To address a gap in DPN treatments, we propose a pragmatic approach towards the development of mechanistically justified therapies to treat DPN. Specifically, we seek to explore undertested non-pharmacological approaches to DPN management through a pilot study establishing safety and feasibility as quantified by biomechanical and sensory-perception changes.
The innovation central to this approach is in the multifactorial combination of pressure, heat, and vibration stimuli to improve foot sensation by 1) reducing edema in the foot and leg via improved venous return and lymphatic return, 2) improving arterial flow both in large, small, and micro-vascular vessels, 3) stimulating endothelial mechanisms like the increase of nitrous oxide that increases microvascular health through alternating compressive pressures from the foot to the thigh, and 4) stimulating nerves through vibration to facilitate nerve repair. This approach has the potential to address an unmet need in DPN, namely, interventions that can address underlying causes of neuropathy. To this end, the proposed research has two specific aims: 1) the construction of a device capable of applying pressure, heat, and vibration to the entire lower extremity for treatment of neuropathy and 2) validation of safety and feasibility of the non-pharmacological intervention device.
At the beginning of the study, foot sensation and blood flow baseline measures will be taken with the foot sensation diagnostic tool and phase-contrast MRI with a foot/ankle coil (Siemens Foot/Ankle 16) at the Auburn University MRI Research Center, respectively. The foot sensation diagnostic tool has undergone testing with over 100 participants with diabetes, and has shown the ability to establish the threshold sensitivity of the sole of the foot from 0.5 to 10 grams force, an order of magnitude more accurate than the standard clinical monofilament-based measure used to establish foot sensitivity and diagnose DPN. The phase-contrast MRI is a highly accurate measure of blood flow, which we will use to validate the mechanistic hypothesis of the proposed non-pharmacological intervention. The phase-contrast MRI does not require the use of contrast-enhancing dyes, and will therefore exclude fewer diabetic participants than contrast-enhanced MRI scans.
During the study, each participant will receive the same 45-minute intervention on 10 days spread over no more than 14 days total, in a similar manner to IPC studies. At the end of each session, pain will be assessed on scales such as the Defense and Veterans Pain Rating Scale (DVPRS) to establish the safety of the proposed intervention. Feasibility will be determined of time to set up, put on, and take off the device. Pre-study baseline measurements of foot sensation via the assessment tool will be compared to post-study measurements to establish any beneficial effect and provide variance for a power analysis to guide the design of future studies. We hypothesize that non-neuropathic diabetic participants may have subclinical neuropathic symptoms which cannot be measured by standard clinical tools but can be measured by the diagnostic device, which may identify the potential for the device to have preventative as well as treatment applications.
Sample Size Justification: A sample size of 16 subjects (8 with non-neuropathic diabetic and 8 with neuropathic diabetic participants) achieves 80% power to detect an effect size as measured in the change in pain scores of 0.55 using a paired t-test with a one tailed Type I error rate of 0.10. Examination of each subgroup will also be conducted. A sample size of 8 subjects achieves 80% power to detect an effect size as measured in the change in pain scores of 0.8 using a paired t-test with a one tailed Type I error rate of 0.10. Therefore, this small study will have statistical power to observe medium to large changes in pain rating (or foot sensation or blood flow). However, it must be noted that achieving statistical significance is not the primary objective of a pilot study. The primary objective is to demonstrate feasibility of the trial by initiating a small version of the trail, identifying areas requiring refinement, and collecting preliminary data provides preliminary evidence of intended effect.
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