Oral Probenecid for Nonhospitalized Adults with Symptomatic Mild-to-Moderate COVID-19
David E Martin, Neelam Pandey, Purvi Chavda, Gurpreet Singh, Rakesh Sutariya, Frederic Sancilio, Ralph A Tripp
Viruses, doi:10.3390/v15071508
Probenecid is an orally bioavailable, uricosuric agent that was first approved in 1951 for the treatment of gout, but was later found to have potent, broad-spectrum antiviral activity against several respiratory viruses including SARS-CoV-2. We conducted a phase 2 randomized, placebocontrolled, single-blind, dose-range finding study in non-hospitalized patients with symptomatic, mild-to-moderate COVID-19. Patients were randomly assigned in a 1:1:1 ratio to receive either 500 mg of probenecid, 1000 mg of probenecid, or a matching placebo every 12 h for five days. The patients' COVID-19 viral load hospitalization, or death from any cause through day 28, as well as safety, were evaluated. COVID-19-related symptoms were assessed at baseline, and on days 3, 5, 10, 15, and 28. The primary endpoints of the study were time to first negative SARS-CoV-2 viral test (or viral clearance) and the proportion of patients that were symptom-free at day 5. A total of 75 patients were randomized, with 25 patients in each group. All of the patients completed the study as planned with no hospitalizations or deaths being reported. The median time to viral clearance was significantly shorter for the probenecid 1000 mg group than for placebo (7 days vs. 11 days, respectively; p < 0.0001), and for the probenecid 500 mg group versus placebo (9 days vs. 11 days, respectively; p < 0.0001). In addition, the median time to viral clearance was significantly shorter for the probenecid 1000 mg group than for the probenecid 500 mg group (7 days vs. 9 days, respectively; p < 0.0001). All patients reported at least one COVID-19-related symptom on days 3 and 5; however, on day 10, a significantly greater proportion of patients receiving probenecid 1000 mg reported the complete resolution of symptoms versus placebo (68% vs. 20%, respectively; p = 0.0006), as well as for those receiving probenecid 500 mg versus placebo (56% vs. 20%, respectively, p = 0.0087). The incidence of adverse events during treatment was similar across all groups for any adverse event, and was 12%. All events were mild with no serious adverse events reported and no discontinuations due to an adverse event. The treatment of patients with symptomatic, mild-to-moderate COVID-19 with probenecid resulted in a significant, dose-dependent decrease in the time to viral clearance and a significantly higher proportion of patients reporting complete symptom resolution by day 10. (Supported by TrippBio; ClinicalTrials.gov number, NCT05442983 and Clinical Trials Registry India number CTRI/2022/07/043726).
Conflicts of Interest: D.E.M is an employee and shareholder of TrippBio, Inc. F.S. and R.A.T. are shareholders of TrippBio, Inc. R.A.T. is an inventor on a granted patent application owned by the University of Georgia Research Foundation covering the method of use of probenecid as a treatment for coronavirus infections.
References
Beyer, Wiebelhaus, Russe, Peck, Mckinney et al., An anticatabolite; Its pharmacological properties, Fed. Proc
Caly, Li, Bogoyevitch, Jans, c-Jun N-terminal kinase activity is required for efficient respiratory syncytial virus production, Biochem. Biophys. Res. Commun,
doi:10.1016/j.bbrc.2017.01.005Collins, Fearns, Graham, Respiratory Syncytial Virus: Virology, Reverse Genetics, and Pathogenesis of Disease
Feng, Xu, Xie, Receptors for Respiratory Syncytial Virus Infection and Host Factors Regulating the Life Cycle of Respiratory Syncytial Virus, Front. Cell Infect. Microbiol,
doi:10.3389/fcimb.2022.858629Karyakarte, Das, Taji, Yanamandra, Shende et al., An Early and Preliminary Assessment of the Clinical Severity of the Emerging SARS-CoV-2 Omicron Variants in Maharashtra, India, Cureus,
doi:10.7759/cureus.31352Martovetsky, Tee, Nigam, Hepatocyte nuclear factors 4α and 1α regulate kidney developmental expression of drug-metabolizing enzymes and drug transporters, Mol. Pharmacol,
doi:10.1124/mol.113.088229Medina, Chiu, Stremska, Lucas, Poon et al., Pannexin 1 channels facilitate communication between T cells to restrict the severity of airway inflammation, Immunity,
doi:10.1016/j.immuni.2021.06.014Murray, Hogan, Martin, Blahunka, Sancilio et al., Probenecid potently inhibits SARS-CoV-2 replication in vivo and in vitro, Sci. Rep,
doi:10.1038/s41598-021-97658-wPerwitasari, Yan, Johnson, White, Brooks et al., Targeting organic anion transporter 3 with probenecid as a novel anti-influenza a virus strategy, Antimicrob. Agents Chemother,
doi:10.1128/AAC.01532-12Rosli, Kirby, Lawlor, Rainczuk, Drummond et al., Repurposing drugs targeting the P2X7 receptor to limit hyperinflammation and disease during influenza virus infection, Br. J. Pharmacol,
doi:10.1111/bph.14787Tripp, Martin, Repurposing Probenecid to Inhibit SARS-CoV-2, Influenza Virus, and Respiratory Syncytial Virus (RSV) Replication, Viruses,
doi:10.3390/v14030612Who, COVID-19 Case Definitions
Who, Coronavirus (COVID-19) Dashboard/WHO Coronavirus (COVID-19) Dashboard with Vaccination Data
Ying, Whitener, Vanblargan, Hassan, Shrihari et al., Protective activity of mRNA vaccines against ancestral and variant SARS-CoV-2 strains, Sci. Transl. Med,
doi:10.1126/scitranslmed.abm3302Zeke, Misheva, Reményi, Bogoyevitch, JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships, Microbiol. Mol. Biol. Rev,
doi:10.1128/MMBR.00043-14{ 'indexed': {'date-parts': [[2024, 1, 23]], 'date-time': '2024-01-23T10:00:37Z', 'timestamp': 1706004037294},
'reference-count': 28,
'publisher': 'MDPI AG',
'issue': '7',
'license': [ { 'start': { 'date-parts': [[2023, 7, 6]],
'date-time': '2023-07-06T00:00:00Z',
'timestamp': 1688601600000},
'content-version': 'vor',
'delay-in-days': 0,
'URL': 'https://creativecommons.org/licenses/by/4.0/'}],
'funder': [{'name': 'TrippBio, Inc.'}],
'content-domain': {'domain': [], 'crossmark-restriction': False},
'abstract': '<jats:p>Probenecid is an orally bioavailable, uricosuric agent that was first approved in '
'1951 for the treatment of gout, but was later found to have potent, broad-spectrum antiviral '
'activity against several respiratory viruses including SARS-CoV-2. We conducted a phase 2 '
'randomized, placebo-controlled, single-blind, dose-range finding study in non-hospitalized '
'patients with symptomatic, mild-to-moderate COVID-19. Patients were randomly assigned in a '
'1:1:1 ratio to receive either 500 mg of probenecid, 1000 mg of probenecid, or a matching '
'placebo every 12 h for five days. The patients’ COVID-19 viral load hospitalization, or death '
'from any cause through day 28, as well as safety, were evaluated. COVID-19-related symptoms '
'were assessed at baseline, and on days 3, 5, 10, 15, and 28. The primary endpoints of the '
'study were time to first negative SARS-CoV-2 viral test (or viral clearance) and the '
'proportion of patients that were symptom-free at day 5. A total of 75 patients were '
'randomized, with 25 patients in each group. All of the patients completed the study as '
'planned with no hospitalizations or deaths being reported. The median time to viral clearance '
'was significantly shorter for the probenecid 1000 mg group than for placebo (7 days vs. 11 '
'days, respectively; p < 0.0001), and for the probenecid 500 mg group versus placebo (9 '
'days vs. 11 days, respectively; p < 0.0001). In addition, the median time to viral '
'clearance was significantly shorter for the probenecid 1000 mg group than for the probenecid '
'500 mg group (7 days vs. 9 days, respectively; p < 0.0001). All patients reported at least '
'one COVID-19-related symptom on days 3 and 5; however, on day 10, a significantly greater '
'proportion of patients receiving probenecid 1000 mg reported the complete resolution of '
'symptoms versus placebo (68% vs. 20%, respectively; p = 0.0006), as well as for those '
'receiving probenecid 500 mg versus placebo (56% vs. 20%, respectively, p = 0.0087). The '
'incidence of adverse events during treatment was similar across all groups for any adverse '
'event, and was 12%. All events were mild with no serious adverse events reported and no '
'discontinuations due to an adverse event. The treatment of patients with symptomatic, '
'mild-to-moderate COVID-19 with probenecid resulted in a significant, dose-dependent decrease '
'in the time to viral clearance and a significantly higher proportion of patients reporting '
'complete symptom resolution by day 10. (Supported by TrippBio; ClinicalTrials.gov number, '
'NCT05442983 and Clinical Trials Registry India number CTRI/2022/07/043726).</jats:p>',
'DOI': '10.3390/v15071508',
'type': 'journal-article',
'created': {'date-parts': [[2023, 7, 7]], 'date-time': '2023-07-07T05:41:36Z', 'timestamp': 1688708496000},
'page': '1508',
'source': 'Crossref',
'is-referenced-by-count': 3,
'title': 'Oral Probenecid for Nonhospitalized Adults with Symptomatic Mild-to-Moderate COVID-19',
'prefix': '10.3390',
'volume': '15',
'author': [ { 'ORCID': 'http://orcid.org/0000-0003-2820-5983',
'authenticated-orcid': False,
'given': 'David E.',
'family': 'Martin',
'sequence': 'first',
'affiliation': [{'name': 'TrippBio, Inc., Jacksonville, FL 32256, USA'}]},
{ 'given': 'Neelam',
'family': 'Pandey',
'sequence': 'additional',
'affiliation': [ { 'name': 'PCMC’s PGI Yashwantrao Chavan Memorial Hospital, Pune 411018, '
'India'}]},
{ 'given': 'Purvi',
'family': 'Chavda',
'sequence': 'additional',
'affiliation': [{'name': 'Zenovel Pharma Services LLP, Ahmedabad 380060, India'}]},
{ 'given': 'Gurpreet',
'family': 'Singh',
'sequence': 'additional',
'affiliation': [{'name': 'Clearway Global, Stuart, FL 34997, USA'}]},
{ 'given': 'Rakesh',
'family': 'Sutariya',
'sequence': 'additional',
'affiliation': [{'name': 'Zenovel Pharma Services LLP, Ahmedabad 380060, India'}]},
{ 'given': 'Frederic',
'family': 'Sancilio',
'sequence': 'additional',
'affiliation': [{'name': 'Clearway Global, Stuart, FL 34997, USA'}]},
{ 'ORCID': 'http://orcid.org/0000-0002-2924-9956',
'authenticated-orcid': False,
'given': 'Ralph A.',
'family': 'Tripp',
'sequence': 'additional',
'affiliation': [ { 'name': 'Department of Infectious Diseases, College of Veterinary '
'Medicine, University of Georgia, Athens, GA 30602, USA'}]}],
'member': '1968',
'published-online': {'date-parts': [[2023, 7, 6]]},
'reference': [ { 'key': 'ref_1',
'doi-asserted-by': 'crossref',
'first-page': '217',
'DOI': '10.1097/JCMA.0000000000000270',
'article-title': 'The outbreak of COVID-19: An overview',
'volume': '83',
'author': 'Wu',
'year': '2020',
'journal-title': 'J. Chin. Med. Assoc.'},
{ 'key': 'ref_2',
'unstructured': 'WHO (2023, January 26). Coronavirus (COVID-19) Dashboard/WHO Coronavirus '
'(COVID-19) Dashboard with Vaccination Data. Available online: '
'https://covid19.who.int/?mapFilter=deaths.'},
{ 'key': 'ref_3',
'doi-asserted-by': 'crossref',
'first-page': '128987',
'DOI': '10.1016/j.bmcl.2022.128987',
'article-title': 'COVID-19: Vaccines and therapeutics',
'volume': '75',
'author': 'Ponnampalli',
'year': '2022',
'journal-title': 'Bioorg. Med. Chem. Lett.'},
{ 'key': 'ref_4',
'unstructured': 'FDA (2023, January 26). Announces Bebtelovimab Is Not Currently '
'Authorized in Any US Region, Available online: '
'https://www.fda.gov/drugs/drug-safety-and-availability/fda-announces-bebtelovimab-not-currently-authorized-any-us-region.'},
{ 'key': 'ref_5',
'doi-asserted-by': 'crossref',
'first-page': 'eabm3302',
'DOI': '10.1126/scitranslmed.abm3302',
'article-title': 'Protective activity of mRNA vaccines against ancestral and variant '
'SARS-CoV-2 strains',
'volume': '14',
'author': 'Ying',
'year': '2022',
'journal-title': 'Sci. Transl. Med.'},
{ 'key': 'ref_6',
'doi-asserted-by': 'crossref',
'first-page': '558',
'DOI': '10.1038/s41586-022-05514-2',
'article-title': 'Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir',
'volume': '613',
'author': 'Iketani',
'year': '2023',
'journal-title': 'Nature'},
{ 'key': 'ref_7',
'first-page': '3',
'article-title': 'Respiratory Syncytial Virus: Virology, Reverse Genetics, and '
'Pathogenesis of Disease',
'volume': 'Volume V372',
'author': 'Anderson',
'year': '2013',
'journal-title': 'Challenges and Opportunities for Respiratory Syncytial Virus Vaccines. '
'Current Topics in Microbiology and Immunology'},
{ 'key': 'ref_8',
'doi-asserted-by': 'crossref',
'first-page': '475',
'DOI': '10.1128/AAC.01532-12',
'article-title': 'Targeting organic anion transporter 3 with probenecid as a novel '
'anti-influenza a virus strategy',
'volume': '57',
'author': 'Perwitasari',
'year': '2013',
'journal-title': 'Antimicrob. Agents Chemother.'},
{ 'key': 'ref_9',
'doi-asserted-by': 'crossref',
'first-page': '8085',
'DOI': '10.1038/s41598-021-97658-w',
'article-title': 'Probenecid potently inhibits SARS-CoV-2 replication in vivo and in '
'vitro',
'volume': '11',
'author': 'Murray',
'year': '2021',
'journal-title': 'Sci. Rep.'},
{ 'key': 'ref_10',
'doi-asserted-by': 'crossref',
'first-page': '3834',
'DOI': '10.1111/bph.14787',
'article-title': 'Repurposing drugs targeting the P2X7 receptor to limit '
'hyperinflammation and disease during influenza virus infection',
'volume': '176',
'author': 'Rosli',
'year': '2019',
'journal-title': 'Br. J. Pharmacol.'},
{ 'key': 'ref_11',
'doi-asserted-by': 'crossref',
'first-page': 'C761',
'DOI': '10.1152/ajpcell.00227.2008',
'article-title': 'Probenecid, a gout remedy, inhibits pannexin 1 channels',
'volume': '295',
'author': 'Silverman',
'year': '2008',
'journal-title': 'Am. J. Physiol. Cell Physiol.'},
{ 'key': 'ref_12',
'doi-asserted-by': 'crossref',
'first-page': '271',
'DOI': '10.1146/annurev-publhealth-052120-101420',
'article-title': 'Environmental Factors Influencing COVID-19 Incidence and Severity',
'volume': '43',
'author': 'Weaver',
'year': '2022',
'journal-title': 'Annu. Rev. Public Health'},
{ 'key': 'ref_13',
'doi-asserted-by': 'crossref',
'first-page': '1715',
'DOI': '10.1016/j.immuni.2021.06.014',
'article-title': 'Pannexin 1 channels facilitate communication between T cells to '
'restrict the severity of airway inflammation',
'volume': '54',
'author': 'Medina',
'year': '2021',
'journal-title': 'Immunity'},
{ 'key': 'ref_14',
'first-page': '258',
'article-title': 'Benemid: An anticatabolite; Its pharmacological properties',
'volume': '9',
'author': 'Beyer',
'year': '1950',
'journal-title': 'Fed. Proc.'},
{ 'key': 'ref_15',
'doi-asserted-by': 'crossref',
'first-page': '83',
'DOI': '10.1001/archinte.1955.00250070099012',
'article-title': 'Probenecid (Benemid): Its uses and side effects in 2502 Patients',
'volume': '95',
'author': 'Boger',
'year': '1955',
'journal-title': 'Am. Med. Assoc. Arch. Intern. Med.'},
{ 'key': 'ref_16',
'doi-asserted-by': 'crossref',
'first-page': '1',
'DOI': '10.1007/s12012-011-9145-8',
'article-title': 'The history and future of probenecid',
'volume': '12',
'author': 'Robbins',
'year': '2012',
'journal-title': 'Cardiovasc. Toxicol.'},
{ 'key': 'ref_17',
'unstructured': 'WHO Working Group on the Clinical Characterisation and Management of '
'COVID-19 infection (2020). A minimal common outcome measure set for '
'COVID-19 clinical research. Lancet Infect Dis., 20, e192–e197.'},
{ 'key': 'ref_18',
'unstructured': 'WHO (2023, January 26). COVID-19 Case Definitions. Available online: '
'https://apps.who.int/iris/rest/bitstreams/1322790/retrieve.'},
{ 'key': 'ref_19',
'unstructured': '(2023, January 26). PROBENECID-Probenecid Tablet, Film Coated Package '
'Insert. Lannett Company, Inc. Revision 1/2021, Available online: '
'https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ab497fd8-00c3-4364-b003-b39d21fbdf38&type=display.'},
{ 'key': 'ref_20',
'doi-asserted-by': 'crossref',
'unstructured': 'Tripp, R.A., and Martin, D.E. (2022). Repurposing Probenecid to Inhibit '
'SARS-CoV-2, Influenza Virus, and Respiratory Syncytial Virus (RSV) '
'Replication. Viruses, 14.',
'DOI': '10.3390/v14030612'},
{ 'key': 'ref_21',
'doi-asserted-by': 'crossref',
'first-page': '64',
'DOI': '10.1016/j.bbrc.2017.01.005',
'article-title': 'c-Jun N-terminal kinase activity is required for efficient respiratory '
'syncytial virus production',
'volume': '483',
'author': 'Caly',
'year': '2017',
'journal-title': 'Biochem. Biophys. Res. Commun.'},
{ 'key': 'ref_22',
'doi-asserted-by': 'crossref',
'first-page': '858629',
'DOI': '10.3389/fcimb.2022.858629',
'article-title': 'Receptors for Respiratory Syncytial Virus Infection and Host Factors '
'Regulating the Life Cycle of Respiratory Syncytial Virus',
'volume': '12',
'author': 'Feng',
'year': '2022',
'journal-title': 'Front. Cell Infect. Microbiol.'},
{ 'key': 'ref_23',
'doi-asserted-by': 'crossref',
'first-page': '104',
'DOI': '10.4062/biomolther.2019.047',
'article-title': 'Inhibitory Effect of Probenecid on Osteoclast Formation via JNK.; ROS '
'and COX-2',
'volume': '28',
'author': 'Cheng',
'year': '2020',
'journal-title': 'Biomol. Ther.'},
{ 'key': 'ref_24',
'doi-asserted-by': 'crossref',
'first-page': '793',
'DOI': '10.1128/MMBR.00043-14',
'article-title': 'JNK Signaling: Regulation and Functions Based on Complex '
'Protein-Protein Partnerships',
'volume': '80',
'author': 'Zeke',
'year': '2016',
'journal-title': 'Microbiol. Mol. Biol. Rev.'},
{ 'key': 'ref_25',
'doi-asserted-by': 'crossref',
'first-page': '48',
'DOI': '10.1016/j.virusres.2018.05.028',
'article-title': 'Role of MAPK/MNK1 signaling in virus replication',
'volume': '253',
'author': 'Kumar',
'year': '2018',
'journal-title': 'Virus Res.'},
{ 'key': 'ref_26',
'doi-asserted-by': 'crossref',
'first-page': '409',
'DOI': '10.1177/1947601913507577',
'article-title': 'Network Motifs in JNK Signaling',
'volume': '4',
'author': 'Sehgal',
'year': '2013',
'journal-title': 'Genes Cancer'},
{ 'key': 'ref_27',
'doi-asserted-by': 'crossref',
'first-page': '808',
'DOI': '10.1124/mol.113.088229',
'article-title': 'Hepatocyte nuclear factors 4α and 1α regulate kidney developmental '
'expression of drug-metabolizing enzymes and drug transporters',
'volume': '84',
'author': 'Martovetsky',
'year': '2013',
'journal-title': 'Mol. Pharmacol.'},
{ 'key': 'ref_28',
'first-page': 'e31352',
'article-title': 'An Early and Preliminary Assessment of the Clinical Severity of the '
'Emerging SARS-CoV-2 Omicron Variants in Maharashtra, India',
'volume': '14',
'author': 'Karyakarte',
'year': '2022',
'journal-title': 'Cureus'}],
'container-title': 'Viruses',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://www.mdpi.com/1999-4915/15/7/1508/pdf',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2023, 7, 7]],
'date-time': '2023-07-07T06:46:52Z',
'timestamp': 1688712412000},
'score': 1,
'resource': {'primary': {'URL': 'https://www.mdpi.com/1999-4915/15/7/1508'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2023, 7, 6]]},
'references-count': 28,
'journal-issue': {'issue': '7', 'published-online': {'date-parts': [[2023, 7]]}},
'alternative-id': ['v15071508'],
'URL': 'http://dx.doi.org/10.3390/v15071508',
'relation': {},
'ISSN': ['1999-4915'],
'subject': [],
'container-title-short': 'Viruses',
'published': {'date-parts': [[2023, 7, 6]]}}
