Early treatment with fluvoxamine, bromhexine, cyproheptadine, and niclosamide to prevent clinical deterioration in patients with symptomatic COVID-19: a randomized clinical trial
Dhammika Leshan Wannigama, Cameron Hurst, Phatthranit Phattharapornjaroen, Parichart Hongsing, Natchalaikorn Sirichumroonwit, Kanokpoj Chanpiwat, Ali Hosseini Rad S.M., Robin James Storer, Puey Ounjai, Phitsanuruk Kanthawee, Natharin Ngamwongsatit, Rosalyn Kupwiwat, Chaisit Kupwiwat, James Michael Brimson, Naveen Kumar Devanga Ragupathi, Somrat Charuluxananan, Asada Leelahavanichkul, Talerngsak Kanjanabuch, Paul G Higgins, Vishnu Nayak Badavath, Mohan Amarasiri, Valerie Verhasselt, al,am,an,ao Anthony Kicic, Tanittha Chatsuwan, Kashif Pirzada, Farid Jalali, as,au Angela M Reiersen, Shuichi Abe, Hitoshi Ishikawa, Chanikan Tanasatitchai, Supamat Amphol, Ladda Nantawong, Prangrawee Sangchan, Varissara Sinkajarern, Thutpharritchn Phoonakh, Phornnapat Utenpattanun, Aye Mya Sithu Shein, Timporn Vitoonpong, Nichapha Chongthavonsatit, Yahya Mankong, Piyapong Chaichana, Jenjira Yaithet, Dumrongsak Pongprajak, Sukjai Traimuangpak, Gasit Saksirisampant, Phimonsiri Lamloeskittinon, Adam Adam Hamdy, Sinthu Sinthu Kosasih, Sirirat Sirirat Luk-In
eClinicalMedicine, doi:10.1016/j.eclinm.2024.102517
Background Repurposed drugs with host-directed antiviral and immunomodulatory properties have shown promise in the treatment of COVID-19, but few trials have studied combinations of these agents. The aim of this trial was to assess the effectiveness of affordable, widely available, repurposed drugs used in combination for treatment of COVID-19, which may be particularly relevant to low-resource countries.
Methods We conducted an open-label, randomized, outpatient, controlled trial in Thailand from October 1, 2021, to June 21, 2022, to assess whether early treatment within 48-h of symptoms onset with combinations of fluvoxamine, bromhexine, cyproheptadine, and niclosamide, given to adults with confirmed mild SARS-CoV-2 infection, can prevent 28-day clinical deterioration compared to standard care. Participants were randomly assigned to receive treatment with fluvoxamine alone, fluvoxamine + bromhexine, fluvoxamine + cyproheptadine, niclosamide + bromhexine, or standard care. The primary outcome measured was clinical deterioration within 9, 14, or 28 days using a 6-point ordinal scale. This trial is registered with ClinicalTrials.gov (NCT05087381). Findings Among 1900 recruited, a total of 995 participants completed the trial. No participants had clinical deterioration by day 9, 14, or 28 days among those treated with fluvoxamine plus bromhexine (0%), fluvoxamine plus cyproheptadine (0%), or niclosamide plus bromhexine (0%). Nine participants (5.6%) in the fluvoxamine arm had clinical deterioration by day 28, requiring low-flow oxygen. In contrast, most standard care arm participants had clinical deterioration by 9, 14, and 28 days. By day 9, 32.7% (110) of patients in the standard care arm had been hospitalized without requiring supplemental oxygen but needing ongoing medical care. By day 28, this percentage increased to 37.5% (21). Additionally, 20.8% (70) of patients in the standard care arm required low-flow oxygen by day 9, and 12.5% ( 16 ) needed non-invasive or mechanical ventilation by day 28. All treated groups significantly differed from the standard care group by days 9, 14, and 28 (p < 0.0001). Also, by day 28, the three 2-drug treatments were significantly better than the fluvoxamine arm (p < 0.0001). No deaths occurred in any study group. Compared to standard care, participants treated with the combination agents had significantly decreased
Cameron Hurst data curation, statistical analysis, supervision, critical review, and editing of the manuscript. Phatthranit Phattharapornjaroen supervision, conception, investigation, funding acquisition, data curation, critical review, and editing of the manuscript. Parichart Hongsing supervision, conception, investigation, data curation, critical review, and editing of the manuscript. Natchalaikorn Sirichumroonwit supervision, conception, investigation, funding acquisition, data curation, critical review and editing of the manuscript. Kanokpoj Chanpiwat supervision, conception, investigation, funding acquisition, data curation, critical review and editing of the manuscript. Ali Hosseini Rad S. M. supervision, critical review and editing of the manuscript. Robin James Storer supervision, critical review and editing of the manuscript. Puey Ounjai supervision, critical review and editing of the manuscript. Phitsanuruk Kanthawee supervision, critical review and editing of the manuscript. Natharin Ngamwongsatit supervision, critical review and editing of the manuscript. Rosalyn Kupwiwat clinical data collection, supervision, critical review and editing of the manuscript. Chaisit Kupwiwat clinical data collection, supervision, critical review and editing of the manuscript. James Michael Brimson clinical data collection, supervision, critical review and editing of the manuscript. Naveen Kumar Devanga Ragupathi supervision, critical review and editing of the manuscript. Sirirat..
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