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      A meta-research study revealed susceptibility of Covid-19 treatment research to white hat bias: First, do no harm

      research-article
      *
      Journal of Clinical Epidemiology
      Elsevier Inc.
      covid-19, remdesivir, hydroxychloroquine, white hat bias, citation bias, meta-analysis

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          Abstract

          Objective

          : To investigate the presence of white hat bias in Covid-19 treatment research by evaluating the effects of citation and reporting bias.

          Study design and setting

          : Citation bias was investigated by assessing the degree of agreement between evidence provided by a remdesivir randomized controlled trial and its citing articles. The dissimilarity of outcomes derived from non-randomized and randomized studies was tested by a meta-analysis of hydroxychloroquine effects on mortality. The differential influence of studies with beneficial over those with neutral results was evaluated by a bibliometric analysis.

          Results

          : The articles citing the ACTT-1 remdesivir trial preferentially presented its positive outcomes in 55.83% and its negative outcomes in 6.43% of cases. The hydroxychloroquine indicated no significant effect by randomized studies, but a significant survival benefit by non-randomized ones. Citation mapping revealed that the study reporting survival benefit from the hydroxychloroquine-azithromycin combination was the most influential, despite subsequent studies reporting potential harmful effects.

          Conclusion

          : The present study raises concerns about citation bias and a predilection of reporting beneficial over harmful effects in the Covid-19 treatment research, potentially in the context of white hat bias. Pre-registration, data sharing and avoidance of selective reporting are crucial to ensure the credibility of future research.

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          Most cited references36

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          Remdesivir for the Treatment of Covid-19 — Final Report

          Abstract Background Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious. Methods We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. Results A total of 1063 patients underwent randomization. The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group. Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%). Conclusions Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 ClinicalTrials.gov number, NCT04280705.)
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            Conducting Meta-Analyses inRwith themetaforPackage

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              Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

              Background Chloroquine and hydroxychloroquine have been found to be efficient on SARS-CoV-2, and reported to be efficient in Chinese COV-19 patients. We evaluate the role of hydroxychloroquine on respiratory viral loads. Patients and methods French Confirmed COVID-19 patients were included in a single arm protocol from early March to March 16th, to receive 600mg of hydroxychloroquine daily and their viral load in nasopharyngeal swabs was tested daily in a hospital setting. Depending on their clinical presentation, azithromycin was added to the treatment. Untreated patients from another center and cases refusing the protocol were included as negative controls. Presence and absence of virus at Day6-post inclusion was considered the end point. Results Six patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight had lower respiratory tract infection symptoms. Twenty cases were treated in this study and showed a significant reduction of the viral carriage at D6-post inclusion compared to controls, and much lower average carrying duration than reported of untreated patients in the literature. Azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination. Conclusion Despite its small sample size our survey shows that hydroxychloroquine treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin.
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                Author and article information

                Journal
                J Clin Epidemiol
                J Clin Epidemiol
                Journal of Clinical Epidemiology
                Elsevier Inc.
                0895-4356
                1878-5921
                26 March 2021
                26 March 2021
                Affiliations
                [0001]1st Department of Internal Medicine and Infectious Diseases, “Sotiria” General and Chest Diseases Hospital of Athens, Greece
                Author notes
                [* ]Correspondence: Ioannis Bellos, MD, 152, Mesogion str., Athens, 115 27
                Article
                S0895-4356(21)00096-2
                10.1016/j.jclinepi.2021.03.020
                7997163
                cb0c4e65-c7bc-4ebb-b622-b949a4f0874d
                © 2021 Elsevier Inc. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 18 March 2021
                Categories
                Article

                Public health
                covid-19,remdesivir,hydroxychloroquine,white hat bias,citation bias,meta-analysis
                Public health
                covid-19, remdesivir, hydroxychloroquine, white hat bias, citation bias, meta-analysis

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