Is Nerve Electrophysiology a Robust Primary Endpoint in Clinical Trials of Treatments for Diabetic Peripheral Neuropathy?

• Published in: Diagnostics (Basel) Vol. 12; no. 3; p. 731
• Main Authors: Al-Bazz, Dalal Y, Nelson, Andrew J, Burgess, Jamie, Petropoulos, Ioannis N, Nizza, Jael, Marshall, Anne, Brown, Emily, Cuthbertson, Daniel J, Marshall, Andrew G, Malik, Rayaz A, Alam, Uazman
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 17.03.2022; MDPI
• Subjects: Clinical trials; Diabetes; Diabetic neuropathy; Endothelium; FDA approval; Growth factors; Kinases; nerve electrophysiology; Neurophysiology; Peptides; Peripheral neuropathy; Proteins; Review; Systematic review; nerve electrophysiology; diabetes; peripheral neuropathy
• ISSN: 2075-4418; 2075-4418
• DOI: 10.3390/diagnostics12030731

There is currently no FDA-approved disease-modifying therapy for diabetic peripheral neuropathy (DPN). Nerve conduction velocity (NCV) is an established primary endpoint of disease-modifying therapies in DPN and clinical trials have been powered with an assumed decline of 0.5 m/s/year. This paper sought to establish the time-dependent change in NCV associated with a placebo, compared to that observed in the active intervention group. A literature search identified twenty-one double-blind, randomised controlled trials in DPN of ≥1 year duration conducted between 1971 and 2021. We evaluated changes in neurophysiology, with a focus on peroneal motor and sural sensory NCV and amplitude in the placebo and treatment groups. There was significant variability in the change and direction of change (reduction/increase) in NCV in the placebo arm, as well as variability influenced by the anatomical site of neurophysiological measurement within a given clinical trial. A critical re-evaluation of efficacy trials should consider placebo-adjusted effects and present the placebo-subtracted change in NCV rather than assume a universal annual decline of 0.5 m/s/year. Importantly, endpoints such as corneal confocal microscopy (CCM) have demonstrated early nerve repair, whilst symptoms and NCV have not changed, and should thus be considered as a viable alternative.