ABSTRACT
Objective: Assess the impact of allocation concealment and blinding on the results of trials addressing COVID-19 therapeutics. Data sources: World Health Organization (WHO) COVID-19 database and the Living Overview of the Evidence (L-OVE) COVID-19 platform by the Epistemonikos Foundation (up to February 4th 2022) Methods: We included trials that compared drug treatments, antiviral antibodies and cellular therapies with placebo or standard care. For the five most commonly reported outcomes, if sufficient data were available, we performed random-effects meta-regression comparing the results of trials with and without allocation concealment and trials in which both healthcare providers and patients were blinded with trials in which healthcare providers and/or patients were aware of the intervention. A ratio of odds ratios (ROR) > 1 or a difference in mean difference (DMD) > 0 indicates that trials without allocation concealment or open-label trials produced larger effects than trials with allocation concealment or blinded trials. Results: As of February 4th 2022, we have identified 488 trials addressing COVID-19 drug treatments and antiviral antibodies and cellular therapies. Of these, 436 trials reported on one or more of our outcomes of interest and were included in our analyses. We found that trials without allocation concealment probably overestimate mortality (ROR 1.14 [95% CI 0.92 to 1.41]), need for mechanical ventilation (ROR 1.26 [95% CI 0.97 to 1.64]), admission to hospital (ROR 1.93 [95% CI 0.83 to 4.48]), duration of hospitalization (DMD 1.94 [95% CI 0.86 to 3.02]), and duration of mechanical ventilation (DMD 2.64 [95% CI -0.90 to 6.18]), but results were imprecise. We did not find compelling evidence that double-blind and open-label trials produce consistently different results for mortality (ROR 1.00 [95% CI 0.87 to 1.15]), need for mechanical ventilation (ROR 1.03 [95% CI 0.84 to 1.26]), and duration of hospitalization (DMD 0.47 days [95% CI -0.38 to 1.32]). We found that open-label trials may overestimate the beneficial effects of interventions for hospitalizations (ROR 1.87 [95% CI 0.95 to 3.67] and duration of mechanical ventilation (DMD 1.02 days [95% CI -1.30 to 3.35]), but results were imprecise. Conclusion: We found compelling evidence that, compared to trials with allocation concealment, trials without allocation concealment may overestimate the beneficial effects of treatments. We did not find evidence that trials without blinding addressing COVID-19 interventions produce consistently different results from trials with blinding. Our results suggest that consideration of blinding status may not be sufficient to judge risk of bias due to imbalances in co-interventions. Evidence users may consider evidence of differences in co-interventions between trial arms when judging the trustworthiness of open-label trials. We suggest, however, evidence users to remain skeptical of trials without allocation concealment.
Subject(s)
COVID-19 , Kidney DiseasesABSTRACT
Rationale Corticosteroids are standard of care for patients with severe COVID-19. However, the optimal dose is uncertain. Objective To compare higher doses of corticosteroids with lower doses in patients with COVID-19. Methods We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, MedRxiv, and Web of Science from inception to August 1st, 2022, for trials that randomized patients with severe-to-critical COVID-19 to corticosteroids, standard care, or placebo. Reviewers, working in duplicate, screened references, extracted data, and assessed risk of bias using a modified version of the Cochrane risk of bias 2.0 tool. We performed a dose-response meta-analysis and used the GRADE framework to assess the certainty of evidence. We present our results both in relative risk and absolute risk difference (RD) per 1000 with 95% confidence intervals (CI). Results We included 20 trials, with 10,155 patients. We show that, compared to lower-dose corticosteroids, higher-dose corticosteroids probably reduce mortality (RD 14 fewer deaths per 1000 [95% CI 26 to 2 fewer]; moderate certainty), may reduce the need for mechanical ventilation (RD 11.6 fewer per 1000 [95% CI 23.2 fewer to 6.9 more]; low certainty) and may or may not reduce risk of nosocomial infections (16.7 fewer infections per 1000 [95% CI 5.4 to 25.0 fewer]; very low certainty). Conclusions Relatively higher doses of corticosteroids may be beneficial in patients with severe-to-critical COVID-19 and may not increase the risk of nosocomial infections.
Subject(s)
COVID-19 , Cross InfectionABSTRACT
Rationale: The COVID-19 pandemic disrupted non-COVID critical care trials globally as intensive care units (ICUs) prioritized patient care and COVID-specific research. The international randomized controlled trial CYCLE (Critical Care Cycling to Improve Lower Extremity Strength) was forced to halt recruitment at all sites in March 2020, creating immediate challenges. We applied the CONSERVE (CONSORT and SPIRIT Extension for RCTs Revised in Extenuating Circumstance) guidance to report the impact of the pandemic on CYCLE and describe our mitigation approaches.Methods On March 23, 2020, the CYCLE Methods Centre distributed a standardized email to determine the number of patients still in-hospital and those requiring imminent 90-day endpoint assessments. We assessed protocol fidelity by documenting attempts to provide the in-hospital randomized intervention (cycling or routine physiotherapy), collect the primary outcome (physical function 3-days post-ICU discharge), and 90-day outcomes. We advised sites to prioritize data for the study’s primary outcome. We sought feedback on pandemic barriers related to trial procedures.Results As of March 17, 2020, 197 patients (of 360 planned) had been randomized; 26 (13.2%) remained in hospital or were pending 90-day assessments. From 15 active sites (12 Canada, 2 US, 1 Australia), we identified 5 patients still receiving the study intervention in ICUs, 6 requiring primary outcomes, and 17 requiring 90-day assessments. All ICU interventions (5/5, 100%), 5/6 (83%) of primary outcomes, and all (17/17, 100%) 90-day assessments were attempted. Out of the 6 primary outcomes, one site was unable to attempt due to a temporary institutional ban on direct patient contact for non-COVID research, 2 were attempted but not completed due to reasons unrelated to the pandemic, and 3 were completed. Our main mitigation strategies included identifying patients at risk for protocol deviations, communicating early and frequently with sites, monitoring patient progress, data entry, and validation, and providing guidance for conducting some research activities remotely.Conclusions We retained all enrolled patients with minimal missing data using several time-sensitive strategies. Although CONSERVE recommends reporting only major modifications incurred by extenuating circumstances, we suggest that there are other benefits to reporting mitigation strategies with the goal of improving research transparency and trial management.Trial Registration: NCT03471247
Subject(s)
COVID-19ABSTRACT
Objective: To compare the effects of interleukin-6 (IL-6) receptor blockers, with or without corticosteroids, on mortality in patients with COVID-19. Design: Systematic review and network meta-analysis Data sources: WHO COVID-19 database, a comprehensive multilingual source of global covid-19 literature, and two prospective meta-analyses Study selection: Trials in which people with suspected, probable, or confirmed COVID-19 were randomized to IL-6 receptor blockers (with or without corticosteroids), corticosteroids, placebo, or standard care. Results: We assessed the risk of bias of included trials using a modification of the Cochrane risk of bias 2.0 tool. We performed a Bayesian fixed effect network meta-analysis and assessed the certainty of evidence using the GRADE approach. We identified 45 eligible trials (20,650 patients), 36 (19,350 patients) of which could be included in the network meta-analysis. 27 of 36 trials were rated at high risk of bias, primarily due to lack of blinding. Tocilizumab (20 more per 1000, 15 fewer to 59 more; low certainty) and sarilumab (11 more per 1000, 38 fewer to 55 more; low certainty) alone may not reduce the risk of death. Tocilizumab, in combination with corticosteroids, probably reduces the risk of death compared to corticosteroids alone (35 fewer per 1000, 52 fewer to 18 more; moderate certainty) and sarilumab, in combination with corticosteroids, may reduce the risk of death compared to corticosteroids alone (43 fewer, 73 fewer to 12 more; low certainty). Tocilizumab and sarilumab, both in combination with corticosteroids, may have similar effects (8 more per 1000, 20 fewer to 35 more; low certainty). Conclusion: IL-6 receptor blockers, when added to standard care that includes corticosteroids, in patients with severe or critical COVID-19, probably reduce mortality. Tocilizumab and sarilumab may have similar effectiveness.
Subject(s)
COVID-19 , DeathABSTRACT
Background: There are several reports of extracorporeal membrane oxygenation (ECMO) use in patients with coronavirus disease 2019 (COVID-19) who develop severe acute respiratory distress syndrome (ARDS). We conducted a systematic review and meta-analysis to guide clinical decision-making and future research. Methods: : We searched MEDLINE, Embase, Cochrane, and Scopus databases from 1 st December 2019 to 10 th January 2021 for observational studies or randomized clinical trials examining ECMO in adults with COVID-19 ARDS. We performed random-effects meta-analyses and metaregression, assessed risk of bias using the Joanna Briggs Institute checklist and rated the certainty of evidence using the GRADE approach. Survival outcomes were presented as pooled proportions while continuous outcomes were presented as pooled means, both with corresponding 95% confidence intervals [CIs]. The primary outcome was in-hospital mortality. Secondary outcomes were duration of ECMO therapy and mechanical ventilation, weaning rate from ECMO and complications during ECMO. Results: : We included twenty-two observational studies with 1896 patients in the meta-analysis. Venovenous ECMO was the predominant mode used (98.6%). The pooled in-hospital mortality in COVID-19 patients (22 studies, 1896 patients) supported with ECMO was 37.1% (95% CI: 32.3%-42.0%, high certainty). Pooled mortality in the venovenous ECMO group was 35.7% (95% CI: 30.7%-40.7%, high certainty). Duration of ECMO support (18 studies, 1844 patients) was 15.1 days (95% CI: 13.4-18.7). Weaning from ECMO (17 studies, 1412 patients) was accomplished in 67.6% (95% CI:50.5%-82.7%) of patients. There were a total of 1583 ECMO complications reported (18 studies, 1721 patients) and renal complications were the most common. Conclusion: Majority of patients received ECMO support for COVID-19-related ARDS. In-hospital mortality in patients receiving ECMO support for COVID-19 was 37.1%, similar to those with non-COVID-19-related ARDS. Increasing age was a risk factor for death. Venovenous ECMO appears to be an effective intervention in selected patients with COVID-19-related ARDS.PROSPERO CRD42020192627
Subject(s)
COVID-19 , Respiratory Distress SyndromeABSTRACT
Objective To determine and compare the effects of drug prophylaxis on severe acute respiratory syndrome coronavirus virus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (covid-19). Design Living systematic review and network meta-analysis. Data sources WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature to 19 January 2021, and six additional Chinese databases to 20 January 2021. Study selection Randomized trials in which people at risk of covid-19 were randomized to drug prophylaxis or no prophylaxis (standard care or placebo). Pairs of reviewers independently screened potentially eligible articles. Methods After duplicate data abstraction, we conducted random-effects bayesian network meta-analysis. We assessed risk of bias of the included studies using a modification of the Cochrane risk of bias 2.0 tool and assessed the certainty of the evidence using the grading of recommendations assessment, development and evaluation (GRADE) approach. Results The first iteration of this living network meta-analysis includes nine randomized trials: six addressing hydroxychloroquine (6,059 participants), one addressing ivermectin combined with iota-carrageenan (234 participants) and two addressing ivermectin alone (540 participants), all compared to standard care or placebo. Hydroxychloroquine has no important effect on admission to hospital (risk difference (RD) 1 fewer per 1,000, 95% credible interval (CrI) 3 fewer to 4 more, high certainty) or mortality (RD 1 fewer per 1,000, 95% CrI 2 fewer to 3 more, high certainty). Hydroxychloroquine probably has no important effect on laboratory-confirmed infection (RD 2 more per 1,000, 95% CrI 18 fewer to 28 more, moderate certainty), probably increases adverse effects leading to drug discontinuation (RD 19 more per 1,000, 95% CrI 1 fewer to 70 more, moderate certainty) and may have no important effect on suspected, probable or laboratory-confirmed infection (RD 15 fewer per 1,000, 95% CrI 64 fewer to 41 more, low certainty). Due to serious risk of bias and very serious imprecision, and thus very low certainty evidence, the effects of ivermectin combined with iota-carrageenan on laboratory-confirmed infection (RD 52 fewer per 1,000, 95% CrI 58 fewer to 37 fewer), and ivermectin alone on laboratory-confirmed infection (RD 50 fewer per 1,000, 95% CrI 59 fewer to 16 fewer) and suspected, probable or laboratory-confirmed infection (RD 159 fewer per 1,000, 95% CrI 165 fewer to 144 fewer) remain uncertain. Conclusion Hydroxychloroquine prophylaxis does not have an important effect on hospital admission and mortality, probably increases adverse effects, and probably does not have an important effect on laboratory-confirmed SARS-CoV-2 infection. Because of serious risk of bias and very serious imprecision, we are highly uncertain whether ivermectin combined with iota-carrageenan and ivermectin alone reduce the risk of SARS-CoV-2 infection. Systematic review registration This review was not registered. The protocol established a priori is included as a supplement. Funding This study was supported by the Canadian Institutes of Health Research (grant CIHR-IRSC:0579001321). Reader note This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.
Subject(s)
Coronavirus Infections , Laboratory Infection , COVID-19ABSTRACT
In this work we have developed, by employing lambda superstrings, a map of candidate vaccines against SARS-CoV-2 with lengths between 9 and 200, based on estimations of the immunogenicity of the epitopes and the binding affinity of epitopes to MHC class I molecules using tools from the IEDB Analysis Resource, as well as the overall predictions obtained using the VaxiJen tool. We have synthesized one of the peptides, specifically the one of length 22, and we have carried out an immunogenicity assay and a cytokine assay, which has given positive results in both cases.
Subject(s)
COVID-19ABSTRACT
Background: The coronavirus disease (Covid-19) pandemic has produced a large number of clinical trial reports with unprecedented rapidity, raising concerns about methodological quality and potential for research waste. Objectives: To describe the characteristics of randomized clinical trials (RCTs) investigating prophylaxis or treatment of Covid-19 infection and examine the effect of trial characteristics on whether the study reported a statistically significant effect on the primary outcome(s). Study Design: Meta-epidemiological study of Covid-19 treatment and prophylaxis RCTs. Eligibility criteria: English-language RCTs (peer-reviewed or preprint) that evaluated pharmacologic agents or blood products compared to standard care, placebo, or an active comparator among participants with suspected or confirmed Covid-19 or at risk for Covid-19. We excluded trials of vaccines or traditional herbal medicines. Information sources: We searched 25 databases in the US Centre for Disease Control Downloadable Database from January 1 to October 21, 2020. Trial appraisal and synthesis methods: We extracted trial characteristics including number of centres, funding sources (industry versus non-industry), and sample size. We assessed risk of bias (RoB) using the modified Cochrane RoB 2.0 Tool. We used descriptive statistics to summarize trial characteristics and logistic regression to evaluate the association between RoB due to the randomization process, centre status (single vs. multicentre), funding source, and sample size, and statistically significant effect in the primary outcome. Results: We included 91 RCTs (46,802 participants) evaluating Covid-19 therapeutic drugs (n = 76), blood products (n = 9) or prophylactic drugs (n = 6). Of these, 40 (44%) were single-centre, 23 (25.3%) enrolled < 50 patients, and 28 (30.8%) received industry funding. RoB varied across trials, with high or probably high overall RoB in 75 (82.4%) trials, most frequently due to deviations from the intended protocol (including blinding) and randomization processes. Thirty-eight trials (41.8%) found a statistically significant effect in the primary outcome. RoB due randomization (odds ratio [OR] 3.77, 95% confidence interval [CI], 1.47 to 9.72) and single centre trials (OR 3.15, 95% CI, 1.25 to 7.97) were associated with higher likelihood of finding a statistically significant effect. Conclusions: There was high variability in RoB amongst Covid-19 trials. RoB attributed to the randomization process and single centre status were associated with a three-fold increase in the odds of finding a statistically significant effect. Researchers, funders, and knowledge users should remain cognizant of the impact of study characteristics, including RoB, on trial results when designing, conducting, and appraising Covid-19 trials. Registration number: CRD42020192095
Subject(s)
COVID-19 , Coronavirus InfectionsABSTRACT
IntroductionIn an attempt to improve outcomes for patients with coronavirus disease 19 (COVID-19), several drugs, such as remdesivir, hydroxychloroquine (with or without azithromycin), and lopinavir/ritonavir, have been evaluated for treatment. While much attention focuses on potential benefits of these drugs, this must be weighed against their adverse effects. MethodsWe searched 32 databases in multiple languages from 1 December 2019 to 27 October 2020. We included randomized trials if they compared any of the drugs of interest to placebo or standard care, or against each other. A related world health organization (WHO) guideline panel selected the interventions to address and identified possible adverse effects that might be important to patients. Pairs of reviewers independently extracted data and assessed risk of bias. We analyzed data using a fixed-effects pairwise meta-analysis and assessed the certainty of evidence using the GRADE approach. ResultsWe included 16 randomized trials which enrolled 8226 patients. Compared to standard care or placebo, low certainty evidence suggests that remdesivir may not have an important effect on acute kidney injury (risk difference [RD] 8 fewer per 1000, 95% confidence interval (CI): 27 fewer to 21 more) or cognitive dysfunction/delirium (RD 3 more per 1000, 95% CI: 12 fewer to 19 more). Low certainty evidence suggests that hydroxychloroquine may increase the risk of serious cardiac toxicity (RD 10 more per 1000, 95% CI: 0 more to 30 more) and cognitive dysfunction/delirium (RD 33 more per 1000, 95% CI: 18 fewer to 84 more), whereas moderate certainty evidence suggests hydroxychloroquine probably increases the risk of diarrhoea (RD 106 more per 1000, 95% CI: 48 more to 175 more) and nausea and/or vomiting (RD 62 more per 1000, 95% CI: 23 more to 110 more) compared to standard care or placebo. Low certainty evidence suggests lopinavir/ritonavir may increase the risk of diarrhoea (RD 168 more per 1000, 95% CI: 58 more to 330 more) and nausea and/or vomiting (RD 160 more per 1000, 95% CI: 100 more to 210 more) compared to standard care or placebo. ConclusionHydroxychloroquine probably increases the risk of diarrhoea and nausea and/or vomiting and may increase the risk of cardiac toxicity and cognitive dysfunction/delirium. Remdesivir may have no effect on risk of acute kidney injury or cognitive dysfunction/delirium. Lopinavir/ritonavir may increase the risk of diarrhoea and nausea and/or vomiting. These findings provide important information to support the development of evidence-based management strategies for patients with COVID-19.
Subject(s)
COVID-19 , Coronavirus InfectionsABSTRACT
Background: The coronavirus disease 19 (covid-19) pandemic has underscored the need to expedite clinical research, which may lead investigators to shift away from measuring patient-important outcomes (PIOs), limiting research applicability. We aim to describe the extent to which randomized controlled trials (RCTs) of covid-19 therapies will determine PIOs. Methods: We will perform a meta-epidemiological study of RCTs that included people at risk for, or with suspected, probable, or confirmed covid-19, examining any pharmacological treatment or blood product aimed at prophylaxis or treatment. We will obtain data from all RCTs identified in a recent published network metanalysis (NMA). To categorize the outcomes according to their importance to patients, we will adapt a previously defined hierarchy: a) mortality, b) quality of life/ functional status/symptoms, c) morbidity, and d) surrogate outcomes. Outcomes within the category a) and b) will be considered critically important to patients, and outcomes within the category c) will be regarded as important. We will use descriptive statistics to assess the proportion of studies that report each category of outcomes. We will perform univariable and multivariable analysis to explore associations between trial characteristics and the likelihood of reporting PIOs. Discussion: The findings from this meta-epidemiological study will help health care professionals and researchers understand if the current covid-19 trials are effectively assessing and reporting the outcomes that are important to patients. If a deficiency in capturing PIOs is identified, this information may help inform the development of future RCTs in covid-19.Systematic Review registrations: Open Science Framework registration: osf.io/6xgjz
Subject(s)
COVID-19 , Coronavirus InfectionsABSTRACT
Introduction: Efforts to mitigate the global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have largely relied on broad compliance with public health recommendations, yet navigating the high volume of evolving information and misinformation related to SARS-CoV-2 can be challenging. We assessed national public perceptions (e.g., severity, concerns, health), knowledge (e.g., transmission, information sources), and behaviors (e.g., physical distancing) related to COVID-19 in Canada to understand public perspectives and inform future public health initiatives. Methods: We administered a national online survey with the goal of obtaining responses from 2000 adults residing in Canada. Respondent sampling was stratified by age, sex, and region. We used descriptive statistics to summarize respondent characteristics and tested for significant overall regional differences using chi-squared tests and t-tests, as appropriate. Results: We collected 1,996 eligible questionnaires between April 26th and May 1st, 2020. One-fifth (20%) of respondents knew someone diagnosed with COVID-19, but few had tested positive themselves (0.6%). Negative impacts of pandemic conditions were evidenced in several areas, including concerns about healthcare (e.g. sufficient equipment, 52%), pandemic stress (45%), and worsening social (49%) and mental/emotional (39%) health. Most respondents (88%) felt they had good to excellent knowledge of virus transmission, and predominantly accessed (74%) and trusted (60%) Canadian news television, newspapers/magazines, or non-government news websites for COVID-19 information. We found high compliance with distancing measures (80% either self-isolating or always physical distancing). We identified regional differences in perceptions, knowledge, and behaviors related to COVID-19. Discussion: We found that knowledge about COVID-19 is largely acquired through domestic news sources, which may explain high self-reported compliance with prevention measures. The results highlight the broader impact of a pandemic on the general public's overall health and wellbeing, outside of personal infection. The study findings should be used to inform public health communications during COVID-19 and future pandemics.