An open-label randomized controlled trial evaluating the efficacy of chloroquine/hydroxychloroquine in severe COVID-19 patients

Abstract

Despite several studies designed to evaluate the efficacy of chloroquine and hydroxychloroquine in the treatment of coronavirus disease 2019 (COVID-19), there is still doubt about the effects of these drugs, especially in patients with severe forms of the disease. This randomized, open-label, controlled, phase III trial assessed the efficacy of chloroquine or hydroxychloroquine for five days in combination with standard care compared to standard care alone in patients hospitalized with severe COVID-19. Chloroquine 450 mg BID on day 1 and 450 mg once daily from days 2 to 5 or hydroxychloroquine 400 mg BID on day 1 and 400 mg once daily from days 2 to 5 were administered in the intervention group. Patients were enrolled from April 16 to August 06, 2020, in 6 hospitals in southern Brazil. The primary outcome was the clinical status measured on day 14 after randomization with a 9-point ordinal scale. The main secondary outcomes were all-cause mortality; invasive mechanical ventilation use; the incidence of acute renal dysfunction in 28 days; and the clinical status of patients on days 5, 7, 10 and 28. All patients with a positive RT-PCR result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were analyzed (modified intention to treat (mITT) population). Arrythmias and cardiovascular complications were assessed as safety outcomes. A total of 105 patients were enrolled and followed for 28 days. The trial was stopped before reaching the planned sample size due to harmful effects. Patients in the intervention group had a worse clinical outcome on the 14th day (odds ratio (OR) 2.45 [1.17 to 4.93], p = 0.016) and on the 28th day (OR 2.47 [1.15 to 5.30], p = 0.020). Moreover, the intervention group had higher incidences of invasive mechanical ventilation use (risk ratio (RR) 2.15 [1.05 to 4.40], p = 0.030) and severe renal dysfunction (KDIGO stage 3) (RR 2.24 [1.01 to 4.99], p = 0.042) until the 28th day of follow-up. No significant arrythmia was noted. In patients with severe COVID-19, the use of chloroquine/hydroxychloroquine added to standard treatment resulted in a significant worsening of clinical status, an increased risk of renal dysfunction and an increased need for invasive mechanical ventilation.Trial Registration: ClinicalTrials.gov, NCT04420247. Registered 09 June 2020-Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/study/NCT04420247 .

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1

Trial profile. aOne of these patients did not receive at least two doses of the assigned treatment and was not included in the safety analyses.

Figure 2

Primary and secondary outcomes in the mITT population from presentation to the evaluation of clinical status with a 9-point ordinal scale. (a) Clinical status evaluated by a 9-point ordinal scale at day 14. (b) Clinical status evaluated by a 9-point ordinal scale at day 5. (c) Clinical status evaluated by a 9-point ordinal scale at day 7. (d) Clinical status evaluated by a 9-point ordinal scale at day 10. (e) Clinical status evaluated by a 9-point ordinal scale at day 28; one patient in the control group did not have an ordinal scale score ascertained at day 28 because of loss to follow-up. The scores on the scale were defined as follows: (0) nonhospitalized and no clinical or virological evidence of infection; (1) nonhospitalized and no limitation on activities; (2) nonhospitalized, but with limitation on activities; (3) hospitalized, but not requiring supplemental oxygen; (4) hospitalized and on oxygen via mask or nasal prongs; (5) hospitalized, on noninvasive ventilation or high-flow oxygen or pressure support ventilation in weaning mode; (6) hospitalized, intubated and on MV; (7) hospitalized on MV and additional organ support (renal replacement therapy, vasoactive drugs or extracorporeal membrane oxygenation), and (8) dead. The percentages shown have been rounded to whole numbers. ORs (95% CIs) and p values were derived from ordinal logistic regression, assuming proportional ORs, adjusted for age and baseline severity (according to ventilatory support) for the mITT population. An OR > 1.00 represents a clinical worsening assessed with the ordinal scale in the Clq/HClq group compared with the control group.

Figure 3

Cumulative incidence of IMV, acute renal dysfunction and mortality until the 28th day. (a) Considering the 44 patients from the Clq/HClq group and 42 from the control group of the mITT population who were not on MV at baseline. (b) Considering the 52 patients from the Clq/HClq group and 51 from the control group of the mITT population who were not at KDIGO stage 3 at baseline. (c) Considering the entire mITT population. *RRs with CIs calculated using the Wald likelihood test.