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

Abstract

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.

Corneal confocal microscopy detects early nerve regeneration after pharmacological and surgical interventions: Systematic review and meta‐analysis

“…Symptoms and signs have not proven to be robust endpoints in clinical trials of disease‐modifying therapies 4 . NCSs are a quantitative measure of large fibre dysfunction, but we previously identified 21 double‐blind randomized controlled trials of disease‐modifying therapies for DPN, which had failed to demonstrate efficacy due to variability in the magnitude of change and direction of change in the placebo and active arms 5 …”

“…4 NCSs are a quantitative measure of large fibre dysfunction, but we previously identified 21 double-blind randomized controlled trials of disease-modifying therapies for DPN, which had failed to demonstrate efficacy due to variability in the magnitude of change and direction of change in the placebo and active arms. 5 Small fibres contribute to painful neuropathy, a blunted blood flow response to tissue injury, 6 reduced pressure-induced vasodilation 7 and diabetic foot ulcers. 8 Quantitative sensory testing (QST), intraepidermal nerve fibre density (IENFD) in skin biopsies and corneal confocal microscopy (CCM) can be used to assess small fibre dysfunction and damage, respectively.…”