A multicenter, double-blind, randomized, parallel-group, placebo-controlled study to evaluate the efficacy and safety of camostat mesilate in patients with COVID-19 (CANDLE study)

{ 'indexed': {'date-parts': [[2023, 10, 5]], 'date-time': '2023-10-05T17:40:34Z', 'timestamp': 1696527634315}, 'reference-count': 33, 'publisher': 'Springer Science and Business Media LLC', 'issue': '1', 'license': [ { 'start': { 'date-parts': [[2022, 9, 27]], 'date-time': '2022-09-27T00:00:00Z', 'timestamp': 1664236800000}, 'content-version': 'tdm', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0'}, { 'start': { 'date-parts': [[2022, 9, 27]], 'date-time': '2022-09-27T00:00:00Z', 'timestamp': 1664236800000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0'}], 'funder': [{'DOI': '10.13039/501100013170', 'name': 'Ono Pharmaceutical', 'doi-asserted-by': 'publisher'}], 'content-domain': {'domain': ['link.springer.com'], 'crossmark-restriction': False}, 'abstract': '<jats:title>Abstract</jats:title><jats:sec>\n' ' <jats:title>Background</jats:title>\n' ' <jats:p>In vitro drug screening studies have indicated that camostat mesilate ' '(FOY-305) may prevent SARS-CoV-2 infection into human airway epithelial cells. This study was ' 'conducted to investigate whether camostat mesilate is an effective treatment for SARS-CoV-2 ' 'infection (COVID-19).</jats:p>\n' ' </jats:sec><jats:sec>\n' ' <jats:title>Methods</jats:title>\n' ' <jats:p>This was a multicenter, double-blind, randomized, parallel-group, ' 'placebo-controlled study. Patients were enrolled if they were admitted to a hospital within ' '5\xa0days of onset of COVID-19 symptoms or within 5\xa0days of a positive test for ' 'asymptomatic patients. Severe cases (e.g., those requiring oxygenation/ventilation) were ' 'excluded. Patients were enrolled, randomized, and allocated to each group using an ' 'interactive web response system. Randomization was performed using a minimization method with ' 'the factors medical institution, age, and underlying diseases (chronic respiratory disease, ' 'chronic kidney disease, diabetes mellitus, hypertension, cardiovascular diseases, and ' 'obesity). The patients, investigators/subinvestigators, study coordinators, and other study ' 'personnel were blinded throughout the study. Patients were administered camostat mesilate ' '(600\xa0mg qid; four to eight times higher than the clinical doses in Japan) or placebo for ' 'up to 14\xa0days. The primary efficacy endpoint was the time to the first two consecutive ' 'negative tests for SARS-CoV-2.</jats:p>\n' ' </jats:sec><jats:sec>\n' ' <jats:title>Results</jats:title>\n' ' <jats:p>One-hundred fifty-five patients were randomized to receive camostat ' 'mesilate (<jats:italic>n</jats:italic>\u2009=\u200978) or placebo ' '(<jats:italic>n</jats:italic>\u2009=\u200977). The median time to the first test was 11.0\xa0' 'days (95% confidence interval [CI]: 9.0–12.0) in the camostat mesilate group and 11.0\xa0days ' '(95% CI: 10.0–13.0) in the placebo group. Conversion to negative viral status by day 14 was ' 'observed in 45 of 74 patients (60.8%) in the camostat mesilate group and 47 of 74 patients ' '(63.5%) in the placebo group. The primary (Bayesian) and secondary (frequentist) analyses ' 'found no significant differences in the primary endpoint between the two groups. No ' 'additional safety concerns beyond those already known for camostat mesilate were ' 'identified.</jats:p>\n' ' </jats:sec><jats:sec>\n' ' <jats:title>Conclusions</jats:title>\n' ' <jats:p>Camostat mesilate did not substantially reduce the time to viral ' 'clearance, based on upper airway viral loads, compared with placebo for treating patients ' 'with mild to moderate SARS-CoV-2 infection with or without symptoms.</jats:p>\n' ' </jats:sec><jats:sec>\n' ' <jats:title>Trial registration</jats:title>\n' ' <jats:p>ClinicalTrials.gov, NCT04657497. Japan Registry for Clinical Trials, ' 'jRCT2031200198.</jats:p>\n' ' </jats:sec>', 'DOI': '10.1186/s12916-022-02518-7', 'type': 'journal-article', 'created': {'date-parts': [[2022, 9, 27]], 'date-time': '2022-09-27T00:02:33Z', 'timestamp': 1664236953000}, 'update-policy': 'http://dx.doi.org/10.1007/springer_crossmark_policy', 'source': 'Crossref', 'is-referenced-by-count': 9, 'title': 'A multicenter, double-blind, randomized, parallel-group, placebo-controlled study to evaluate ' 'the efficacy and safety of camostat mesilate in patients with COVID-19 (CANDLE study)', 'prefix': '10.1186', 'volume': '20', 'author': [ {'given': 'Taku', 'family': 'Kinoshita', 'sequence': 'first', 'affiliation': []}, {'given': 'Masahiro', 'family': 'Shinoda', 'sequence': 'additional', 'affiliation': []}, {'given': 'Yasuhiro', 'family': 'Nishizaki', 'sequence': 'additional', 'affiliation': []}, {'given': 'Katsuya', 'family': 'Shiraki', 'sequence': 'additional', 'affiliation': []}, {'given': 'Yuji', 'family': 'Hirai', 'sequence': 'additional', 'affiliation': []}, {'given': 'Yoshiko', 'family': 'Kichikawa', 'sequence': 'additional', 'affiliation': []}, {'given': 'Kenji', 'family': 'Tsushima', 'sequence': 'additional', 'affiliation': []}, {'given': 'Masaharu', 'family': 'Shinkai', 'sequence': 'additional', 'affiliation': []}, {'given': 'Naoyuki', 'family': 'Komura', 'sequence': 'additional', 'affiliation': []}, {'given': 'Kazuo', 'family': 'Yoshida', 'sequence': 'additional', 'affiliation': []}, {'given': 'Yasutoshi', 'family': 'Kido', 'sequence': 'additional', 'affiliation': []}, {'given': 'Hiroshi', 'family': 'Kakeya', 'sequence': 'additional', 'affiliation': []}, {'given': 'Naoto', 'family': 'Uemura', 'sequence': 'additional', 'affiliation': []}, {'given': 'Junichi', 'family': 'Kadota', 'sequence': 'additional', 'affiliation': []}], 'member': '297', 'published-online': {'date-parts': [[2022, 9, 27]]}, 'reference': [ { 'key': '2518_CR1', 'doi-asserted-by': 'publisher', 'unstructured': 'Hale T, Angrist N, Hale AJ, Kira B, Majumdar S,\xa0Petherick\xa0A, et ' 'al. 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' '2022;66(7):e0019222.\xa0https://doi.org/10.1128/aac.00192-22.\xa0', 'DOI': '10.1128/aac.00192-22'}], 'container-title': 'BMC Medicine', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://link.springer.com/content/pdf/10.1186/s12916-022-02518-7.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://link.springer.com/article/10.1186/s12916-022-02518-7/fulltext.html', 'content-type': 'text/html', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://link.springer.com/content/pdf/10.1186/s12916-022-02518-7.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2022, 12, 9]], 'date-time': '2022-12-09T07:03:46Z', 'timestamp': 1670569426000}, 'score': 1, 'resource': { 'primary': { 'URL': 'https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-022-02518-7'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2022, 9, 27]]}, 'references-count': 33, 'journal-issue': {'issue': '1', 'published-online': {'date-parts': [[2022, 12]]}}, 'alternative-id': ['2518'], 'URL': 'http://dx.doi.org/10.1186/s12916-022-02518-7', 'relation': {}, 'ISSN': ['1741-7015'], 'subject': ['General Medicine'], 'container-title-short': 'BMC Med', 'published': {'date-parts': [[2022, 9, 27]]}, 'assertion': [ { 'value': '28 April 2022', 'order': 1, 'name': 'received', 'label': 'Received', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '5 August 2022', 'order': 2, 'name': 'accepted', 'label': 'Accepted', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '27 September 2022', 'order': 3, 'name': 'first_online', 'label': 'First Online', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '8 December 2022', 'order': 4, 'name': 'change_date', 'label': 'Change Date', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': 'Correction', 'order': 5, 'name': 'change_type', 'label': 'Change Type', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': 'A Correction to this paper has been published:', 'order': 6, 'name': 'change_details', 'label': 'Change Details', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': 'https://doi.org/10.1186/s12916-022-02695-5', 'URL': 'https://doi.org/10.1186/s12916-022-02695-5', 'order': 7, 'name': 'change_details', 'label': 'Change Details', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, {'order': 1, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Declarations'}}, { 'value': 'This study adhered to the Declaration of Helsinki, Good Clinical Practice, and ' 'relevant local/international guidelines. The protocol and patient consent forms ' 'were first reviewed and approved by the institutional review board at the ' 'leading study site (International University of Health and Welfare Narita ' 'Hospital, approval number FN-1-2005-075) and subsequently by the institutional ' 'review boards/ethics committees at all participating sites, which are listed in ' 'Additional file InternalRef removed: IRB information. All patients provided ' 'written informed consent to participate in this study.', 'order': 2, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Ethics approval and consent to participate'}}, { 'value': 'Not applicable.', 'order': 3, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Consent for publication'}}, { 'value': 'The sponsor provided funding for the study and publication of the manuscript. ' 'Employees of the sponsor were involved in the study design and collection, ' 'analysis, and interpretation of the data and reviewed the manuscript. The ' 'corresponding author had full access to all the data and had final ' 'responsibility for the decision to submit the manuscript for publication.TK, ' 'MS1, KS, YH, and KT report institution research funding from Ono Pharmaceutical ' 'Co. Ltd. in relation to this work.YN reports institution research funding from ' 'Ono Pharmaceutical Co. Ltd. in relation to this work and institution research ' 'funding from ITO EN Co. Ltd., AstaReal Co. Ltd., Mizkan Holdings Co. Ltd., and ' 'Kanagawa Institute of Industrial Science and Technology unrelated to this ' 'work.YK1 reports institution research funding from Ono Pharmaceutical Co. Ltd. ' 'in relation to this work and institution research funding from Nobelpharma Co. ' 'Ltd., Chugai Pharmaceutical Co. Ltd., Japan Tobacco Inc., and Pfizer Japan Inc. ' 'unrelated to this work.MS2 reports institution research funding from Ono ' 'Pharmaceutical Co. Ltd. in relation to this work and institutional research ' 'funding from FUJIFILM Toyama Chemical Co. Ltd., AstraZeneca K.K., Chugai ' 'Pharmaceutical Co. Ltd., Pfizer Japan Inc., and Genova Inc. unrelated to this ' 'work.NK and KY are employees of Ono Pharmaceutical Co. Ltd.YK2 reports ' 'consultancy fees from Ono Pharmaceutical Co. Ltd. in relation to this work; ' 'research funding from Abbott Medical Japan, LLC, and ROHTO Pharmaceutical Co. ' 'Ltd. unrelated to this work; lecture fees from Abbott Medical Japan, LLC, ' 'unrelated to this work; equity in Quantum Molecular Diagnostics Japan, LLC, ' 'unrelated to this work; and reagents for serological testing from Abbott ' 'Medical Japan, LLC, unrelated to this work.HK reports consultancy fees from Ono ' 'Pharmaceutical Co., Ltd. in relation to this work and lecture fees from MSD ' 'K.K., Pfizer Japan Inc., and Shionogi & Co. Ltd. unrelated to this work.NU ' 'reports consultancy fees from Ono Pharmaceutical Co. Ltd. in relation to this ' 'work and the following activities unrelated to this work: institution research ' 'grants from Regeneron Pharma Inc., Eli Lilly Japan K.K., Japan Agency for ' 'Medical Research and Development, ARTham Therapeutics Inc., EA Pharma Co. Ltd., ' 'and VLP Therapeutics, LLC; consultancy fees from Ono Pharmaceutical Co. Ltd., ' 'Mitsubishi Tanabe Pharma Corp., Sato Pharmaceutical, Co. Ltd., ARTham ' 'Therapeutics Inc., Otsuka Pharmaceutical Co. Ltd., EA Pharma Co. Ltd., and ' 'Maruho Co. Ltd., honoraria from Mochida Pharmaceutical Co. Ltd., fees for ' 'participating on advisory boards from Japan Research Foundation Clinical ' 'Pharmacology, the Ministry of Education, Culture, Sports, Science and ' 'Technology, and the Ministry of Health, Labour and Welfare; fees for leadership ' 'or fiduciary roles for American Society for Clinical Pharmacology and ' 'Therapeutics and GHIT Fund; unpaid board member for Japanese Society for ' 'Clinical Pharmacology and Therapeutics, Clinical Research Support Center Kyushu ' 'and Oita IAM; stock or stock options in ARTham Therapeutics Inc. and Oita IAM; ' 'and monetary gifts to the institution from Oita IAM.JK reports consultancy fees ' 'from Ono Pharmaceutical Co. Ltd. in relation to this work and consultancy fees ' 'from FUJIFILM Toyama Chemical Co. Ltd., KOBAYASHI Pharma Co. Ltd., and Kyorin ' 'Pharma Co. Ltd. unrelated to this work; institutional research funding from MSD ' 'Co. Ltd., Taisho Pharma Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Daiichi ' 'Sankyo Co. Ltd., Pfizer Japan Inc., Kyorin Pharma Co. Ltd., Astellas Pharma ' 'Inc., Chugai Pharmaceutical Co. Ltd., Shionogi & Co. Ltd., and Teijin Pharma ' 'Ltd. unrelated to this work; and lecture fees from Ono Pharmaceutical Co. Ltd., ' 'MSD Co. Ltd., AstraZeneca K.K., Nippon Boehringer Ingelheim Co. Ltd., Pfizer ' 'Japan Inc., Shionogi & Co. Ltd., Taisho Toyama Pharma Co. Ltd., Meiji Seika ' 'Pharma Co. Ltd., Sanofi K.K., Kyorin Pharma Co. Ltd., Astellas Pharma Inc., ' 'Sumitomo Dainippon Pharma Co. Ltd., Bristol-Myers Squibb Company, Daiichi ' 'Sankyo Co. Ltd., Chugai Pharmaceutical Co. Ltd., Novartis Pharma K.K., Taisho ' 'Pharma Co. Ltd., FUJIFILM Medical Co. Ltd., GlaxoSmithKline K.K., and DENKA ' 'SEIKEN Co. Ltd. unrelated to this work.', 'order': 4, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Competing interests'}}], 'article-number': '342'}