Nitazoxanide in Patients Hospitalized With COVID-19 Pneumonia: A Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial

Abstract

Background: Nitazoxanide exerts antiviral activity in vitro and in vivo and anti-inflammatory effects, but its impact on patients hospitalized with COVID-19 pneumonia is uncertain.

Methods: A multicentre, randomized, double-blind, placebo-controlled trial was conducted in 19 hospitals in Brazil. Hospitalized adult patients requiring supplemental oxygen, with COVID-19 symptoms and a chest computed tomography scan suggestive of viral pneumonia or positive RT-PCR test for COVID-19 were enrolled. Patients were randomized 1:1 to receive nitazoxanide (500 mg) or placebo, 3 times daily, for 5 days, and were followed for 14 days. The primary outcome was intensive care unit admission due to the need for invasive mechanical ventilation. Secondary outcomes included clinical improvement, hospital discharge, oxygen requirements, death, and adverse events within 14 days.

Results: Of the 498 patients, 405 (202 in the nitazoxanide group and 203 in the placebo group) were included in the analyses. Admission to the intensive care unit did not differ between the groups (hazard ratio [95% confidence interval], 0.68 [0.38-1.20], p = 0.179); death rates also did not differ. Nitazoxanide improved the clinical outcome (2.75 [2.21-3.43], p < 0.0001), time to hospital discharge (1.37 [1.11-1.71], p = 0.005), and reduced oxygen requirements (0.77 [0.64-0.94], p = 0.011). C-reactive protein, D-dimer, and ferritin levels were lower in the nitazoxanide group than the placebo group on day 7. No serious adverse events were observed.

Conclusions: Nitazoxanide, compared with placebo, did not prevent admission to the intensive care unit for patients hospitalized with COVID-19 pneumonia.

Clinical trial registration: Brazilian Registry of Clinical Trials (REBEC) RBR88bs9x; ClinicalTrials.gov, NCT04561219.

Keywords: COVID-19; D-dimer; SARS-CoV-2; oxygenation; pneumonia.

Figure 1

Enrolment, randomization, follow-up, and treatment. Five hundred patients were assessed for eligibility at the study sites. Of these, 498 underwent randomization, 2 patients were excluded for not meeting the inclusion criteria. After randomization (n = 249/group), patients were excluded because they were withdrawn by the investigator, had mild/moderate adverse events, were transferred to another hospital, withdrew consent at any time during the study, refused to allow collection of blood and/or nasopharyngeal samples. Therefore, the modified intention-to-treat population consisted of 202 patients in the nitazoxanide group and 203 patients in the placebo group.

Figure 2

Primary and secondary outcomes in the nitazoxanide and placebo groups at the different time points. (A) Primary outcome: intensive care unit admission. (B) Secondary outcomes: clinical improvement, hospital discharge, oxygen requirement and death in the mITT population treated with nitazoxanide or placebo until day 14. The Kaplan-Meier curves and hazard ratios with corresponding 95% confidence intervals were calculated from a Cox proportional hazards model. mITT, modified intention-to-treat.

Figure 3

Eight-point ordinal scale of clinical status in the mITT (modified intention-to-treat) population treated with nitazoxanide or placebo until day 14. NIV, non-invasive ventilation; IMV, invasive mechanical ventilation.

Figure 4

Forest plot according to the primary outcome in the nitazoxanide and placebo groups. BMI, body mass index; CI, confidence interval; OR, odds ratio; SpO₂, peripheral saturation of oxygen. ORs and 95% CIs were calculated for each category individually.