervention. This pilot trial is a crucial step in our preparation to effectively launch a full-scale multisite clinical trial, eventually translating our scientifically meritorious biomechanical principle of CASA and research findings in...