Early treatment with fluvoxamine, bromhexine, cyproheptadine, and niclosamide to prevent clinical deterioration in patients with symptomatic COVID-19: a randomized clinical trial
Issued Date
2024-04-01
Resource Type
eISSN
25895370
Scopus ID
2-s2.0-85187957790
Journal Title
eClinicalMedicine
Volume
70
Rights Holder(s)
SCOPUS
Bibliographic Citation
eClinicalMedicine Vol.70 (2024)
Suggested Citation
Wannigama D.L., Hurst C., Phattharapornjaroen P., Hongsing P., Sirichumroonwit N., Chanpiwat K., Ali A.H., Storer R.J., Ounjai P., Kanthawee P., Ngamwongsatit N., Kupwiwat R., Kupwiwat C., Brimson J.M., Devanga Ragupathi N.K., Charuluxananan S., Leelahavanichkul A., Kanjanabuch T., Higgins P.G., Badavath V.N., Amarasiri M., Verhasselt V., Kicic A., Chatsuwan T., Pirzada K., Jalali F., Reiersen A.M., Abe S., Ishikawa H., Tanasatitchai C., Amphol S., Nantawong L., Sangchan P., Sinkajarern V., Phoonakh T., Utenpattanun P., Sithu Shein A.M., Vitoonpong T., Chongthavonsatit N., Mankong Y., Chaichana P., Yaithet J., Pongprajak D., Traimuangpak S., Saksirisampant G., Lamloeskittinon P., Hamdy A.A., Kosasih S.S., Luk-in S.S. Early treatment with fluvoxamine, bromhexine, cyproheptadine, and niclosamide to prevent clinical deterioration in patients with symptomatic COVID-19: a randomized clinical trial. eClinicalMedicine Vol.70 (2024). doi:10.1016/j.eclinm.2024.102517 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/97739
Title
Early treatment with fluvoxamine, bromhexine, cyproheptadine, and niclosamide to prevent clinical deterioration in patients with symptomatic COVID-19: a randomized clinical trial
Author(s)
Wannigama D.L.
Hurst C.
Phattharapornjaroen P.
Hongsing P.
Sirichumroonwit N.
Chanpiwat K.
Ali A.H.
Storer R.J.
Ounjai P.
Kanthawee P.
Ngamwongsatit N.
Kupwiwat R.
Kupwiwat C.
Brimson J.M.
Devanga Ragupathi N.K.
Charuluxananan S.
Leelahavanichkul A.
Kanjanabuch T.
Higgins P.G.
Badavath V.N.
Amarasiri M.
Verhasselt V.
Kicic A.
Chatsuwan T.
Pirzada K.
Jalali F.
Reiersen A.M.
Abe S.
Ishikawa H.
Tanasatitchai C.
Amphol S.
Nantawong L.
Sangchan P.
Sinkajarern V.
Phoonakh T.
Utenpattanun P.
Sithu Shein A.M.
Vitoonpong T.
Chongthavonsatit N.
Mankong Y.
Chaichana P.
Yaithet J.
Pongprajak D.
Traimuangpak S.
Saksirisampant G.
Lamloeskittinon P.
Hamdy A.A.
Kosasih S.S.
Luk-in S.S.
Hurst C.
Phattharapornjaroen P.
Hongsing P.
Sirichumroonwit N.
Chanpiwat K.
Ali A.H.
Storer R.J.
Ounjai P.
Kanthawee P.
Ngamwongsatit N.
Kupwiwat R.
Kupwiwat C.
Brimson J.M.
Devanga Ragupathi N.K.
Charuluxananan S.
Leelahavanichkul A.
Kanjanabuch T.
Higgins P.G.
Badavath V.N.
Amarasiri M.
Verhasselt V.
Kicic A.
Chatsuwan T.
Pirzada K.
Jalali F.
Reiersen A.M.
Abe S.
Ishikawa H.
Tanasatitchai C.
Amphol S.
Nantawong L.
Sangchan P.
Sinkajarern V.
Phoonakh T.
Utenpattanun P.
Sithu Shein A.M.
Vitoonpong T.
Chongthavonsatit N.
Mankong Y.
Chaichana P.
Yaithet J.
Pongprajak D.
Traimuangpak S.
Saksirisampant G.
Lamloeskittinon P.
Hamdy A.A.
Kosasih S.S.
Luk-in S.S.
Author's Affiliation
Yamagata Prefectural Central Hospital
Medizinische Fakultät
Siriraj Hospital
Mae Fah Luang University Hospital
UWA Medical School
Yamagata Prefectural University of Health Sciences
Kitasato University Graduate School of Medical Science
Perth Children's Hospital
The Faculty of Health Sciences
Narsee Monjee Institute of Management Studies, Mumbai
The University of Western Australia
Chulalongkorn University
Sahlgrenska Akademin
McMaster University, Faculty of Health Sciences
Washington University School of Medicine in St. Louis
King Chulalongkorn Memorial Hospital
University of Toronto Faculty of Medicine
Mae Fah Luang University
University of Otago
Faculty of Medicine Ramathibodi Hospital, Mahidol University
Thailand Ministry of Public Health
Mahidol University
Rajavithi Hospital
Charles Darwin University
Faculty of Medicine, Chulalongkorn University
The University of Sheffield
Telethon Kids Institute
Bioberrys Healthcare and Research Centre
Partner Site Bonn-Cologne
Saddleback Medical Group
Vibhavadi Hospital
Medizinische Fakultät
Siriraj Hospital
Mae Fah Luang University Hospital
UWA Medical School
Yamagata Prefectural University of Health Sciences
Kitasato University Graduate School of Medical Science
Perth Children's Hospital
The Faculty of Health Sciences
Narsee Monjee Institute of Management Studies, Mumbai
The University of Western Australia
Chulalongkorn University
Sahlgrenska Akademin
McMaster University, Faculty of Health Sciences
Washington University School of Medicine in St. Louis
King Chulalongkorn Memorial Hospital
University of Toronto Faculty of Medicine
Mae Fah Luang University
University of Otago
Faculty of Medicine Ramathibodi Hospital, Mahidol University
Thailand Ministry of Public Health
Mahidol University
Rajavithi Hospital
Charles Darwin University
Faculty of Medicine, Chulalongkorn University
The University of Sheffield
Telethon Kids Institute
Bioberrys Healthcare and Research Centre
Partner Site Bonn-Cologne
Saddleback Medical Group
Vibhavadi Hospital
Corresponding Author(s)
Other Contributor(s)
Abstract
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 viral loads as early as day 3 of treatment (p < 0.0001), decreased levels of serum cytokines interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) as early as day 5 of treatment, and interleukin-8 (IL-8) by day 7 of treatment (p < 0.0001) and lower incidence of post-acute sequelae of COVID-19 (PASC) symptoms (p < 0.0001). 23 serious adverse events occurred in the standard care arm, while only 1 serious adverse event was reported in the fluvoxamine arm, and zero serious adverse events occurred in the other arms. Interpretation: Early treatment with these combinations among outpatients diagnosed with COVID-19 was associated with lower likelihood of clinical deterioration, and with significant and rapid reduction in the viral load and serum cytokines, and with lower burden of PASC symptoms. When started very soon after symptom onset, these repurposed drugs have high potential to prevent clinical deterioration and death in vaccinated and unvaccinated COVID-19 patients. Funding: Ped Thai Su Phai (Thai Ducks Fighting Danger) social giver group.