Dataset Information

Use of hydroxychloroquine and chloroquine in COVID-19: How good is the quality of randomized controlled trials?

ABSTRACT:

Objectives

We critically evaluated the quality of evidence and quality of harm reporting in clinical trials that evaluated the effectiveness of hydroxychloroquine (HCQ) or chloroquine (CQ) for the treatment of coronavirus disease 2019 (COVID-19).

Study design and setting

Scientific databases were systematically searched to identify relevant trials of HCQ/CQ for the treatment of COVID-19 published up to 10 September 2020. The Cochrane risk-of-bias tools for randomized trials and non-randomized trials of interventions were used to assess risk of bias in the included studies. A 10-item Consolidated Standards of Reporting Trials (CONSORT) harm extension was used to assess quality of harm reporting in the included trials.

Results

Sixteen trials, including fourteen randomized trials and two non-randomized trials, met the inclusion criteria. The results from the included trials were conflicting and lacked effect estimates adjusted for baseline disease severity or comorbidities in many cases, and most of the trials recruited a fairly small cohort of patients. None of the clinical trials met the CONSORT criteria in full for reporting harm data in clinical trials. None of the 16 trials had an overall 'low' risk of bias, while four of the trials had a 'high', 'critical', or 'serious' risk of bias. Biases observed in these trials arise from the randomization process, potential deviation from intended interventions, outcome measurements, selective reporting, confounding, participant selection, and/or classification of interventions.

Conclusion

In general, the quality of currently available evidence for the effectiveness of CQ/HCQ in patients with COVID-19 is suboptimal. The importance of a properly designed and reported clinical trial cannot be overemphasized amid the COVID-19 pandemic, and its dismissal could lead to poorer clinical and policy decisions, resulting in wastage of already stretched invaluable health care resources.

SUBMITTER: Mazhar F

PROVIDER: S-EPMC7524513 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.

Project description:The coronavirus disease 19 (COVID-19) pandemic has caused significant morbidity and mortality worldwide and an effective treatment is needed. Chloroquine (CQ) and hydroxychloroquine (HCQ) have shown in vitro antiviral activity against SARS-CoV-2 which causes the disease, but the evidence from in vivo studies so far has been inconclusive.ObjectiveTo evaluate the efficacy and safety of CQ and HCQ in the treatment of COVID-19.Data sourcesWe systematically searched the PubMed, Embase, MEDLINE, Cochrane CENTRAL, CINAHL, Scopus, Joanna Briggs Institute Database, ClinicalTrials.gov, and Chinese Clinical Trial Registry (ChiCTR) for all articles published between 01 January 2020 to 15 September 2020 on CQ/HCQ and COVID-19 using a predefined search protocol; without any language restrictions. A search of grey literature repositories (New York Academy of Medicine Grey Literature and Open Grey), and pre-publication server deposits (medRxIV and bioRxIV) was also performed.Study selectionRandomized clinical trials (RCT) which compared CQ/HCQ to standard supportive therapy in treating COVID-19 were included.Data extraction and synthesisData were extracted from original publications by four independent reviewers. Risk of bias was assessed using the Cochrane Collaboration's assessment tool. Data were meta-analyzed using a random-effect models. Results are reported according to PRISMA guidelines. Main Outcome(s) and Measure(s): The primary prespecified efficacy outcome was all-cause mortality. The primary safety outcome was any adverse effect attributed to use of CQ/HCQ.ResultsEight RCTs were included and pooled in the mortality meta-analysis (6,592 unique participants; mean age = 59.4 years; 42% women). CQ/HCQ did not show any mortality benefit when compared to standard supportive therapy (Pooled Relative Risk [RR] 1.07; 95% CI = 0.97-1.18; I2 statistic = 0.00%). Sensitivity and sub-group analyses showed similar findings. Any adverse event was significantly higher in patients randomized to CQ/HCQ (RR = 2.51; 95% CI = 1.53-4.12; n = 1,818 patients), but the risk of developing severe adverse event was not statistically significant (RR = 0.99, 95% CI = 0.53-1.86; n = 6,456 patients).Conclusions and relevanceEvidence from currently published RCTs do not demonstrate any added benefit for the use of CQ or HCQ in the treatment of COVID-19 patients.

Project description: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 .