{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T01:58:16Z","timestamp":1792461496307,"version":"4.5.0"},"reference-count":18,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T00:00:00Z","timestamp":1655769600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Pain"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Painful diabetic peripheral neuropathy (PDPN) affects up to 26% of patients with diabetes mellitus, with major impacts on their general health and well\u2010being. Most available drugs fail to deliver acceptable pain reduction in the majority of patients and are often poorly tolerated. NRD.E1 is a novel product that has shown anti\u2010nociceptive preclinical effects and good tolerability in healthy volunteer studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This phase 2a, randomized, dose\u2010finding, Proof of Concept study enrolled patients with PDPN of \u22653\u2009months duration. After at least one treatment\u2010free week (WO week), 88 patients entered a 1\u2010week single\u2010blind (SB)\u2010placebo run\u2010in period, followed by 3\u2009weeks' double\u2010blind (DB) treatment, during which they received NRD.E1 at 10, 40 or 150\u00a0mg\/day or placebo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The primary endpoint (change from SB\u2010placebo run\u2010in week to week 3 in weekly mean of daily average numerical rating scale [NRS] pain intensity) showed clinically relevant placebo\u2010corrected treatment effect pain reductions at 40\u2009mg and 150\u2009mg\/day of 0.82 (95% CI: 0.07, 1.58, <jats:italic>p<\/jats:italic>\u00a0=\u00a00.034) and 0.66 (95% CI: \u22120.03, 1.35; <jats:italic>p<\/jats:italic>\u00a0=\u00a00.061) NRS points, respectively, though did not meet the pre\u2010specified value of <jats:italic>p<\/jats:italic>\u00a0=\u00a00.016 required due to multiplicity. An additional <jats:italic>post hoc<\/jats:italic> endpoint looking at the change from WO baseline to week 3 in weekly mean of daily average NRS showed the placebo\u2010corrected treatment effect was 1.46 (95% CI: 0.26, 2.66), and 1.20 (95% CI: 0.10, 2.29) NRS points, respectively. Secondary and <jats:italic>post hoc<\/jats:italic> analyses of NRS pain data (including 30 &amp; 50% responder rate and NNT), sleep interference, Short\u2010form McGill pain questionnaire (especially pain intensity assessed on Visual Analogue Scale), Patient's and Clinician's Global Impression of Change showed effects consistent with the primary findings. NRD.E1 was well tolerated, with only headache reported in more than two patients and more frequently on NRD.E1 than placebo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The data suggest that NRD.E1 potentially represents a novel non\u2010opioid therapeutic option for patients with PDPN, with at least similar efficacy and better tolerability than available therapies, justifying its further evaluation in larger\u2010scale confirmatory studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>NRD.E1 is a novel non\u2010opioid therapeutic which is being developed for the treatment of PDPN. In this randomized, controlled, dose\u2010finding, Proof of Concept study, NRD.E1 induced a clinically relevant pain reduction and it was well tolerated. Available data suggest that NRD.E1 has at least similar efficacy and better tolerability than the currently available therapies, potentially offering a promising new therapeutic option to patients with PDPN and possibly other neuropathic pain indications.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ejp.1989","type":"journal-article","created":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T15:44:46Z","timestamp":1654616686000},"page":"1665-1678","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["NRD.E1, an innovative non\u2010opioid therapy for painful diabetic peripheral neuropathy\u2014A randomized proof of concept study"],"prefix":"10.1002","volume":"26","author":[{"given":"Eva","family":"Tiecke","sequence":"first","affiliation":[{"name":"Novaremed AG  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4450-5751","authenticated-orcid":false,"given":"Maurizio","family":"Rainisio","sequence":"additional","affiliation":[{"name":"Novaremed AG  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3748-1349","authenticated-orcid":false,"given":"Elon","family":"Eisenberg","sequence":"additional","affiliation":[{"name":"Faculty of Medicine Technion, Israel Institute of Technology  Haifa Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2035-9243","authenticated-orcid":false,"given":"Julio","family":"Wainstein","sequence":"additional","affiliation":[{"name":"Wolson Medical Center  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eli","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Novaremed AG  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Silverberg","sequence":"additional","affiliation":[{"name":"Novaremed Ltd  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liat","family":"Hochman","sequence":"additional","affiliation":[{"name":"Novaremed Ltd  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Mangialaio","sequence":"additional","affiliation":[{"name":"Novaremed AG  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,6,21]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2004.12.010"},{"key":"e_1_2_9_3_1","volume-title":"Statistical power analysis for the behavioral sciences","author":"Cohen J.","year":"1998"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc05\u20102228"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2012.03.003"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1474\u20104422(14)70251\u20100"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000001340"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2014.05.025"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000259085.61898.9e"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.3132\/dvdr.2006.013"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304\u20103959(87)91074\u20108"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc16\u20102042"},{"issue":"4","key":"e_1_2_9_13_1","first-page":"103","article-title":"An overview of peripheral neuropathy in diabetes","volume":"21","author":"Sheehan P.","year":"2009","journal-title":"Wounds"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000001849"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/papr.12054"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.1103"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20591"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1080\/00031305.2016.1154108"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdiacomp.2014.08.008"}],"container-title":["European Journal of Pain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ejp.1989","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ejp.1989","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ejp.1989","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T06:12:13Z","timestamp":1693548733000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ejp.1989"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,21]]},"references-count":18,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2022,9]]}},"alternative-id":["10.1002\/ejp.1989"],"URL":"https:\/\/doi.org\/10.1002\/ejp.1989","archive":["Portico"],"relation":{},"ISSN":["1090-3801","1532-2149"],"issn-type":[{"value":"1090-3801","type":"print"},{"value":"1532-2149","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,21]]},"assertion":[{"value":"2021-12-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-05-30","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-06-21","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}