Diagnostics (Mar 2022)

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

  • Dalal Y. Al-Bazz,
  • Andrew J. Nelson,
  • Jamie Burgess,
  • Ioannis N. Petropoulos,
  • Jael Nizza,
  • Anne Marshall,
  • Emily Brown,
  • Daniel J. Cuthbertson,
  • Andrew G. Marshall,
  • Rayaz A. Malik,
  • Uazman Alam

DOI
https://doi.org/10.3390/diagnostics12030731
Journal volume & issue
Vol. 12, no. 3
p. 731

Abstract

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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.

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