Assessing the efficacy and safety of hydroxychloroquine as outpatient treatment of COVID-19: a randomized controlled trial

Schwartz, Ilan S.; Boesen, Mari E.; Cerchiaro, Graziela; Edwards, Brett; Ganesh, Aravind; Greenfield, Jamie; Jamieson, Scott; Karnik, Vikram; Kenney, Carol; Lim, Rachel; Menon, Bijoy K; Mponponsuo, Kwadwo; Rathwell, Sarah; Ryckborst, Karla J; Stewart, Breanne; Yaskina, Maryna; Metz, Luanne M.; Richer, Lawrence; Hill, Michael D

doi:10.9778/cmajo.20210069

Cited by 34 publications

(44 citation statements)

References 40 publications

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“…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 ).…”

Section: Resultsmentioning

confidence: 99%

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

Zhang

Jin

Wen

et al. 2021

Front. Public Health

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Background: We provided a comprehensive evaluation of efficacy of available treatments for coronavirus disease 2019 (COVID-19).Methods: We searched for candidate COVID-19 studies in WHO COVID-19 Global Research Database up to August 19, 2021. Randomized controlled trials for suspected or confirmed COVID-19 patients published on peer-reviewed journals were included, regardless of demographic characteristics. Outcome measures included mortality, mechanical ventilation, hospital discharge and viral clearance. Bayesian network meta-analysis with fixed effects was conducted to estimate the effect sizes using posterior means and 95% equal-tailed credible intervals (CrIs). Odds ratio (OR) was used as the summary measure for treatment effect. Bayesian hierarchical models were used to estimate effect sizes of treatments grouped by the treatment classifications.Results: We identified 222 eligible studies with a total of 102,950 patients. Compared with the standard of care, imatinib, intravenous immunoglobulin and tocilizumab led to lower risk of death; baricitinib plus remdesivir, colchicine, dexamethasone, recombinant human granulocyte colony stimulating factor and tocilizumab indicated lower occurrence of mechanical ventilation; tofacitinib, sarilumab, remdesivir, tocilizumab and baricitinib plus remdesivir increased the hospital discharge rate; convalescent plasma, ivermectin, ivermectin plus doxycycline, hydroxychloroquine, nitazoxanide and proxalutamide resulted in better viral clearance. From the treatment class level, we found that the use of antineoplastic agents was associated with fewer mortality cases, immunostimulants could reduce the risk of mechanical ventilation and immunosuppressants led to higher discharge rates.Conclusions: This network meta-analysis identified superiority of several COVID-19 treatments over the standard of care in terms of mortality, mechanical ventilation, hospital discharge and viral clearance. Tocilizumab showed its superiority compared with SOC on preventing severe outcomes such as death and mechanical ventilation as well as increasing the discharge rate, which might be an appropriate treatment for patients with severe or mild/moderate illness. We also found the clinical efficacy of antineoplastic agents, immunostimulants and immunosuppressants with respect to the endpoints of mortality, mechanical ventilation and discharge, which provides valuable information for the discovery of potential COVID-19 treatments.

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Section: Resultsmentioning

confidence: 99%

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

Zhang

Jin

Wen

et al. 2021

Front. Public Health

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“…Eleven new RCTs were retrieved by the SLR search update, adding to the existing eight RCTs on HCQ included in the previous SLR. Out of these 11 new studies, 4 have been stopped early for futility, 4–7 2 have been stopped for harmful effects of one or several compounds in the intervention arms, 8 9 and 1 is underpowered, 10 hence the results are not described in this manuscript. Out of the six studies that included patients with moderate to severe COVID-19, one compared HCQ to chloroquine or ivermectine showing no efficacy on death, progression to invasive mechanical ventilation (IMV) or admission to intensive care unit (ICU) at day 90.…”

Section: Resultsmentioning

confidence: 99%

Immunomodulatory therapies for the treatment of SARS-CoV-2 infection: an update of the systematic literature review to inform EULAR points to consider

et al. 2021

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ObjectiveTo update the EULAR 2020 systematic literature review (SLR) on efficacy and safety of immunomodulatory agents in SARS-CoV-2 infection.MethodsAs part of a EULAR taskforce, a systematic literature search update was conducted from 11 December 2020 to 14 July 2021. Two reviewers independently identified eligible studies and extracted data on efficacy and safety of immunomodulatory agents used therapeutically in SARS-CoV-2 infection at any stage of disease. The risk of bias (RoB) was assessed with validated tools.ResultsOf the 26 959 records, 520 articles were eligible for inclusion. Studies were mainly at high or unclear RoB. New randomised controlled trials (RCTs) on tocilizumab clarified its benefit in patients with severe and critical COVID-19, mainly if associated with glucocorticoids. There are emergent data on the usefulness of baricitinib and tofacitinib in severe COVID-19. Other therapeutic strategies such as the use of convalescent plasma and anti-SARS-CoV-2 monoclonal antibodies showed efficacy in subjects not mounting normal anti-SARS-CoV-2 antibody responses.ConclusionThis new SLR confirms that some immunomodulators (tocilizumab and JAK inhibitors) have a role for treating severe and critical COVID-19. Although better evidence is available compared with the previous SLR, the need of RCT with combination therapy (glucocorticoids+anti-cytokines) versus monotherapy with glucocorticoids still remains alongside the need for standardisation of inclusion criteria and outcomes to ultimately improve the care and prognosis of affected people. This SLR informed the 2021 update of the EULAR points to consider on the use of immunomodulatory therapies in COVID-19.

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“…Third, there was no data on ICU admissions, need of mechanical ventilation, or specific adverse events. Fourth, four of the five RCTs [19][20][21][22] had fewer patients randomized than originally planned; this may have been resulted in lack of power to detect effects of hydroxychloroquine on outcomes. Finally, we did not evaluate the effect of adding azithromycin to hydroxychloroquine in our study.…”

Section: Discussionmentioning

confidence: 99%

“…After removing duplicates and P r e p r i n t applying our inclusion and exclusion criteria (Fig. S1), we identified five RCTs [18][19][20][21][22] (n=1848) which were all homogenous enough to warrant meta-analyses.…”

Section: Selection Of Studiesmentioning

confidence: 99%

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Efficacy of early treatment with hydroxychloroquine in people with mild to moderate COVID-19: A systematic review and meta-analysis

et al. 2021

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IntroductionNo early treatment intervention for COVID-19 has proven effective to date. We systematically reviewed the efficacy of hydroxychloroquine as early treatment for COVID-19.Material and methodsRandomized controlled trials (RCTs) evaluating hydroxychloroquine for early treatment of COVID-19 were searched in five engines and preprint websites until September 14, 2021. Primary outcomes were hospitalization and all-cause mortality. Secondary outcomes included COVID-19 symptom resolution, viral clearance, and adverse events. Inverse variance random-effects meta-analyses were performed and quality of evidence (QoE) per outcome was assessed with GRADE methods.ResultsFive RCTs (n=1848) were included. The comparator was placebo in four RCTs and usual care in one RCT. The RCTs used hydroxychloroquine total doses between 1,600 and 4,400 mg and had follow up times between 14 and 90 days. Compared to the controls, early treatment with hydroxychloroquine did not reduce hospitalizations (RR 0.80, 95%CI 0.47-1.36, I2=2%, 5 RCTs, low QoE), all-cause mortality (RR 0.77, 95%CI 0.16-3.68, I2=0%, 5 RCTs, very low QoE), symptom resolution (RR 0.94, 95%CI 0.77-1.16, I2=71%, 3 RCTs, low QoE) or viral clearance at 14 days (RR 1.02, 95%CI 0.82-1.27, I2=65%, 2 RCTs, low QoE). There was a higher non-significant increase of adverse events with hydroxychloroquine vs. controls (RR 2.17, 95%CI 0.86-5.45, I2=92%, 5 RCTs, very low QoE).ConclusionsHydroxychloroquine was not efficacious as early treatment for COVID-19 infections in RCTs with low to very low quality of evidence for all outcomes. More RCTs are needed to elucidate the efficacy of hydroxychloroquine as early treatment intervention.

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Assessing the efficacy and safety of hydroxychloroquine as outpatient treatment of COVID-19: a randomized controlled trial

Cited by 34 publications

References 40 publications

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

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

Immunomodulatory therapies for the treatment of SARS-CoV-2 infection: an update of the systematic literature review to inform EULAR points to consider

Efficacy of early treatment with hydroxychloroquine in people with mild to moderate COVID-19: A systematic review and meta-analysis

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