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We included randomized controlled trials evaluating oral or inhaled therapeutics administered to adults with acute SARS-CoV-2 infection in outpatient settings and excluded non-randomized and observational studies. Outcomes of interest included severe clinical outcomes. Random-effects meta-analyses were performed where feasible.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 124 randomized controlled trials evaluating 137 therapeutics across 35 countries were included. Most interventions were repurposed agents (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200988), with 33 antiviral and three combination regimens. Molnupiravir shortened time to recovery and reduced hospitalization in a subgroup pool of unvaccinated, higher-risk outpatients (OR 0.68, 95% CI 0.52\u20130.89), although this effect attenuated when mostly vaccinated patients was included (OR 0.83, 95% CI 0.58\u20131.19). Inhaled budesonide and metformin showed modest or setting-specific benefits, while most repurposed drugs, including fluvoxamine, ivermectin, and hydroxychloroquine, had no consistent clinical impact. Safety profiles were class-typical with no new signals identified.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Most repurposed and antiviral therapies evaluated in outpatient COVID-19 trials showed no consistent benefit for severe clinical outcomes. Modest or setting-specific effects were observed for inhaled budesonide, metformin, and molnupiravir, with molnupiravir\u2019s effect on hospitalization most evident in unvaccinated, higher-risk outpatients and unreplicated for mortality.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical trial number<\/jats:title>\n                    <jats:p>Not applicable.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12879-026-13901-7","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T02:11:48Z","timestamp":1784772708000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Effectiveness of oral and inhaled repurposed and antiviral pharmaceutical treatments for acute SARS-CoV-2 in outpatient settings: a systematic review of 124 randomized trials"],"prefix":"10.1186","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3962-2777","authenticated-orcid":false,"given":"Banafshe","family":"Hosseini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lesley Anne","family":"Pablo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolanta","family":"Piszczek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4948-4707","authenticated-orcid":false,"given":"Yoav","family":"Keynan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7068-8056","authenticated-orcid":false,"given":"Peter","family":"Daley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8293-9238","authenticated-orcid":false,"given":"Becky","family":"Skidmore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1841-9347","authenticated-orcid":false,"given":"Andrew D.","family":"Pinto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"13901_CR1","unstructured":"World Health Organization. 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