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Orexin Receptor Antagonism in Painful Diabetic Neuropathy

A Phase 2 Trial With Filorexant

Joseph Herring, W. MD, PhD; Ge, Joy Y. PhD; Jackson, Saheeda BS; Assaid, Christopher PhD; Connor, Kathryn M. MD, MHS; Michelson, David MD

doi: 10.1097/AJP.0000000000000503
Original Articles
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Objectives: To evaluate whether orexin receptor antagonism with filorexant provides pain relief in patients with painful diabetic neuropathy (PDN).

Methods: In this double-blind, placebo-controlled, enriched-enrollment, randomized-withdrawal proof-of-concept study, patients with PDN (aged 18 to 75 y) entered a 2-week, single-blind active run-in period with filorexant 10 mg nightly, before randomization 1:1 to placebo or filorexant in a 2-week, double-blind treatment period. The primary efficacy endpoint was time to efficacy failure among “primary responders” (≥30% decrease in evening pain intensity during the run-in). Secondary endpoints were time to efficacy failure among “all responders” (≥20% decrease in evening pain intensity during the run-in) and mean change from baseline in evening pain intensity throughout last 3 days of the double-blind period.

Results: Of the 182 patients treated during the run-in, 170 were randomized in the double-blind period, including 65 primary responders and 88 responders. There was no significant difference in proportion of patients with efficacy failure during the double-blind period with filorexant versus placebo among primary (24.3% vs. 32.1% [P=0.411]) or all (34.0% vs. 43.9% [nominal P=0.302]) responders or in mean change from baseline in evening pain intensity scores (estimated treatment difference: −0.587 [P=0.269], primary; −0.687 [P=0.108], all). Adverse events were reported by 24.7% of patients during the run-in. A higher proportion of patients treated with filorexant versus placebo reported adverse events during the double-blind period (23.9% vs. 13.4%).

Discussion: These data do not provide evidence for the efficacy of nightly filorexant for the treatment of PDN.

Merck & Co. Inc., Kenilworth, NJ

W.J.H.: contributed to the conception/design of the work, data acquisition, analysis, and interpretation; drafted and critically reviewed/revised the manuscript for important intellectual content; approved the version to be published; agreed to be accountable for all aspects of the work. J.Y.G.: contributed to the conception/design of the work, data analysis and interpretation; critically reviewed/revised the manuscript for important intellectual content; approved the version to be published; agreed to be accountable for all aspects of the work. S.J.: contributed to data acquisition; drafted and critically reviewed/revised the manuscript for important intellectual content; approved the version to be published; agreed to be accountable for all aspects of the work. K.M.C.: contributed to data interpretation; drafted and critically reviewed/revised the manuscript for important intellectual content; approved the version to be published; agreed to be accountable for all aspects of the work. C.A. and D.M.: contributed to the conception/design of the work, and to data interpretation; critically reviewed/revised the manuscript for important intellectual content; approved the version to be published; agreed to be accountable for all aspects of the work.

Supported by Merck & Co. Inc., Kenilworth, NJ, W.J.H., J.Y.G., S.J., C.A., K.M.C., and D.M. are current or former employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, and own or owned stock or stock options.

Reprints: W. Joseph Herring, MD, PhD, Merck, UG 4C-13, P.O. Box 1000, North Wales, PA 19454-1099 (e-mail: william_herring@merck.com).

Received September 13, 2016

Received in revised form January 9, 2017

Accepted March 24, 2017

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