Background: The transepithelial nasal potential difference (NPD) is used to assess cystic fibrosis transmembrane conductance regulator (CFTR) activity. Unreliability, excessive artifacts, and lack of standardization of current testing systems can compromise its use as a diagnostic test and outcome measure for clinical trials. Methods: To determine whether a nonperfusing (agar gel) nasal catheter for NPD measurement is more reliable and less susceptible to artifacts than a continuously perfusing nasal catheter, we performed a multicenter, randomized, crossover trial comparing a standardized NPD protocol using an agar nasal catheter with the same protocol using a continuously perfusing catheter. The data capture technique was identical in both protocols. A total of 26 normal adult subjects underwent NPD testing at six different centers. Results: Artifact frequency was reduced by 75% (P < .001), and duration was less pronounced using the agar catheter. The measurement of sodium conductance was similar between the two catheter methods, but the agar catheter demonstrated significantly greater CFTR-dependent hyperpolarization, because Δ zero Cl- + isoproterenol measurements were significantly more hyperpolarized with the agar catheter (-24.2 ± 12.9 mV with agar vs 18.2 ± 9.1 mV with perfusion, P < .05). Conclusions: The agar nasal catheter approach demonstrates superior reliability compared with the perfusion nasal catheter method for measurement of NPD. This nonperfusion catheter method should be considered for adoption as a standardized protocol to monitor CFTR activity in clinical trials.
Bibliographical noteFunding Information:
Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Konstan has been a paid consultant during the past 3 years to Boehringer-Ingelheim, CSL-Behring, Genentech, GlaxoSmithKline (GSK), Gilead, NanoBio, Nektar, Novartis, PTC Therapeutics, Transave, and Vertex. He is a member of a scientific advisory board for Aradigm and Genentech and has participated as a speaker for Genentech and Roche. Dr Accurso has received grants from pharmaceutic companies for the conduct of clinical trials. He has received grant monies from the National Institutes of Health (NIH), the Cystic Fibrosis Foundation (CFF), and the CFF Therapeutics for the conduct of research. He has received one honorarium from Inspire Pharmaceuticals for one speaking activity. Dr Ashlock declares, in the general course of her work in the field of CF and therapeutics discovery and development, that she participated, and will likely continue to participate, as an advisor, speaker, and consultant for various events related to the and general subject of this manuscript. In some instances, these events have been sponsored by, or the work has been performed for, commercial entities that perform clinical trials in CF. Dr Clancy has received grant funding from the NIH, CFF, and Maternal Child Health Bureau to support investigator-initiated research projects. He has also received grants from industry to support the conduct of clinical trials. These companies include Vertex, PTC, GSK, Transave, Gilead, Inspire, Novartis, and Kalabios. Dr Rowe receives research grants from the NIH and the CFF, and contracts for clinical trials from PTC Therapeutics and Vertex Pharmaceuticals, and has provided consulting services for PTC, Vertex, and CFF. Drs Solomon, Wilschanski, Billings, Sermet-Gaudelus, Vermeulen, Hill, and Mayer-Hamblett, and Mss Levin, Hathorne, Reeves, and Sabbatini have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Funding/Support: This research was funded by the US National Institutes of Health [Grants 1K23DK075788-01 and 1R03DK084110-01 (to Dr Rowe) and Grant 1P30DK072482-01A1 (to Eric J. Sorscher) ] and the Cystic Fibrosis Foundation [Grants CLANCY05Y2 (Drs Clancy and Rowe) and RAMSEY03Y0 (to the Therapeutics Development Network Coordinating Center)].
Role of sponsors: This project was supported in part by grants from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; or the NIH.