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.

Efficacy of COVID-19 Treatments: A Bayesian Network Meta-Analysis of Randomized Controlled Trials

“…Overall, 115 studies with 77,128 patients reported the number of patients requiring mechanical ventilation during the study period. We included ACEIs/ARBs, ammonium chloride, azithromycin, bamlanivimab, baricitinib plus remdesivir, bromhexine, budesonide, camostat mesilate, canakinumab, chloroquine, colchicine, convalescent plasma, dexamethasone, doxycycline, favipiravir, hydroxychloroquine, hydroxychloroquine plus azithromycin, hydroxychloroquine plus favipiravir, imatinib, INM005, interferon beta, intravenous immunoglobulin, ivermectin, lopinavir/ritonavir, methylprednisolone, recombinant human GCSF, remdesivir, sarilumab, sofosbuvir plus daclatasvir, sulodexide, tocilizumab, tofacitinib, vitamin D3 and SOC as treatment nodes in the NMA, for which observations came from 84 studies ( 3 , 6 , 22 – 26 , 28 – 31 , 35 , 42 , 43 , 46 , 47 , 50 , 53 , 55 , 57 – 61 , 63 , 64 , 66 , 67 , 71 , 73 – 77 , 79 , 80 , 82 , 83 , 85 – 87 , 89 , 92 – 94 , 96 – 100 , 102 , 105 – 107 , 109 , 111 – 118 , 120 – 124 , 126 , 128 – 132 , 134 , 135 , 139 , 140 , 145 , 151 , 152 , 154 – 156 ). About one-third (26/84) of the included studies were evaluated as low risk ( Supplementary Table 6 ).…”

“…The hospital discharge rate was reported in 65 studies including 53,636 patients and 34,247 events. Treatment nodes included in the network were azithromycin, bamlanivimab, baricitinib plus remdesivir, camostat mesilate, canakinumab, convalescent plasma, dapagliflozin, dexamethasone, favipiravir, hydroxychloroquine, hydroxychloroquine plus azithromycin, hydroxychloroquine plus favipiravir, interferon beta, ivermectin, lopinavir/ritonavir, mesenchymal stem cells, remdesivir, sarilumab, tocilizumab, tofacitinib and SOC, which were investigated in 48 studies ( 3 , 6 , 22 – 26 , 31 , 43 , 46 , 55 , 57 , 64 , 71 – 73 , 76 , 80 , 82 , 84 , 89 , 91 , 93 , 96 – 98 , 100 , 101 , 106 , 107 , 109 , 110 , 115 , 116 , 121 , 122 , 124 , 126 , 128 – 132 , 145 – 147 , 157 , 158 ). Out of the 48 studies included in the NMA, 19 were evaluated as low risk ( Supplementary Table 7 ).…”

Mapping Trends and Hotspots Regarding Clinical Research on COVID-19: A Bibliometric Analysis of Global Research

“…Hydroxychloroquine, as a treatment for malaria, has also received widespread attention. Hydroxychloroquine has been shown to have a certain effect on the treatment of patients with mild disease; however, in patients with severe COVID-19, the use of hydroxychloroquine resulted in significant worsening of clinical status because of renal dysfunction and increased need for invasive mechanical ventilation ( 37 ). The clinical use of hydroxychloroquine still needs to be studied.…”

Effects of hydroxychloroquine and its metabolites in patients with connective tissue diseases

“…Hydroxychloroquine has been one of these drugs. Several clinical trials and in vitro studies have reported promising results in the early stages regarding the role of hydroxychloroquine in the treatment of COVID-19, while subsequent observational studies and clinical trials have reported no effect of hydroxychloroquine (Gautret et al 2020 ; Chen et al 2020a ; Kamran et al 2020 ; Réa-Neto et al 2021 ; Tang et al 2021 ). The open-label Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial in the United Kingdom announced the early closure of the hydroxychloroquine arm after finding that among patients hospitalized with COVID-19 who received hydroxychloroquine did not have lower mortality rates at 28th day compared to those who received usual care.…”

“…Chloroquine and hydroxychloroquine are the most discussed drugs among the repurposing drugs tried as potential therapeutic agents in the treatment of COVID-19. Although initial studies have shown that chloroquine and hydroxychloroquine to be beneficial in the treatment of COVID-19, recent clinical studies lacking critical pharmacology considerations and reliable drug quantifications to ensure optimal dosing and standardization have provided conflicting results (Gautret et al 2020 ; Chen et al 2020a ; Kamran et al 2020 ; Réa-Neto et al 2021 ; Tang et al 2021 ). Hydroxychloroquine has antimalarial, anti-inflammatory, immunomodulatory, anti-infective, antitumoral, metabolic and antithrombotic effects.…”