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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)

Kinoshita et al., BMC Medicine, doi:10.1186/s12916-022-02518-7, CANDLE, NCT04657497
Sep 2022  
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Progression to non-invasi.. 67% Improvement Relative Risk Oxygen at LE 50% Recovery -1% Viral clearance -1% Camostat  CANDLE  EARLY TREATMENT  DB RCT Is early treatment with camostat beneficial for COVID-19? Double-blind RCT 155 patients in Japan (November 2020 - March 2021) Lower need for oxygen therapy with camostat (not stat. sig., p=0.37) c19early.org Kinoshita et al., BMC Medicine, September 2022 Favorscamostat Favorscontrol 0 0.5 1 1.5 2+
RCT 155 hospitalized patients showing no significant differences with camostat.
progression to non-invasive ventilation or high-flow oxygen, 66.7% lower, RR 0.33, p = 1.00, treatment 0 of 74 (0.0%), control 1 of 74 (1.4%), NNT 74, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), Figure 4.
oxygen at LE, 50.0% lower, RR 0.50, p = 0.37, treatment 4 of 74 (5.4%), control 8 of 74 (10.8%), NNT 18, Figure 4.
risk of no recovery, 1.5% higher, RR 1.01, p = 1.00, treatment 30 of 53 (56.6%), control 29 of 52 (55.8%).
risk of no viral clearance, 1.0% higher, HR 1.01, p = 0.97, treatment 78, control 77, inverted to make HR<1 favor treatment.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Kinoshita et al., 27 Sep 2022, Double Blind Randomized Controlled Trial, placebo-controlled, Japan, peer-reviewed, 14 authors, study period November 2020 - March 2021, trial NCT04657497 (history) (CANDLE). Contact: uemura@oita-u.ac.jp (corresponding author).
This PaperMiscellaneousAll
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)
Taku Kinoshita, Masahiro Shinoda, Yasuhiro Nishizaki, Katsuya Shiraki, Yuji Hirai, Yoshiko Kichikawa, Kenji Tsushima, Masaharu Shinkai, Naoyuki Komura, Kazuo Yoshida, Yasutoshi Kido, Hiroshi Kakeya, Naoto Uemura, Junichi Kadota
BMC Medicine, doi:10.1186/s12916-022-02518-7
Background: 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 . Methods: This was a multicenter, double-blind, randomized, parallel-group, placebo-controlled study. Patients were enrolled if they were admitted to a hospital within 5 days of onset of COVID-19 symptoms or within 5 days 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 mg qid; four to eight times higher than the clinical doses in Japan) or placebo for up to 14 days. The primary efficacy endpoint was the time to the first two consecutive negative tests for SARS-CoV-2. Results: One-hundred fifty-five patients were randomized to receive camostat mesilate (n = 78) or placebo (n = 77). The median time to the first test was 11.0 days (95% confidence interval [CI]: 9.0-12.0) in the camostat mesilate group and 11.0 days (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
Abbreviations ACE2: Angiotensin-converting enzyme II; BMI: Body mass index; CANDLE: Camostat could bring delight to people; EC 50 : Half maximal effective concentration; GBPA: 4-(4-Guanidinobenzoyloxy)phenylacetic acid; LAMP: Loopmediated isothermal amplification; NOAEL: No-observed adverse effect level; PD: Pharmacodynamic; PK: Pharmacokinetic; RT-PCR: Reverse transcriptasepolymerase chain reaction; TMPRSS2: Type II transmembrane serine protease. Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1186/ s12916-022-02518-7. Additional file 1: Study protocol. Additional file 2: IRB information. Sample size calculation. Table S1 . Discontinuation criteria. Table S2 . Ordinal scale of severity. Table S3 . Events and reasons for censoring patients for the analysis of time to SARS-CoV-2 negativity. Table S4 . Events and reasons for censoring patients in the sensitivity analysis of the time to SARS-CoV-2 negativity. Table S5 . Changes to the statistical analyses plan from the protocol. Table S6 . Patient disposition. Table S7 . Results of the sensitivity analysis of the primary endpoint. Table S8 . Time to negative SARS-CoV-2 status as measured by the central laboratory. Table S9 . Results of the subgroup analyses of time to negative SARS-CoV-2 status. Additional file 3: CONSORT Checklist. Authors' contributions Conceptualization: NK and JK. Data curation: not applicable. Formal analysis: KY. Funding..
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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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' 'https://doi.org/10.1111/cts.13052.', 'journal-title': 'Clin Transl Sci'}, { 'key': '2518_CR21', 'unstructured': 'World Health Organization R&D Blue Print Team. WHO R&D Blueprint: novel ' 'coronavirus - COVID-19 therapeutic trial synopsis. Available at: ' 'https://www.who.int/publications/i/item/covid-19-therapeutic-trial-synopsis. ' 'Accessed: July 22, 2021.'}, { 'key': '2518_CR22', 'doi-asserted-by': 'publisher', 'first-page': '707', 'DOI': '10.1007/s00134-021-06395-1', 'volume': '47', 'author': 'Y Sakr', 'year': '2021', 'unstructured': 'Sakr Y, Bensasi H, Taha A, Bauer M, Ismail K. Camostat mesylate therapy ' 'in critically ill patients with COVID-19 pneumonia. Intensive Care Med. ' '2021;47:707–9. https://doi.org/10.1007/s00134-021-06395-1.', 'journal-title': 'Intensive Care Med'}, { 'key': '2518_CR23', 'doi-asserted-by': 'publisher', 'unstructured': 'Gunst JD, Staerke NB, Pahus MH, Kristensen LH, Bodilsen J, Lohse N, 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'}
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