One Week of Oral Camostat Versus Placebo in Nonhospitalized Adults With Mild-to-Moderate Coronavirus Disease 2019 (COVID-19): A Randomized Controlled Phase 2 Trial

{ 'indexed': {'date-parts': [[2023, 9, 21]], 'date-time': '2023-09-21T09:51:22Z', 'timestamp': 1695289882746}, 'reference-count': 32, 'publisher': 'Oxford University Press (OUP)', 'license': [ { 'start': { 'date-parts': [[2023, 6, 5]], 'date-time': '2023-06-05T00:00:00Z', 'timestamp': 1685923200000}, 'content-version': 'am', 'delay-in-days': 0, 'URL': 'https://academic.oup.com/pages/standard-publication-reuse-rights'}], 'funder': [ { 'DOI': '10.13039/100000060', 'name': 'National Institute of Allergy and Infectious Diseases', 'doi-asserted-by': 'publisher'}, { 'DOI': '10.13039/100000002', 'name': 'National Institutes of Health', 'doi-asserted-by': 'publisher', 'award': ['UM1AI068636']}], 'content-domain': {'domain': [], 'crossmark-restriction': False}, 'abstract': '<jats:title>Abstract</jats:title>\n' ' <jats:sec>\n' ' <jats:title>Background</jats:title>\n' ' <jats:p>Camostat inhibits severe acute respiratory syndrome coronavirus 2 ' '(SARS-CoV-2) infection in vitro. We studied the safety and efficacy of camostat in ' 'ACTIV-2/A5401, a phase 2/3 platform trial of therapeutics for COVID-19 in nonhospitalized ' 'adults.</jats:p>\n' ' </jats:sec>\n' ' <jats:sec>\n' ' <jats:title>Methods</jats:title>\n' ' <jats:p>We conducted a phase 2 study in adults with mild-to-moderate ' 'COVID-19 randomized to oral camostat for 7 days or a pooled placebo arm. Primary outcomes ' 'were time to improvement in COVID-19 symptoms through day 28, proportion of participants with ' 'SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) from nasopharyngeal swabs ' 'through day 14, and grade ≥3 treatment-emergent adverse events (TEAEs) through day ' '28.</jats:p>\n' ' </jats:sec>\n' ' <jats:sec>\n' ' <jats:title>Results</jats:title>\n' ' <jats:p>Of 216 participants (109 randomized to camostat, 107 to placebo) ' 'who initiated study intervention, 45% reported ≤5\u2005days of symptoms at study entry and ' '26% met the protocol definition of higher risk of progression to severe COVID-19. Median age ' 'was 37\u2005years. Median time to symptom improvement was 9\u2005days in both arms (P = .99). ' 'There were no significant differences in the proportion of participants with SARS-CoV-2 RNA ' '&amp;lt;LLoQ on days 3, 7, and 14. Through day 28, 6 (5.6%) participants in the camostat arm ' 'and 5 (4.7%) in the placebo arm were hospitalized; 1 participant in the camostat arm ' 'subsequently died. Grade ≥3 TEAEs occurred in 10.1% of camostat versus 6.5% of placebo ' 'participants (P = .35).</jats:p>\n' ' </jats:sec>\n' ' <jats:sec>\n' ' <jats:title>Conclusions</jats:title>\n' ' <jats:p>In a phase 2 study of nonhospitalized adults with mild-to-moderate ' 'COVID-19, oral camostat did not accelerate viral clearance or time to symptom improvement, or ' 'reduce hospitalizations or deaths.</jats:p>\n' ' <jats:p>Clinical Trials Registration.\u2003ClinicalTrials.gov identifier: ' 'NCT 04518410.</jats:p>\n' ' </jats:sec>', 'DOI': '10.1093/cid/ciad342', 'type': 'journal-article', 'created': {'date-parts': [[2023, 6, 9]], 'date-time': '2023-06-09T13:34:09Z', 'timestamp': 1686317649000}, 'source': 'Crossref', 'is-referenced-by-count': 1, 'title': 'One Week of Oral Camostat Versus Placebo in Nonhospitalized Adults With Mild-to-Moderate ' 'Coronavirus Disease 2019 (COVID-19): A Randomized Controlled Phase 2 Trial', 'prefix': '10.1093', 'author': [ { 'ORCID': 'http://orcid.org/0000-0001-9154-2769', 'authenticated-orcid': False, 'given': 'Nikolaus', 'family': 'Jilg', 'sequence': 'first', 'affiliation': [ { 'name': 'Department of Medicine, Massachusetts General Hospital and ' "Department of Medicine, Brigham Women's Hospital, Harvard " 'Medical School , Boston, Massachusetts , USA'}]}, { 'given': 'Kara W', 'family': 'Chew', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medicine, University of California , Los Angeles, ' 'California , USA'}]}, { 'given': 'Mark J', 'family': 'Giganti', 'sequence': 'additional', 'affiliation': [ { 'name': 'Harvard T.H. Chan School of Public Health , Boston, ' 'Massachusetts , USA'}]}, { 'given': 'Eric S', 'family': 'Daar', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medicine, University of California Los Angeles ' 'Center , Torrance, California , USA'}]}, { 'given': 'David A', 'family': 'Wohl', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medicine, University of North Carolina , Chapel ' 'Hill, North Carolina , USA'}]}, { 'given': 'Arzhang Cyrus', 'family': 'Javan', 'sequence': 'additional', 'affiliation': [ { 'name': 'Division of AIDS, National Institutes of Health , Rockville, ' 'Maryland , USA'}]}, { 'given': 'Amy', 'family': 'Kantor', 'sequence': 'additional', 'affiliation': [ { 'name': 'Harvard T.H. Chan School of Public Health , Boston, ' 'Massachusetts , USA'}]}, { 'given': 'Carlee', 'family': 'Moser', 'sequence': 'additional', 'affiliation': [ { 'name': 'Harvard T.H. Chan School of Public Health , Boston, ' 'Massachusetts , USA'}]}, { 'given': 'Robert W', 'family': 'Coombs', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medicine, University of Washington , Seattle, ' 'Washington , USA'}]}, { 'given': 'Gene', 'family': 'Neytman', 'sequence': 'additional', 'affiliation': [{'name': 'Quantum Clinical Trials , Miami Beach, Florida , USA'}]}, { 'given': 'Keila', 'family': 'Hoover', 'sequence': 'additional', 'affiliation': [{'name': 'Miami Clinical Research , Miami, Florida , USA'}]}, { 'given': 'Atasi', 'family': 'Jana', 'sequence': 'additional', 'affiliation': [{'name': 'Sagent Pharmaceuticals , Schaumburg, Illinois , USA'}]}, { 'given': 'Phil A', 'family': 'Hart', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medicine, The Ohio State University Wexner Medical ' 'Center , Columbus, Ohio , USA'}]}, { 'given': 'Alexander L', 'family': 'Greninger', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medicine, University of Washington , Seattle, ' 'Washington , USA'}]}, { 'given': 'Bob', 'family': 'Szurgot', 'sequence': 'additional', 'affiliation': [{'name': 'Sagent Pharmaceuticals , Schaumburg, Illinois , USA'}]}, { 'given': 'Joseph J', 'family': 'Eron', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medicine, University of North Carolina , Chapel ' 'Hill, North Carolina , USA'}]}, { 'given': 'Judith S', 'family': 'Currier', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medicine, University of Los Angeles , Los Angeles, ' 'California , USA'}]}, { 'given': 'Michael D', 'family': 'Hughes', 'sequence': 'additional', 'affiliation': [ { 'name': 'Harvard T.H. Chan School of Public Health , Boston, ' 'Massachusetts , USA'}]}, { 'given': 'Davey M', 'family': 'Smith', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medicine, University of California, San Diego , ' 'San Diego, California , USA'}]}, { 'given': 'Jonathan Z', 'family': 'Li', 'sequence': 'additional', 'affiliation': [ { 'name': "Department of Medicine, Brigham and Women's Hospital, Harvard " 'Medical School , Boston, Massachusetts , USA'}]}, {'given': 'Lara', 'family': 'Hosey', 'sequence': 'additional', 'affiliation': []}, {'given': 'Jhoanna', 'family': 'Roa', 'sequence': 'additional', 'affiliation': []}, {'given': 'Nilam', 'family': 'Patel', 'sequence': 'additional', 'affiliation': []}, {'given': 'Emily', 'family': 'Degli-Angeli', 'sequence': 'additional', 'affiliation': []}, {'given': 'Erin', 'family': 'Goecker', 'sequence': 'additional', 'affiliation': []}, {'given': 'Glenda', 'family': 'Daza', 'sequence': 'additional', 'affiliation': []}, {'given': 'Socorro', 'family': 'Harb', 'sequence': 'additional', 'affiliation': []}, {'given': 'Joan', 'family': 'Dragavon', 'sequence': 'additional', 'affiliation': []}, {'given': 'Grace', 'family': 'Aldrovandi', 'sequence': 'additional', 'affiliation': []}, {'given': 'William', 'family': 'Murtaugh', 'sequence': 'additional', 'affiliation': []}, {'given': 'Marlene', 'family': 'Cooper', 'sequence': 'additional', 'affiliation': []}, {'given': 'Howard', 'family': 'Gutzman', 'sequence': 'additional', 'affiliation': []}, {'given': 'Kevin', 'family': 'Knowles', 'sequence': 'additional', 'affiliation': []}, {'given': 'Peter', 'family': 'Kim', 'sequence': 'additional', 'affiliation': []}, {'given': 'Bill', 'family': 'Erhardt', 'sequence': 'additional', 'affiliation': []}, {'given': 'Lorraine', 'family': 'Waring', 'sequence': 'additional', 'affiliation': []}, {'given': 'Diane', 'family': 'Hessinger', 'sequence': 'additional', 'affiliation': []}, {'given': 'Stacey', 'family': 'Adams', 'sequence': 'additional', 'affiliation': []}, {'name': 'for the ACTIV-2/A5401 Study Team', 'sequence': 'additional', 'affiliation': []}], 'member': '286', 'published-online': {'date-parts': [[2023, 6, 5]]}, 'reference': [ { 'key': '2023062300024026300_ciad342-B1', 'author': 'Centers for Disease Control and Prevention'}, { 'key': '2023062300024026300_ciad342-B2', 'author': 'Johns Hopkins Coronavirus Resource Center'}, { 'key': '2023062300024026300_ciad342-B3', 'doi-asserted-by': 'crossref', 'first-page': '305', 'DOI': '10.1056/NEJMoa2116846', 'article-title': 'Early remdesivir to prevent progression to severe Covid-19 in ' 'outpatients', 'volume': '386', 'author': 'Gottlieb', 'year': '2022', 'journal-title': 'N Engl J Med'}, { 'key': '2023062300024026300_ciad342-B4', 'doi-asserted-by': 'crossref', 'first-page': '509', 'DOI': '10.1056/NEJMoa2116044', 'article-title': 'Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients', 'volume': '386', 'author': 'Jayk Bernal', 'year': '2022', 'journal-title': 'N Engl J Med'}, { 'key': '2023062300024026300_ciad342-B5', 'doi-asserted-by': 'crossref', 'first-page': '1397', 'DOI': '10.1056/NEJMoa2118542', 'article-title': 'Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19', 'volume': '386', 'author': 'Hammond', 'year': '2022', 'journal-title': 'N Engl J Med'}, { 'key': '2023062300024026300_ciad342-B6', 'doi-asserted-by': 'crossref', 'first-page': '553', 'DOI': '10.1038/s41586-022-04594-4', 'article-title': 'Antibody evasion properties of SARS-CoV-2 Omicron sublineages', 'volume': '604', 'author': 'Iketani', 'year': '2022', 'journal-title': 'Nature'}, { 'key': '2023062300024026300_ciad342-B7', 'doi-asserted-by': 'crossref', 'first-page': '468', 'DOI': '10.1056/NEJMc2207519', 'article-title': 'Efficacy of antibodies and antiviral drugs against Omicron BA.2.12.1, ' 'BA.4, and BA.5 subvariants', 'volume': '387', 'author': 'Takashita', 'year': '2022', 'journal-title': 'N Engl J Med'}, { 'key': '2023062300024026300_ciad342-B8', 'doi-asserted-by': 'crossref', 'first-page': '271', 'DOI': '10.1016/j.cell.2020.02.052', 'article-title': 'SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a ' 'clinically proven protease inhibitor', 'volume': '181', 'author': 'Hoffmann', 'year': '2020', 'journal-title': 'Cell'}, { 'key': '2023062300024026300_ciad342-B9', 'article-title': 'In silico molecular characterization of human TMPRSS2 protease ' 'polymorphic variants and associated SARS-CoV-2 susceptibility', 'volume': '12', 'author': 'Salleh', 'year': '2022', 'journal-title': 'Life (Basel)'}, { 'key': '2023062300024026300_ciad342-B10', 'doi-asserted-by': 'crossref', 'DOI': '10.1128/JVI.00861-21', 'article-title': 'Structural basis of covalent inhibitory mechanism of TMPRSS2-related ' 'serine proteases by camostat', 'volume': '95', 'author': 'Sun', 'year': '2021', 'journal-title': 'J Virol'}, { 'key': '2023062300024026300_ciad342-B11', 'doi-asserted-by': 'crossref', 'DOI': '10.1073/pnas.2108728118', 'article-title': 'A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and ' 'MERS-CoV viral entry and protect human epithelial lung cells', 'volume': '118', 'author': 'Mahoney', 'year': '2021', 'journal-title': 'Proc Natl Acad Sci USA'}, { 'key': '2023062300024026300_ciad342-B12', 'doi-asserted-by': 'crossref', 'DOI': '10.1016/j.ebiom.2021.103255', 'article-title': 'Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related ' 'proteases and its metabolite GBPA exerts antiviral activity', 'volume': '65', 'author': 'Hoffmann', 'year': '2021', 'journal-title': 'EBioMedicine'}, { 'key': '2023062300024026300_ciad342-B13', 'doi-asserted-by': 'crossref', 'first-page': '76', 'DOI': '10.1016/j.antiviral.2015.01.011', 'article-title': 'Protease inhibitors targeting coronavirus and filovirus entry', 'volume': '116', 'author': 'Zhou', 'year': '2015', 'journal-title': 'Antiviral Res'}, { 'key': '2023062300024026300_ciad342-B14', 'article-title': 'Clinical experience with FOY-305 for pancreatitis', 'author': 'Horiguchi', 'year': '1980', 'journal-title': 'New Horiz Med'}, { 'key': '2023062300024026300_ciad342-B15', 'doi-asserted-by': 'crossref', 'first-page': '622', 'DOI': '10.1016/S1473-3099(21)00751-9', 'article-title': 'Efficacy and safety of two neutralising monoclonal antibody therapies, ' 'sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with ' 'COVID-19 (TICO): a randomised controlled trial', 'volume': '22', 'author': 'ACTIV-3/Therapeutics for Inpatients with COVID-19 (TICO) Study Group', 'year': '2022', 'journal-title': 'Lancet Infect Dis'}, { 'key': '2023062300024026300_ciad342-B16', 'doi-asserted-by': 'crossref', 'first-page': '905', 'DOI': '10.1056/NEJMoa2033130', 'article-title': 'A neutralizing monoclonal antibody for hospitalized patients with ' 'COVID-19', 'volume': '384', 'author': 'ACTIV-3/TICO LY-CoV555 Study Group', 'year': '2021', 'journal-title': 'N Engl J Med'}, { 'key': '2023062300024026300_ciad342-B17', 'doi-asserted-by': 'crossref', 'first-page': '1266', 'DOI': '10.7326/M22-1503', 'article-title': 'Efficacy and safety of ensovibep for adults hospitalized with COVID-19: ' 'a randomized controlled trial', 'volume': '175', 'author': 'ACTIV-3/TICO Study Group', 'year': '2022', 'journal-title': 'Ann Intern Med'}, { 'key': '2023062300024026300_ciad342-B18', 'doi-asserted-by': 'crossref', 'first-page': '342', 'DOI': '10.1186/s12916-022-02518-7', 'article-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)', 'volume': '20', 'author': 'Kinoshita', 'year': '2022', 'journal-title': 'BMC Med'}, { 'key': '2023062300024026300_ciad342-B19', 'doi-asserted-by': 'crossref', 'DOI': '10.1016/j.eclinm.2021.100849', 'article-title': 'Efficacy of the TMPRSS2 inhibitor camostat mesilate in patients ' 'hospitalized with Covid-19—a double-blind randomized controlled trial', 'volume': '35', 'author': 'Gunst', 'year': '2021', 'journal-title': 'EClinicalMedicine'}, { 'key': '2023062300024026300_ciad342-B20', 'doi-asserted-by': 'crossref', 'first-page': '628', 'DOI': '10.1016/j.ijid.2022.06.054', 'article-title': 'Efficacy and safety of camostat mesylate in early COVID-19 disease in ' 'an ambulatory setting: a randomized placebo-controlled phase II trial', 'volume': '122', 'author': 'Tobback', 'year': '2022', 'journal-title': 'Int J Infect Dis'}, { 'key': '2023062300024026300_ciad342-B21', 'article-title': 'A phase 2 randomized, double-blind, placebo-controlled trial of oral ' 'camostat mesylate for early treatment of COVID-19 outpatients showed ' 'shorter illness course and attenuation of loss of smell and taste', 'author': 'Chupp', 'year': '2022', 'journal-title': 'medRxiv'}, { 'key': '2023062300024026300_ciad342-B22', 'doi-asserted-by': 'crossref', 'first-page': 'e0045222', 'DOI': '10.1128/aac.00452-22', 'article-title': 'A double-blind, randomized, placebo-controlled, phase II clinical study ' 'to evaluate the efficacy and safety of camostat mesylate (DWJ1248) in ' 'adult patients with mild to moderate COVID-19', 'volume': '67', 'author': 'Kim', 'year': '2023', 'journal-title': 'Antimicrob Agents Chemother'}, { 'key': '2023062300024026300_ciad342-B23', 'doi-asserted-by': 'crossref', 'DOI': '10.1016/j.jcv.2021.104945', 'article-title': 'Development of the RealTime SARS-CoV-2 quantitative laboratory ' 'developed test and correlation with viral culture as a measure of ' 'infectivity', 'volume': '143', 'author': 'Berg', 'year': '2021', 'journal-title': 'J Clin Virol'}, { 'key': '2023062300024026300_ciad342-B24', 'first-page': '175', 'article-title': 'A randomized controlled trial of camostat in outpatients with COVID-19 ' '[CROI Abstract 459]', 'volume': '30', 'author': 'Jilg', 'year': '2022', 'journal-title': 'Top Antiv Med'}, { 'key': '2023062300024026300_ciad342-B25', 'article-title': 'Hydroxychloroquine versus placebo in the treatment of non-hospitalised ' 'patients with COVID-19 (COPE—Coalition V): a double-blind, multicentre, ' 'randomised, controlled trial', 'volume': '11', 'author': 'Avezum', 'year': '2022', 'journal-title': 'Lancet Reg Health Am'}, { 'issue': '3', 'key': '2023062300024026300_ciad342-B26', 'doi-asserted-by': 'crossref', 'first-page': '524', 'DOI': '10.1111/cts.13468', 'article-title': 'Hydroxychloroquine for treatment of non-hospitalized adults with ' 'COVID-19: a meta-analysis of individual participant data of randomized ' 'trials', 'volume': '16', 'author': 'Mitja', 'year': '2023', 'journal-title': 'Clin Transl Sci'}, { 'key': '2023062300024026300_ciad342-B27', 'doi-asserted-by': 'crossref', 'first-page': '732', 'DOI': '10.1093/cid/ciaa237', 'article-title': 'In vitro antiviral activity and projection of optimized dosing design ' 'of hydroxychloroquine for the treatment of severe acute respiratory ' 'syndrome coronavirus 2 (SARS-CoV-2)', 'volume': '71', 'author': 'Yao', 'year': '2020', 'journal-title': 'Clin Infect Dis'}, { 'key': '2023062300024026300_ciad342-B28', 'doi-asserted-by': 'crossref', 'first-page': '1031', 'DOI': '10.1007/s40261-022-01213-y', 'article-title': 'The effect of nitazoxanide on the clinical outcomes in patients with ' 'COVID-19: a systematic review and meta-analysis of randomized ' 'controlled trials', 'volume': '42', 'author': 'Abuelazm', 'year': '2022', 'journal-title': 'Clin Drug Investig'}, { 'key': '2023062300024026300_ciad342-B29', 'doi-asserted-by': 'crossref', 'first-page': '867', 'DOI': '10.1016/j.chom.2020.11.004', 'article-title': 'Cryo-EM structures of SARS-CoV-2 spike without and with ACE2 reveal a ' 'pH-dependent switch to mediate endosomal positioning of ' 'receptor-binding domains', 'volume': '28', 'author': 'Zhou', 'year': '2020', 'journal-title': 'Cell Host Microbe'}, { 'key': '2023062300024026300_ciad342-B30', 'doi-asserted-by': 'crossref', 'DOI': '10.15252/embj.2021107821', 'article-title': 'TMPRSS2 expression dictates the entry route used by SARS-CoV-2 to ' 'infect host cells', 'volume': '40', 'author': 'Koch', 'year': '2021', 'journal-title': 'EMBO J'}, { 'key': '2023062300024026300_ciad342-B31', 'doi-asserted-by': 'crossref', 'first-page': '706', 'DOI': '10.1038/s41586-022-04474-x', 'article-title': 'Altered TMPRSS2 usage by SARS-CoV-2 omicron impacts infectivity and ' 'fusogenicity', 'volume': '603', 'author': 'Meng', 'year': '2022', 'journal-title': 'Nature'}, { 'key': '2023062300024026300_ciad342-B32', 'doi-asserted-by': 'crossref', 'DOI': '10.26508/lsa.202101116', 'article-title': 'Topical TMPRSS2 inhibition prevents SARS-CoV-2 infection in ' 'differentiated human airway cultures', 'volume': '5', 'author': 'Guo', 'year': '2022', 'journal-title': 'Life Sci Alliance'}], 'container-title': 'Clinical Infectious Diseases', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://academic.oup.com/cid/advance-article-pdf/doi/10.1093/cid/ciad342/50682365/ciad342.pdf', 'content-type': 'application/pdf', 'content-version': 'am', 'intended-application': 'syndication'}, { 'URL': 'https://academic.oup.com/cid/advance-article-pdf/doi/10.1093/cid/ciad342/50682365/ciad342.pdf', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2023, 6, 24]], 'date-time': '2023-06-24T17:53:48Z', 'timestamp': 1687629228000}, 'score': 1, 'resource': { 'primary': { 'URL': 'https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciad342/7190261'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2023, 6, 5]]}, 'references-count': 32, 'URL': 'http://dx.doi.org/10.1093/cid/ciad342', 'relation': {}, 'ISSN': ['1058-4838', '1537-6591'], 'subject': ['Infectious Diseases', 'Microbiology (medical)'], 'published': {'date-parts': [[2023, 6, 5]]}}