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Nitazoxanide In Vitro Efficacy Against SARS CoV-2 and In Vivo Superiority to Placebo to Treat Moderate COVID-19 – A Phase 2 Randomized Double-Blind Clinical Trial

30 Pages Posted: 22 Jan 2021

See all articles by Vinicius Fontanesi Blum

Vinicius Fontanesi Blum

Federal University of São Paulo (UNIFESP)

Sérgio Cimerman

Institute of Infectious Diseases Emilio Ribas

James R. Hunter

Federal University of São Paulo (UNIFESP)

Paulo Tierno

Hospital Municipal Dr. Francisco Moran

Acioly Lacerda

SPDM

Alexandre Soeiro

INCOR and Beneficência Portuguesa

Florentino Cardoso

Hospital Vera Cruz

Nancy Cristina Belley

Federal University of São Paulo (UNIFESP)

Juliana Maricato

Federal University of São Paulo (UNIFESP)

Nathalia Mantovani

Federal University of São Paulo (UNIFESP)

Marcella Vassao

Federal University of São Paulo (UNIFESP)

Danilo Dias

Federal University of São Paulo (UNIFESP)

Juliana Galinskas

Federal University of São Paulo (UNIFESP)

Daniel Karcher

Federal University of São Paulo (UNIFESP)

Fatima Morgana Pio Fonseca

Federal University of São Paulo (UNIFESP)

Renan Novaes Pinto

Federal University of São Paulo (UNIFESP)

Luis Mário Ramos Janini

Federal University of São Paulo (UNIFESP)

Joanna Reis Santos-Oliveira

Intituto Federal de Educação - Ciencia e Tecnologia do Rio de Janeiro

Alda Maria Da-Cruz

Instituto Oswaldo Cruz/FIOCRUZ

Ricardo Sobhie Diaz

Federal University of São Paulo (UNIFESP)

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Abstract

Background: The absence of specific antivirals to treat COVID-19 leads to the repositioning of candidates’ drugs.  Nitazoxanide (NTZ) has a broad antiviral effect.

Methods:  The in vitro effect of NTZ in VERO E6 cells was evaluated, followed by a randomized double-blind phase two clinical trial comparing NTZ 600 mg BID versus placebo for 7 days among 50 individuals (25 each arm) with SARS-COV-2 RT-PCR+ (PCR) that were hospitalized with mild respiratory insufficiency. Clinical and virologic end-points and inflammatory biomarkers were evaluated. A five-point scale for disease severity (SSD) was used.

Results: The in vitro inhibition of SARS-CoV-2 infection was 90% with 0.5 µM, with no cytotoxicity. Two patients died in the NTZ arm compared to 6 in the placebo arm (p=NS). NTZ was superior to placebo when considering SSD (p<0001), mean time for hospital discharge (6.6 vs 14 days, p=0.021), and negative PCR at day 21 (p=0.035), whereas placebo group presented more adverse events (p=0.04). A decrease from baseline was higher in the NTZ group for d-Dimer (p=0.001), US-RCP (p<0.002), TNF (p<0.038), IL-6 (p<0.001), IL-8 (p=0.014), and CD38+ on CD4+ T lymphocytes (p=0.271), HLA-DR+ on CD4 (p=.0.199), CD38+ on CD8 (p=0.431) and CD38+/HLADR+ on CD4 (p=0.694).

Conclusions: The superiority of NTZ as compared to placebo in clinical and virologic outcomes, as wells as improvement of inflammatory outcomes, warrants further investigation of this drug for moderate COVID-19 in larger clinical trials. A higher incidence of adverse events in the placebo arm might be attributed to COVID-19 related symptoms.

Trial Registration: This study was registered at ClinicalTrials.gov (NCT04348409).

Funding Statement: This clinical trial was funded by FQM Farma.

Declaration of Interests: AL has received grants and personal fees from Janssen Pharmaceutical;
has received personal fees from Daiichi Sankyo, Cristalia Produtos Quımicos e Farmaceuticos, Libbs, Pfizer, Myralis Farma, Ache Laboratorios, Hypera Pharma, and Sanofi-Aventis; and has received grants from FQM Farma, Eli Lilly, H. Lundbeck A/S, Servier Laboratories, Hoffman-La Roche, Biophytis, and Forum Pharmaceutical. All other authors have nothing to declare.

Ethics Approval Statement: This trial was approved by the Brazilian National Institutional Review Board (CONEP; approval # CAAE- 30628420.0.0000.5412) and each local Institutional Review Boards. Informed consent has been obtained.

Keywords: COVID-19; Nitazoxanide; randomized controlled clinical trial; lymphocytes cell activation markers, interleukins

Suggested Citation

Blum, Vinicius Fontanesi and Cimerman, Sérgio and Hunter, James R. and Tierno, Paulo and Lacerda, Acioly and Soeiro, Alexandre and Cardoso, Florentino and Belley, Nancy Cristina and Maricato, Juliana and Mantovani, Nathalia and Vassao, Marcella and Dias, Danilo and Galinskas, Juliana and Karcher, Daniel and Fonseca, Fatima Morgana Pio and Pinto, Renan Novaes and Janini, Luis Mário Ramos and Santos-Oliveira, Joanna Reis and Da-Cruz, Alda Maria and Diaz, Ricardo Sobhie, Nitazoxanide In Vitro Efficacy Against SARS CoV-2 and In Vivo Superiority to Placebo to Treat Moderate COVID-19 – A Phase 2 Randomized Double-Blind Clinical Trial. Available at SSRN: https://ssrn.com/abstract=3763773 or http://dx.doi.org/10.2139/ssrn.3763773

Vinicius Fontanesi Blum

Federal University of São Paulo (UNIFESP) ( email )

Rua Sena Madureira, 1500 - 5º andar
Vila Clementino
São Paulo, Sao Paulo 04021001
Brazil

Sérgio Cimerman

Institute of Infectious Diseases Emilio Ribas ( email )

Brazil

James R. Hunter

Federal University of São Paulo (UNIFESP) ( email )

Rua Sena Madureira, 1500 - 5º andar
Vila Clementino
São Paulo, Sao Paulo 04021001
Brazil

Paulo Tierno

Hospital Municipal Dr. Francisco Moran

Alexandre Soeiro

INCOR and Beneficência Portuguesa ( email )

Florentino Cardoso

Hospital Vera Cruz ( email )

Nancy Cristina Belley

Federal University of São Paulo (UNIFESP) ( email )

Rua Sena Madureira, 1500 - 5º andar
Vila Clementino
São Paulo, Sao Paulo 04021001
Brazil

Juliana Maricato

Federal University of São Paulo (UNIFESP)

Rua Sena Madureira, 1500 - 5º andar
Vila Clementino
São Paulo, Sao Paulo 04021001
Brazil

Nathalia Mantovani

Federal University of São Paulo (UNIFESP) ( email )

Rua Sena Madureira, 1500 - 5º andar
Vila Clementino
São Paulo, Sao Paulo 04021001
Brazil

Marcella Vassao

Federal University of São Paulo (UNIFESP) ( email )

Rua Sena Madureira, 1500 - 5º andar
Vila Clementino
São Paulo, Sao Paulo 04021001
Brazil

Danilo Dias

Federal University of São Paulo (UNIFESP)

Rua Sena Madureira, 1500 - 5º andar
Vila Clementino
São Paulo, Sao Paulo 04021001
Brazil

Juliana Galinskas

Federal University of São Paulo (UNIFESP) ( email )

Rua Sena Madureira, 1500 - 5º andar
Vila Clementino
São Paulo, Sao Paulo 04021001
Brazil

Daniel Karcher

Federal University of São Paulo (UNIFESP) ( email )

Rua Sena Madureira, 1500 - 5º andar
Vila Clementino
São Paulo, Sao Paulo 04021001
Brazil

Fatima Morgana Pio Fonseca

Federal University of São Paulo (UNIFESP) ( email )

Rua Sena Madureira, 1500 - 5º andar
Vila Clementino
São Paulo, Sao Paulo 04021001
Brazil

Renan Novaes Pinto

Federal University of São Paulo (UNIFESP) ( email )

Rua Sena Madureira, 1500 - 5º andar
Vila Clementino
São Paulo, Sao Paulo 04021001
Brazil

Luis Mário Ramos Janini

Federal University of São Paulo (UNIFESP) ( email )

Rua Sena Madureira, 1500 - 5º andar
Vila Clementino
São Paulo, Sao Paulo 04021001
Brazil

Joanna Reis Santos-Oliveira

Intituto Federal de Educação - Ciencia e Tecnologia do Rio de Janeiro ( email )

Alda Maria Da-Cruz

Instituto Oswaldo Cruz/FIOCRUZ ( email )

Ricardo Sobhie Diaz (Contact Author)

Federal University of São Paulo (UNIFESP)

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