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Various Combinations of Favipiravir, Lopinavir-Ritonavir, Darunavir-Ritonavir, High-Dose Oseltamivir, and Hydroxychloroquine for the Treatment of COVID-19: A Randomized Controlled Trial (FIGHT-COVID-19 Study)

29 Pages Posted: 5 Oct 2021

See all articles by Kriangsak Atipornwanich

Kriangsak Atipornwanich

Rajavithi Hospital

Subsai Kongsaengdao

Rajavithi Hospital - Division of Neurology

Piyathida Harnsomburana

Rajavithi Hospital

Rienthong Nanna

Monkutwattana Hospital - Department of Medicine

Chatchawan Chtuparisute

Monkutwattana Hospital - Department of Medicine

Piamlarp Saengsayan

Central Chest Institute of Thailand - Department of Medicine

Kittima Bangpattanasiri

Central Chest Institute of Thailand - Department of Medicine

Weerawat Manosuthi

Bamrasnaradura Infectious Disease Institute

Narumol Sawanpanyalert

Ministry of Public Health, Nonthaburi - Department of Medical Services

Attasit Srisubat

Ministry of Public Health, Nonthaburi - Department of Medical Services

Somchai Thanasithichai

Ministry of Public Health, Nonthaburi - Department of Medical Services

Benchalak Maneeton

Chiang Mai University

Narong Maneeton

Chiang Mai University

Chuthamanee Suthisisang

Mahidol University

Jaturong Pratuangdejkul

Mahidol University

Somsak Akksilp

Rangsit University - Department of Medicine

More...

Abstract

Background: Monotherapy with Remdesivir, Favipiravir, Lopinavir-Ritonavir, or Hydroxychloroquine has been evaluated for the treatment of coronavirus disease 2019 (Covid-19). No antiviral agents have yet been shown to be efficacious in terms of viral clearance and reduction of death in moderate to severe Covid-19 in randomized controlled trials.

Methods: We conducted an open-label, randomized, controlled trial of various oral combinations of Favipiravir, Lopinavir-Ritonavir, Darunavir-Ritonavir, high-dose Oseltamivir, and Hydroxychloroquine in adults who were hospitalized with Covid-19.  Ninety patients were randomly assigned to receive either 1) high-dose Oseltamivir and Hydroxychloroquine, 2) Lopinavir-Ritonavir and high-dose Oseltamivir, or 3) Darunavir- Ritonavir, high-dose Oseltamivir, and Hydroxychloroquine, compared to thirty voluntary quarantine patients without antiviral agent for mild Covid-19. In addition, two hundred patients were randomly assigned to receive 1) high-dose Oseltamivir and Lopinavir- Ritonavir, 2) Favipiravir and Lopinavir-Ritonavir, 3) high-dose Oseltamivir and Darunavir-Ritonavir, or 4) Favipiravir and Darunavir-Ritonavir and Hydroxychloroquine for moderate to severe Covid-19.

Results: A total of 320 patients were enrolled. Those mild Covid-19 patients who received high-dose Oseltamivir and Hydroxychloroquine had a better median time for negative Polymerase Chain Reaction test (PCR) for SARS-CoV-2 than who were voluntarily quarantined without antiviral agent (ITT:  7.5 days (IQR, 4 to 25) versus 11.5 days (IQR, 8 to 18) (P=0.02), LOCF: 7.5 days (IQR, 4.5 to 14) versus 10 days (IQR, 6.5 to18.5) (P=0.01), and PP 8 days (IQR, 4 to 15) versus 9 days (IQR, 6 to17) (P=0.01).For moderate to severe Covid-19 patients, Favipiravir plus Darunavir-Ritonavir plus Hydroxychloroquine had a better median time to negative PCR for SARS-CoV-2 than who received high-dose Oseltamivir plus Lopinavir-Ritonavir (ITT:  10 days (IQR, 5.5 to 13) versus 12 days (IQR, 7 to 15) (P=0.15), LOCF: 10 days (IQR, 5to 13) versus 11 days (IQR, 6 to 15) (P=0.005), and PP 10 days (IQR, 5 to 13) versus 9.5 days (IQR, 5 to15) (P=0.003). In moderate to severe Covid -19, The Kaplan–Meier estimates of mortality were 16.0% with high-dose Oseltamivir plus Lopinavir-Ritonavir compared to 4.0% with Favipiravir plus Darunavir-Ritonavir plus Hydroxychloroquine (P=0.04), and more patient deaths with high-dose Oseltamivir plus Lopinavir-Ritonavir, and Favipiravir plus Lopinavir-Ritonavir, compared to Favipiravir plus Darunavir-Ritonavir plus Hydroxychloroquine ( P=0.04).

Conclusions: High-dose Oseltamivir and Hydroxychloroquine were superior to voluntary quarantine without antiviral agent in terms of viral clearance in mild Covid -19. Favipiravir plus Darunavir-Ritonavir plus Hydroxychloroquine were superior to other antiviral agent combinations in terms viral clearance and death in moderate to severe Covid -19.

Clinical Trial Registration Details: ClinicalTrials.gov number NCT04303299.

Funding Information: Department of Medical Services of Ministry of Public Health, Health System Research Institute of Ministry of Public Health, and The Office of the National Broadcasting and Telecommunications Commission Institute of Thailand.

Declaration of Interests: All authors declare no conflicts of interest, no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous three years, and no other relationships or activities that could appear to have influenced the submitted work.

Ethics Approval Statement: The trial protocol was approved by the institutional review board at each site and the centralized institutional review board of the Ethics Committee of the Ministry of Public Health, Thailand. There were independent data and safety monitoring boards. Written informed consent was obtained from each patient or from the patient’s legally authorized representative if the patient was unable to provide consent.

Keywords: COVID-19, mild COVID-19, Moderate to severe COVID-19

Suggested Citation

Atipornwanich, Kriangsak and Kongsaengdao, Subsai and Harnsomburana, Piyathida and Nanna, Rienthong and Chtuparisute, Chatchawan and Saengsayan, Piamlarp and Bangpattanasiri, Kittima and Manosuthi, Weerawat and Sawanpanyalert, Narumol and Srisubat, Attasit and Thanasithichai, Somchai and Maneeton, Benchalak and Maneeton, Narong and Suthisisang, Chuthamanee and Pratuangdejkul, Jaturong and Akksilp, Somsak, Various Combinations of Favipiravir, Lopinavir-Ritonavir, Darunavir-Ritonavir, High-Dose Oseltamivir, and Hydroxychloroquine for the Treatment of COVID-19: A Randomized Controlled Trial (FIGHT-COVID-19 Study). Available at SSRN: https://ssrn.com/abstract=3936499 or http://dx.doi.org/10.2139/ssrn.3936499

Kriangsak Atipornwanich

Rajavithi Hospital

Subsai Kongsaengdao (Contact Author)

Rajavithi Hospital - Division of Neurology ( email )

Bangkok
Thailand

Piyathida Harnsomburana

Rajavithi Hospital

Bangkok
Thailand

Rienthong Nanna

Monkutwattana Hospital - Department of Medicine ( email )

United States

Chatchawan Chtuparisute

Monkutwattana Hospital - Department of Medicine ( email )

United States

Piamlarp Saengsayan

Central Chest Institute of Thailand - Department of Medicine ( email )

United States

Kittima Bangpattanasiri

Central Chest Institute of Thailand - Department of Medicine ( email )

United States

Weerawat Manosuthi

Bamrasnaradura Infectious Disease Institute ( email )

Nonthaburi
Thailand

Narumol Sawanpanyalert

Ministry of Public Health, Nonthaburi - Department of Medical Services ( email )

United States

Attasit Srisubat

Ministry of Public Health, Nonthaburi - Department of Medical Services ( email )

United States

Somchai Thanasithichai

Ministry of Public Health, Nonthaburi - Department of Medical Services ( email )

United States

Benchalak Maneeton

Chiang Mai University

Huay Kaew Road
Chiang Mai, 50100
Thailand

Narong Maneeton

Chiang Mai University

Huay Kaew Road
Chiang Mai, 50100
Thailand

Chuthamanee Suthisisang

Mahidol University

69 Vipawadee Rangsit Road
Phayatai, Bangkok, 10400
Thailand

Jaturong Pratuangdejkul

Mahidol University

69 Vipawadee Rangsit Road
Phayatai, Bangkok, 10400
Thailand

Somsak Akksilp

Rangsit University - Department of Medicine ( email )

United States

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