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Randomized Controlled Trial
. 2021 Jul 8;58(1):2003725.
doi: 10.1183/13993003.03725-2020. Print 2021 Jul.

Early use of nitazoxanide in mild COVID-19 disease: randomised, placebo-controlled trial

Patricia R M Rocco  1   2 , Pedro L Silva  1   2 , Fernanda F Cruz  1   2 , Marco Antonio C Melo-Junior  3 , Paulo F G M M Tierno  4 , Marcos A Moura  5 , Luís Frederico G De Oliveira  6 , Cristiano C Lima  7 , Ezequiel A Dos Santos  8 , Walter F Junior  9 , Ana Paula S M Fernandes  10 , Kleber G Franchini  11 , Erick Magri  3 , Nara F de Moraes  4 , José Mário J Gonçalves  5 , Melanie N Carbonieri  6 , Ivonise S Dos Santos  7 , Natália F Paes  8 , Paula V M Maciel  9 , Raissa P Rocha  10 , Alex F de Carvalho  10 , Pedro Augusto Alves  12 , José Luiz Proença-Módena  13 , Artur T Cordeiro  11 , Daniela B B Trivella  11 , Rafael E Marques  11 , Ronir R Luiz  1 , Paolo Pelosi  14 , Jose Roberto Lapa E Silva  1 ; SARITA-2 investigators
Affiliations
Randomized Controlled Trial

Early use of nitazoxanide in mild COVID-19 disease: randomised, placebo-controlled trial

Patricia R M Rocco et al. Eur Respir J. .

Abstract

Background: Nitazoxanide is widely available and exerts broad-spectrum antiviral activity in vitro. However, there is no evidence of its impact on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Methods: In a multicentre, randomised, double-blind, placebo-controlled trial, adult patients presenting up to 3 days after onset of coronavirus disease 2019 (COVID-19) symptoms (dry cough, fever and/or fatigue) were enrolled. After confirmation of SARS-CoV-2 infection using reverse transcriptase PCR on a nasopharyngeal swab, patients were randomised 1:1 to receive either nitazoxanide (500 mg) or placebo, three times daily, for 5 days. The primary outcome was complete resolution of symptoms. Secondary outcomes were viral load, laboratory tests, serum biomarkers of inflammation and hospitalisation rate. Adverse events were also assessed.

Results: From June 8 to August 20, 2020, 1575 patients were screened. Of these, 392 (198 placebo, 194 nitazoxanide) were analysed. Median (interquartile range) time from symptom onset to first dose of study drug was 5 (4-5) days. At the 5-day study visit, symptom resolution did not differ between the nitazoxanide and placebo arms. Swabs collected were negative for SARS-CoV-2 in 29.9% of patients in the nitazoxanide arm versus 18.2% in the placebo arm (p=0.009). Viral load was reduced after nitazoxanide compared to placebo (p=0.006). The percentage viral load reduction from onset to end of therapy was higher with nitazoxanide (55%) than placebo (45%) (p=0.013). Other secondary outcomes were not significantly different. No serious adverse events were observed.

Conclusions: In patients with mild COVID-19, symptom resolution did not differ between nitazoxanide and placebo groups after 5 days of therapy. However, early nitazoxanide therapy was safe and reduced viral load significantly.

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Conflict of interest statement

Conflict of interest: P.R.M. Rocco reports personal fees for data monitoring committee work from Sanofi, outside the submitted work. Conflict of interest: P.L. Silva has nothing to disclose. Conflict of interest: F.F. Cruz has nothing to disclose. Conflict of interest: M.A.C.M. Junior has nothing to disclose. Conflict of interest: P.F.G.M.M. Tierno has nothing to disclose. Conflict of interest: M.A. Moura has nothing to disclose. Conflict of interest: L.F.G. De Oliveira has nothing to disclose. Conflict of interest: C.C. Lima has nothing to disclose. Conflict of interest: E.A. Dos Santos has nothing to disclose. Conflict of interest: W.F. Junior has nothing to disclose. Conflict of interest: A.P.S.M. Fernandes has nothing to disclose. Conflict of interest: K.G. Franchini has nothing to disclose. Conflict of interest: E. Magri has nothing to disclose. Conflict of interest: N.F. de Moraes has nothing to disclose. Conflict of interest: J.M.J Gonçalves has nothing to disclose. Conflict of interest: M.N. Carbonieri has nothing to disclose. Conflict of interest: I.S. Dos Santos has nothing to disclose. Conflict of interest: N.F. Paes has nothing to disclose. Conflict of interest: P.V.M. Maciel has nothing to disclose. Conflict of interest: R.P. Rocha has nothing to disclose. Conflict of interest: A.F. de Carvalho has nothing to disclose. Conflict of interest: P.A. Alves has nothing to disclose. Conflict of interest: J.L.P. Modena has nothing to disclose. Conflict of interest: A.T. Cordeiro has nothing to disclose. Conflict of interest: D.B.B. Trivella has nothing to disclose. Conflict of interest: R.E. Marques has nothing to disclose. Conflict of interest: R.R. Luiz has nothing to disclose. Conflict of interest: P. Pelosi has nothing to disclose. Conflict of interest: J.R. Lapa e Silva has nothing to disclose.

Figures

FIGURE 1
FIGURE 1
Timeline of study design. RT-PCR: real-time reverse-transcriptase PCR; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; CRP: C-reactive protein.
FIGURE 2
FIGURE 2
Enrolment, randomisation, follow-up and treatment. 1575 patients were assessed for eligibility at the study sites. Of these, 475 tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by reverse transcriptase (RT)-PCR and underwent randomisation. Reasons for exclusion before randomisation included negative RT-PCR collected at day 0 (baseline) and/or absence of coronavirus disease 2019 (COVID-19) symptoms (n=1062), refusal to participate (n=27), hospitalisation before the first dose of therapy (n=5) and other reasons (n=6). After randomisation (n=475), patients were excluded due to discontinued intervention (n=39), moderate adverse events (n=7) (all gastrointestinal upset) and hospitalisation (n=10) (n=5 patients from each group, none of whom completed therapy). During analysis, 12 patients were excluded from the nitazoxanide arm and 15 from the placebo arm due to protocol deviation, missing data on the primary outcome or non-evaluability, resulting in a studied population of 392 patients (194 in the nitazoxanide arm and 198 in the placebo arm).
FIGURE 3
FIGURE 3
Kaplan–Meier curve of symptom resolution after 5 days of therapy.
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