Sensitivity and Specificity of Using GPT-3.5 Turbo Models for Title and Abstract Screening in Systematic Reviews and Meta-analyses.

BACKGROUND: Systematic reviews are performed manually despite the exponential growth of scientific literature. OBJECTIVE: To investigate the sensitivity and specificity of GPT-3.5 Turbo, from OpenAI, as a single reviewer, for title and abstract screening in systematic reviews. DESIGN: Diagnostic test accuracy study. SETTING: Unannotated bibliographic databases from 5 systematic reviews representing 22 665 citations. PARTICIPANTS: None. MEASUREMENTS: A generic prompt framework to instruct GPT to perform title and abstract screening was designed. The output of the model was compared with decisions from authors under 2 rules. The first rule balanced sensitivity and specificity, for example, to act as a second reviewer. The second rule optimized sensitivity, for example, to reduce the number of citations to be manually screened. RESULTS: Under the balanced rule, sensitivities ranged from 81.1% to 96.5% and specificities ranged from 25.8% to 80.4%. Across all reviews, GPT identified 7 of 708 citations (1%) missed by humans that should have been included after full-text screening at the cost of 10 279 of 22 665 false-positive recommendations (45.3%) that would require reconciliation during the screening process. Under the sensitive rule, sensitivities ranged from 94.6% to 99.8% and specificities ranged from 2.2% to 46.6%. Limiting manual screening to citations not ruled out by GPT could reduce the number of citations to screen from 127 of 6334 (2%) to 1851 of 4077 (45.4%), at the cost of missing from 0 to 1 of 26 citations (3.8%) at the full-text level. LIMITATIONS: Time needed to fine-tune prompt. Retrospective nature of the study, convenient sample of 5 systematic reviews, and GPT performance sensitive to prompt development and time. CONCLUSION: The GPT-3.5 Turbo model may be used as a second reviewer for title and abstract screening, at the cost of additional work to reconcile added false positives. It also showed potential to reduce the number of citations before screening by humans, at the cost of missing some citations at the full-text level. PRIMARY FUNDING SOURCE: None.

Development and Evaluation of a Framework for Identifying and Addressing Spin for Harms in Systematic Reviews of Interventions.

"Spin" refers to misleading reporting, interpretation, and extrapolation of findings in primary and secondary research (such as in systematic reviews). The study of spin primarily focuses on beneficial outcomes. The objectives of this research were threefold: first, to develop a framework for identifying spin associated with harms in systematic reviews of interventions; second, to apply the framework to a set of reviews, thereby pinpointing instances where spin may be present; and finally, to revise the spin examples, offering guidance on how spin can be rectified.The authors developed their framework through an iterative process that engaged an international group of researchers specializing in spin and reporting bias. The framework comprises 12 specific types of spin for harms, grouped by 7 categories across the 3 domains (reporting, interpretation, and extrapolation). The authors subsequently gathered instances of spin from a random sample of 100 systematic reviews of interventions. Of the 58 reviews that assessed harm and the 42 that did not, they found that 28 (48%) and 6 (14%), respectively, had at least 1 of the 12 types of spin for harms. Inappropriate extrapolation of the results and conclusions for harms to populations, interventions, outcomes, or settings not assessed in a review was the most common category of spin in 17 of 100 reviews.The authors revised the examples to remove spin, taking into consideration the context (for example, medical discipline, source population), findings for harms, and methodological limitations of the original reviews. They provide guidance for authors, peer reviewers, and editors in recognizing and rectifying or (preferably) avoiding spin, ultimately enhancing the clarity and accuracy of harms reporting in systematic review publications.

Oral resveratrol in adults with knee osteoarthritis: A randomized placebo-controlled trial (ARTHROL).

BACKGROUND: Resveratrol is a natural compound found in red wine. It has demonstrated anti-inflammatory properties in preclinical models. We compared the effect of oral resveratrol in a new patented formulation to oral placebo for individuals with painful knee osteoarthritis. METHODS AND FINDINGS: ARTHROL was a double-blind, randomized, placebo-controlled, Phase 3 trial conducted in 3 tertiary care centers in France. We recruited adults who fulfilled the 1986 American College of Rheumatology criteria for knee osteoarthritis and reported a pain intensity score of at least 40 on an 11-point numeric rating scale (NRS) in 10-point increments (0, no pain, to 100, maximal pain). Participants were randomly assigned (1:1) by using a computer-generated randomization list with permuted blocks of variable size (2, 4, or 6) to receive oral resveratrol (40 mg [2 caplets] twice a day for 1 week, then 20 mg [1 caplet] twice a day; resveratrol group) or matched oral placebo (placebo group) for 6 months. The primary outcome was the mean change from baseline in knee pain on a self-administered 11-point pain NRS at 3 months. The trial was registered at ClinicalTrials.gov: (NCT02905799). Between October 20, 2017 and November 8, 2021, we assessed 649 individuals for eligibility, and from November 9, 2017, we recruited 142 (22%) participants (mean age 61.4 years [standard deviation (SD) 9.6] and 101 [71%] women); 71 (50%) were randomly assigned to the resveratrol group and 71 (50%) to the placebo group. At baseline, the mean knee pain score was 56.2/100 (SD 13.5). At 3 months, the mean reduction in knee pain was -15.7 (95% confidence interval (CI), -21.1 to -10.3) in the resveratrol group and -15.2 (95% CI, -20.5 to -9.8) in the placebo group (absolute difference -0.6 [95% CI, -8.0 to 6.9]; p = 0.88). Serious adverse events (not related to the interventions) occurred in 3 (4%) in the resveratrol group and 2 (3%) in the placebo group. Our study has limitations in that it was underpowered and the effect size, estimated to be 0.55, was optimistically estimated. CONCLUSIONS: In this study, we observed that compared with placebo, oral resveratrol did not reduce knee pain in people with painful knee osteoarthritis. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02905799.

A novel framework to assess haematology and oncology registration trials: The THEOREMM project.

BACKGROUND: Methodological limitations affect a significant number of oncology and haematology trials, raising concerns about the applicability of their results. For example, a suboptimal control arm or limited access to best care upon progression may skew the trial results toward a benefit in the experimental arm. Beyond the fact that such limitations do not prevent drugs reaching the market, other assessment tools, such as those developed by professional societies-ESMO-MCBS and ASCO Value Framework-do not integrate these important shortcomings. METHODS: We propose creating a novel framework with the scope of assessing registration cancer clinical trials in haematology and oncology (randomized or single arm)-that is trials leading to a marketing authorization. The main steps of the methods are (1) assembling a scientific board; (2) defining the scope, goal and methods through pre-specified, pre-registered and protocolized methodology; (3) preregistration of the protocol; (4) conducting a scoping review of limitations and biases affecting oncology trials and assessing existing scores or methods; (5) developing a list of features to be included and assessed within the framework; (6) assessing each feature through a questionnaire sent to highly cited haematologists and oncologists involved in clinical trials; and (7) finalizing the first version of framework. RESULTS: Not applicable. CONCLUSIONS: Our proposal emerged in response to the lack of consideration for key limitations in current trial assessments. The goal is to create a framework specifically designed to assess single trials leading to marketing authorization in the field of oncology and haematogy.

Comparison of effect estimates between preprints and peer-reviewed journal articles of COVID-19 trials.

BACKGROUND: Preprints are increasingly used to disseminate research results, providing multiple sources of information for the same study. We assessed the consistency in effect estimates between preprint and subsequent journal article of COVID-19 randomized controlled trials. METHODS: The study utilized data from the COVID-NMA living systematic review of pharmacological treatments for COVID-19 (covid-nma.com) up to July 20, 2022. We identified randomized controlled trials (RCTs) evaluating pharmacological treatments vs. standard of care/placebo for patients with COVID-19 that were originally posted as preprints and subsequently published as journal articles. Trials that did not report the same analysis in both documents were excluded. Data were extracted independently by pairs of researchers with consensus to resolve disagreements. Effect estimates extracted from the first preprint were compared to effect estimates from the journal article. RESULTS: The search identified 135 RCTs originally posted as a preprint and subsequently published as a journal article. We excluded 26 RCTs that did not meet the eligibility criteria, of which 13 RCTs reported an interim analysis in the preprint and a final analysis in the journal article. Overall, 109 preprint-article RCTs were included in the analysis. The median (interquartile range) delay between preprint and journal article was 121 (73-187) days, the median sample size was 150 (71-464) participants, 76% of RCTs had been prospectively registered, 60% received industry or mixed funding, 72% were multicentric trials. The overall risk of bias was rated as 'some concern' for 80% of RCTs. We found that 81 preprint-article pairs of RCTs were consistent for all outcomes reported. There were nine RCTs with at least one outcome with a discrepancy in the number of participants with outcome events or the number of participants analyzed, which yielded a minor change in the estimate of the effect. Furthermore, six RCTs had at least one outcome missing in the journal article and 14 RCTs had at least one outcome added in the journal article compared to the preprint. There was a change in the direction of effect in one RCT. No changes in statistical significance or conclusions were found. CONCLUSIONS: Effect estimates were generally consistent between COVID-19 preprints and subsequent journal articles. The main results and interpretation did not change in any trial. Nevertheless, some outcomes were added and deleted in some journal articles.

Completeness of reporting in abstracts of randomized controlled trials assessing interventional radiology for liver disease.

PURPOSE: To assess the completeness of reporting in abstracts of published randomized controlled trials (RCTs) assessing interventional radiology (IR) for liver disease; to assess whether publication of the 2017 CONSORT update for nonpharmacological treatments (NPT) resulted in changes in abstract reporting; and to identify factors associated with better reporting. MATERIAL AND METHODS: MEDLINE and Embase were searched to identify RCTs of IR for liver disease (January 2015-September 2020). Two reviewers assessed the completeness of abstract reporting according to the CONSORT-NPT-2017-update. The primary outcome was the mean number of CONSORT items completely reported among 10 items reported in <50% of the abstracts published in 2015. A time series analysis assessed the evolution trend over time. A multivariate regression model was used to identify factors associated with better reporting. RESULTS: A total of 107 abstracts of RCTs published in 61 journals were included. Overall, 74% (45/61) of journals endorsed the main CONSORT guidelines, of which 60% (27/45) had a policy to implement them. The mean number of primary outcome items completely reported increased by 0.19 over the study period. The publication of the CONSORT-NPT update did not lead to an increase in the trend of items reported (increase of 0.04 items/month before vs. 0.02 after, P=0.41). Factors associated with more complete reporting were impact factor (OR=1.13; 95%CI:1.07-1.18) and endorsement of CONSORT with an implementation policy (OR=8.29; 95%CI:2.04-33.65). CONCLUSION: Completeness of reporting is incomplete in abstracts of trials of IR liver disease and did not improve after publication of the CONSORT-NPT-2017 update with abstract guidance.

Interleukin-6 blocking agents for treating COVID-19: a living systematic review.

BACKGROUND: It has been reported that people with COVID-19 and pre-existing autoantibodies against type I interferons are likely to develop an inflammatory cytokine storm responsible for severe respiratory symptoms. Since interleukin 6 (IL-6) is one of the cytokines released during this inflammatory process, IL-6 blocking agents have been used for treating people with severe COVID-19. OBJECTIVES: To update the evidence on the effectiveness and safety of IL-6 blocking agents compared to standard care alone or to a placebo for people with COVID-19. SEARCH METHODS: We searched the World Health Organization (WHO) International Clinical Trials Registry Platform, the Living OVerview of Evidence (L·OVE) platform, and the Cochrane COVID-19 Study Register to identify studies on 7 June 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) evaluating IL-6 blocking agents compared to standard care alone or to placebo for people with COVID-19, regardless of disease severity. DATA COLLECTION AND ANALYSIS: Pairs of researchers independently conducted study selection, extracted data and assessed risk of bias. We assessed the certainty of evidence using the GRADE approach for all critical and important outcomes. In this update we amended our protocol to update the methods used for grading evidence by establishing minimal important differences for the critical outcomes. MAIN RESULTS: This update includes 22 additional trials, for a total of 32 trials including 12,160 randomized participants all hospitalized for COVID-19 disease. We identified a further 17 registered RCTs evaluating IL-6 blocking agents without results available as of 7 June 2022.  The mean age range varied from 56 to 75 years; 66.2% (8051/12,160) of enrolled participants were men. One-third (11/32) of included trials were placebo-controlled. Twenty-two were published in peer-reviewed journals, three were reported as preprints, two trials had results posted only on registries, and results from five trials were retrieved from another meta-analysis. Eight were funded by pharmaceutical companies.  Twenty-six included studies were multicenter trials; four were multinational and 22 took place in single countries. Recruitment of participants occurred between February 2020 and June 2021, with a mean enrollment duration of 21 weeks (range 1 to 54 weeks). Nineteen trials (60%) had a follow-up of 60 days or more. Disease severity ranged from mild to critical disease. The proportion of participants who were intubated at study inclusion also varied from 5% to 95%. Only six trials reported vaccination status; there were no vaccinated participants included in these trials, and 17 trials were conducted before vaccination was rolled out. We assessed a total of six treatments, each compared to placebo or standard care. Twenty trials assessed tocilizumab, nine assessed sarilumab, and two assessed clazakizumab. Only one trial was included for each of the other IL-6 blocking agents (siltuximab, olokizumab, and levilimab). Two trials assessed more than one treatment. Efficacy and safety of tocilizumab and sarilumab compared to standard care or placebo for treating COVID-19 At day (D) 28, tocilizumab and sarilumab probably result in little or no increase in clinical improvement (tocilizumab: risk ratio (RR) 1.05, 95% confidence interval (CI) 1.00 to 1.11; 15 RCTs, 6116 participants; moderate-certainty evidence; sarilumab: RR 0.99, 95% CI 0.94 to 1.05; 7 RCTs, 2425 participants; moderate-certainty evidence). For clinical improvement at ≥ D60, the certainty of evidence is very low for both tocilizumab (RR 1.10, 95% CI 0.81 to 1.48; 1 RCT, 97 participants; very low-certainty evidence) and sarilumab (RR 1.22, 95% CI 0.91 to 1.63; 2 RCTs, 239 participants; very low-certainty evidence). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score (WHO-CPS) of level 7 or above remains uncertain at D28 (RR 0.90, 95% CI 0.72 to 1.12; 13 RCTs, 2117 participants; low-certainty evidence) and that for sarilumab very uncertain (RR 1.10, 95% CI 0.90 to 1.33; 5 RCTs, 886 participants; very low-certainty evidence). Tocilizumab reduces all cause-mortality at D28 compared to standard care/placebo (RR 0.88, 95% CI 0.81 to 0.94; 18 RCTs, 7428 participants; high-certainty evidence). The evidence about the effect of sarilumab on this outcome is very uncertain (RR 1.06, 95% CI 0.86 to 1.30; 9 RCTs, 3305 participants; very low-certainty evidence). The evidence is uncertain for all cause-mortality at ≥ D60 for tocilizumab (RR 0.91, 95% CI 0.80 to 1.04; 9 RCTs, 2775 participants; low-certainty evidence) and very uncertain for sarilumab (RR 0.95, 95% CI 0.84 to 1.07; 6 RCTs, 3379 participants; very low-certainty evidence). Tocilizumab probably results in little to no difference in the risk of adverse events (RR 1.03, 95% CI 0.95 to 1.12; 9 RCTs, 1811 participants; moderate-certainty evidence). The evidence about adverse events for sarilumab is uncertain (RR 1.12, 95% CI 0.97 to 1.28; 4 RCT, 860 participants; low-certainty evidence).  The evidence about serious adverse events is very uncertain for tocilizumab (RR 0.93, 95% CI 0.81 to 1.07; 16 RCTs; 2974 participants; very low-certainty evidence) and uncertain for sarilumab (RR 1.09, 95% CI 0.97 to 1.21; 6 RCTs; 2936 participants; low-certainty evidence). Efficacy and safety of clazakizumab, olokizumab, siltuximab and levilimab compared to standard care or placebo for treating COVID-19 The evidence about the effects of clazakizumab, olokizumab, siltuximab, and levilimab comes from only one or two studies for each blocking agent, and is uncertain or very uncertain. AUTHORS' CONCLUSIONS: In hospitalized people with COVID-19, results show a beneficial effect of tocilizumab on all-cause mortality in the short term and probably little or no difference in the risk of adverse events compared to standard care alone or placebo. Nevertheless, both tocilizumab and sarilumab probably result in little or no increase in clinical improvement at D28. Evidence for an effect of sarilumab and the other IL-6 blocking agents on critical outcomes is uncertain or very uncertain. Most of the trials included in our review were done before the waves of different variants of concern and before vaccination was rolled out on a large scale. An additional 17 RCTs of IL-6 blocking agents are currently registered with no results yet reported. The number of pending studies and the number of participants planned is low. Consequently, we will not publish further updates of this review.

A Framework for the Development of Living Practice Guidelines in Health Care.

BACKGROUND: Living practice guidelines are increasingly being used to ensure that recommendations are responsive to rapidly emerging evidence. OBJECTIVE: To develop a framework that characterizes the processes of development of living practice guidelines in health care. DESIGN: First, 3 background reviews were conducted: a scoping review of methods papers, a review of handbooks of guideline-producing organizations, and an analytic review of selected living practice guidelines. Second, the core team drafted the first version of the framework. Finally, the core team refined the framework through an online survey and online discussions with a multidisciplinary international group of stakeholders. SETTING: International. PARTICIPANTS: Multidisciplinary group of 51 persons who have experience with guidelines. MEASUREMENTS: Not applicable. RESULTS: A major principle of the framework is that the unit of update in a living guideline is the individual recommendation. In addition to providing definitions, the framework addresses several processes. The planning process should address the organization's adoption of the living methodology as well as each specific guideline project. The production process consists of initiation, maintenance, and retirement phases. The reporting should cover the evidence surveillance time stamp, the outcome of reassessment of the body of evidence (when applicable), and the outcome of revisiting a recommendation (when applicable). The dissemination process may necessitate the use of different venues, including one for formal publication. LIMITATION: This study does not provide detailed or practical guidance for how the described concepts would be best implemented. CONCLUSION: The framework will help guideline developers in planning, producing, reporting, and disseminating living guideline projects. It will also help research methodologists study the processes of living guidelines. PRIMARY FUNDING SOURCE: None.

Availability of Results of Trials Studying Pancreatic Adenocarcinoma over the Past 10 Years.

BACKGROUND: Pancreatic adenocarcinoma (PDAC) is a lethal cancer with few therapeutic options. Availability of results is a crucial step in interventional research. Our aim was to evaluate results availability for trials in patients with PDAC and explore associated factors. MATERIALS AND METHODS: We performed a retrospective cohort study and searched the ClinicalTrials.gov registry for trials evaluating PDAC management with a primary completion date between 1 January 2010 and 1 June 2020. Then, we searched for results submitted on ClinicalTrials.gov and/or published. Our primary outcome was the proportion of PDAC trials with available results: submitted on ClinicalTrials.gov (either publicly available or undergoing quality control check) and/or published in a full-text article. The association of predefined trial characteristics with results availability was assessed. RESULTS: We identified 551 trials of which 386 (70%) had available results. The cumulative percentage of trials with available results was 21% (95% CI, 18-25%) at 12 months after the primary completion date, 44% (95% CI, 30-48%) at 24 months and 57% (95% CI, 53-61%) at 36 months. Applicable clinical trials, required to comply with the 2007 Food and Drug Administration Amendments Act 801 and its final rule on reporting of results on ClinicalTrials.gov, were more likely to have available results over time (HR 2.1 [95% CI 1.72-2.63], P < .001). Industry-funded, small sample size, and terminated trials were less likely to have available results. Other trial characteristics showed no association with results availability. CONCLUSION: Our results highlight a waste in interventional research studying PDAC.

Transparency and reporting characteristics of COVID-19 randomized controlled trials.

BACKGROUND: In the context of the COVID-19 pandemic, randomized controlled trials (RCTs) are essential to support clinical decision-making. We aimed (1) to assess and compare the reporting characteristics of RCTs between preprints and peer-reviewed publications and (2) to assess whether reporting improves after the peer review process for all preprints subsequently published in peer-reviewed journals. METHODS: We searched the Cochrane COVID-19 Study Register and L·OVE COVID-19 platform to identify all reports of RCTs assessing pharmacological treatments of COVID-19, up to May 2021. We extracted indicators of transparency (e.g., trial registration, data sharing intentions) and assessed the completeness of reporting (i.e., some important CONSORT items, conflict of interest, ethical approval) using a standardized data extraction form. We also identified paired reports published in preprint and peer-reviewed publications. RESULTS: We identified 251 trial reports: 121 (48%) were first published in peer-reviewed journals, and 130 (52%) were first published as preprints. Transparency was poor. About half of trials were prospectively registered (n = 140, 56%); 38% (n = 95) made their full protocols available, and 29% (n = 72) provided access to their statistical analysis plan report. A data sharing statement was reported in 68% (n = 170) of the reports of which 91% stated their willingness to share. Completeness of reporting was low: only 32% (n = 81) of trials completely defined the pre-specified primary outcome measures; 57% (n = 143) reported the process of allocation concealment. Overall, 51% (n = 127) adequately reported the results for the primary outcomes while only 14% (n = 36) of trials adequately described harms. Primary outcome(s) reported in trial registries and published reports were inconsistent in 49% (n = 104) of trials; of them, only 15% (n = 16) disclosed outcome switching in the report. There were no major differences between preprints and peer-reviewed publications. Of the 130 RCTs published as preprints, 78 were subsequently published in a peer-reviewed journal. There was no major improvement after the journal peer review process for most items. CONCLUSIONS: Transparency, completeness, and consistency of reporting of COVID-19 clinical trials were insufficient both in preprints and peer-reviewed publications. A comparison of paired reports published in preprint and peer-reviewed publication did not indicate major improvement.

Assessment of transparency and selective reporting of interventional trials studying colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is currently one of the most frequently diagnosed cancers. Our aim was to evaluate transparency and selective reporting in interventional trials studying CRC. METHODS: First, we assessed indicators of transparency with completeness of reporting, according to the CONSORT statement, and data sharing. We evaluated a selection of reporting items for a sample of randomized controlled trials (RCTs) studying CRC with published full-text articles between 2021-03-22 and 2018-03-22. Selected items were issued from the previously published CONSORT based peer-review tool (COBPeer tool). Then, we evaluated selective reporting through retrospective registration and primary outcome(s) switching between registration and publication. Finally, we determined if primary outcome(s) switching favored significant outcomes. RESULTS: We evaluated 101 RCTs with published full-text articles between 2021-03-22 and 2018-03-22. Five trials (5%) reported all selected CONSORT items completely. Seventy-four (73%), 53 (52%) and 13 (13%) trials reported the primary outcome(s), the allocation concealment process and harms completely. Twenty-five (25%) trials were willing to share data. In our sample, 49 (49%) trials were retrospectively registered and 23 (23%) trials had primary outcome(s) switching. The influence of primary outcome(s) switching could be evaluated in 16 (16/23 = 70%) trials, with 6 (6/16 = 38%) trials showing a discrepancy that favored statistically significant results. CONCLUSIONS: Our results highlight a lack of transparency as well as frequent selective reporting in interventional trials studying CRC.

Evaluation of the usefulness of ultrasound measurement of the lower uterine segment before delivery of women with a prior cesarean delivery: a randomized trial.

BACKGROUND: The main reason to avoid trial of labor after cesarean delivery is the possibility of uterine rupture. Identifying women at risk is thus an important aim, for it would enable women at low risk to proceed with a secure planned vaginal birth. OBJECTIVE: To evaluate the impact of proposing mode of delivery based on the ultrasound measurement of the lower uterine segment thickness on a composite outcome of maternal-fetal mortality and morbidity, compared with usual management, among pregnant women with a previous cesarean delivery. STUDY DESIGN: This multicenter, randomized, controlled, parallel-group, unmasked trial was conducted at 8 referral university hospitals with a neonatal intensive care unit and enrolled 2948 women at 36 weeks 0 days to 38 weeks 6 days of gestation with 1 previous low transverse cesarean delivery and no contraindication to trial of labor. Women in the study group had their lower uterine segment thickness measured by ultrasound. Those with measurements >3.5 mm, were encouraged to choose a planned vaginal delivery, and those with measurements ≤3.5 mm, were encouraged to choose a planned repeat cesarean delivery. This measurement was not taken in the control group; their mode of delivery was decided according to standard management. The primary outcome was a composite criterion comprising maternal mortality, uterine rupture, uterine dehiscence, hysterectomy, thromboembolic disease, transfusion, endometritis, perinatal death, or neonatal encephalopathy. Prespecified secondary outcomes were repeat cesarean deliveries, elective or after trial of labor. RESULTS: The study group included 1472 women, and the control group included 1476 women. These groups were similar at baseline. The primary outcome occurred in 3.4% of the study group and 4.3% of the control group (relative risk, 0.78; 95% confidence interval, 0.54-1.13: risk difference, -1.0%; 95% confidence interval, -2.4 to 0.5). The uterine rupture rate in the study group was 0.4% and in the control group 0.9% (relative risk, 0.43; 95% confidence interval, 0.15-1.19). The planned cesarean delivery rate was 16.4% in the study group and 13.7% in the control group (relative risk, 1.21; 95% confidence interval, 1.00-1.47), whereas the rates of cesarean delivery during labor were 25.1% and 25.0% (relative risk, 1.01; 95% confidence interval, 0.89-1.14) in the study and control groups, respectively. CONCLUSION: Ultrasound measurements of lower uterine segment thickness did not result in a statistically significant lower frequency of maternal and perinatal adverse outcomes than standard management. However, because this study was underpowered, further research should be encouraged.

Interleukin-1 blocking agents for treating COVID-19.

BACKGROUND: Interleukin-1 (IL-1) blocking agents have been used for treating severe coronavirus disease 2019 (COVID-19), on the premise that their immunomodulatory effect might be beneficial in people with COVID-19. OBJECTIVES: To assess the effects of IL-1 blocking agents compared with standard care alone or with placebo on effectiveness and safety outcomes in people with COVID-19. We will update this assessment regularly. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register and the COVID-19 L-OVE Platform (search date 5 November 2021). These sources are maintained through regular searches of MEDLINE, Embase, CENTRAL, trial registers and other sources. We also checked the World Health Organization International Clinical Trials Registry Platform, regulatory agency websites, Retraction Watch (search date 3 November 2021). SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating IL-1 blocking agents compared with standard care alone or with placebo for people with COVID-19, regardless of disease severity. DATA COLLECTION AND ANALYSIS: We followed Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two researchers independently screened and extracted data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. We rated the certainty of evidence using the GRADE approach for the critical outcomes of clinical improvement (Day 28; ≥ D60); WHO Clinical Progression Score of level 7 or above (i.e. the proportion of participants with mechanical ventilation +/- additional organ support OR death) (D28; ≥ D60); all-cause mortality (D28; ≥ D60); incidence of any adverse events; and incidence of serious adverse events. MAIN RESULTS: We identified four RCTs of anakinra (three published in peer-reviewed journals, one reported as a preprint) and two RCTs of canakinumab (published in peer-reviewed journals). All trials were multicentre (2 to 133 centres). Two trials stopped early (one due to futility and one as the trigger for inferiority was met). The median/mean age range varied from 58 to 68 years; the proportion of men varied from 58% to 77%. All participants were hospitalised; 67% to 100% were on oxygen at baseline but not intubated; between 0% and 33% were intubated at baseline. We identified a further 16 registered trials with no results available, of which 15 assessed anakinra (four completed, four terminated, five ongoing, three not recruiting) and one (completed) trial assessed canakinumab. Effectiveness of anakinra for people with COVID-19 Anakinra probably results in little or no increase in clinical improvement at D28 (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.97 to 1.20; 3 RCTs, 837 participants; absolute effect: 59 more per 1000 (from 22 fewer to 147 more); moderate-certainty evidence. The evidence is uncertain about an effect of anakinra on 1) the proportion of participants with a WHO Clinical Progression Score of level 7 or above at D28 (RR 0.67, 95% CI 0.36 to 1.22; 2 RCTs, 722 participants; absolute effect: 55 fewer per 1000 (from 107 fewer to 37 more); low-certainty evidence) and ≥ D60 (RR 0.54, 95% CI 0.30 to 0.96; 1 RCT, 606 participants; absolute effect: 47 fewer per 1000 (from 72 fewer to 4 fewer) low-certainty evidence); and 2) all-cause mortality at D28 (RR 0.69, 95% CI 0.34 to 1.39; 2 RCTs, 722 participants; absolute effect: 32 fewer per 1000 (from 68 fewer to 40 more); low-certainty evidence).  The evidence is very uncertain about an effect of anakinra on 1) the proportion of participants with clinical improvement at ≥ D60 (RR 0.93, 95% CI 0.78 to 1.12; 1 RCT, 115 participants; absolute effect: 59 fewer per 1000 (from 186 fewer to 102 more); very low-certainty evidence); and 2) all-cause mortality at ≥ D60 (RR 1.03, 95% CI 0.68 to 1.56; 4 RCTs, 1633 participants; absolute effect: 8 more per 1000 (from 84 fewer to 147 more); very low-certainty evidence). Safety of anakinra for people with COVID-19 Anakinra probably results in little or no increase in adverse events (RR 1.02, 95% CI 0.94 to 1.11; 2 RCTs, 722 participants; absolute effect: 14 more per 1000 (from 43 fewer to 78 more); moderate-certainty evidence).  The evidence is uncertain regarding an effect of anakinra on serious adverse events (RR 0.95, 95% CI 0.58 to 1.56; 2 RCTs, 722 participants; absolute effect: 12 fewer per 1000 (from 104 fewer to 138 more); low-certainty evidence). Effectiveness of canakinumab for people with COVID-19 Canakinumab probably results in little or no increase in clinical improvement at D28 (RR 1.05, 95% CI 0.96 to 1.14; 2 RCTs, 499 participants; absolute effect: 42 more per 1000 (from 33 fewer to 116 more); moderate-certainty evidence).  The evidence of an effect of canakinumab is uncertain on 1) the proportion of participants with a WHO Clinical Progression Score of level 7 or above at D28 (RR 0.72, 95% CI 0.44 to 1.20; 2 RCTs, 499 participants; absolute effect: 35 fewer per 1000 (from 69 fewer to 25 more); low-certainty evidence); and 2) all-cause mortality at D28 (RR:0.75; 95% CI 0.39 to 1.42); 2 RCTs, 499 participants; absolute effect: 20 fewer per 1000 (from 48 fewer to 33 more); low-certainty evidence).  The evidence is very uncertain about an effect of canakinumab on all-cause mortality at ≥ D60 (RR 0.55, 95% CI 0.16 to 1.91; 1 RCT, 45 participants; absolute effect: 112 fewer per 1000 (from 210 fewer to 227 more); very low-certainty evidence). Safety of canakinumab for people with COVID-19 Canakinumab probably results in little or no increase in adverse events (RR 1.02; 95% CI 0.86 to 1.21; 1 RCT, 454 participants; absolute effect: 11 more per 1000 (from 74 fewer to 111 more); moderate-certainty evidence). The evidence of an effect of canakinumab on serious adverse events is uncertain (RR 0.80, 95% CI 0.57 to 1.13; 2 RCTs, 499 participants; absolute effect: 44 fewer per 1000 (from 94 fewer to 28 more); low-certainty evidence). AUTHORS' CONCLUSIONS: Overall, we did not find evidence for an important beneficial effect of IL-1 blocking agents. The evidence is uncertain or very uncertain for several outcomes. Sixteen trials of anakinra and canakinumab with no results are currently registered, of which four are completed, and four terminated. The findings of this review are updated on the COVID-NMA platform (covid-nma.com).

Efficacy and safety of COVID-19 vaccines.

BACKGROUND: Different forms of vaccines have been developed to prevent the SARS-CoV-2 virus and subsequent COVID-19 disease. Several are in widespread use globally.  OBJECTIVES: To assess the efficacy and safety of COVID-19 vaccines (as a full primary vaccination series or a booster dose) against SARS-CoV-2. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register and the COVID-19 L·OVE platform (last search date 5 November 2021). We also searched the WHO International Clinical Trials Registry Platform, regulatory agency websites, and Retraction Watch. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing COVID-19 vaccines to placebo, no vaccine, other active vaccines, or other vaccine schedules. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We used GRADE to assess the certainty of evidence for all except immunogenicity outcomes.  We synthesized data for each vaccine separately and presented summary effect estimates with 95% confidence intervals (CIs).  MAIN RESULTS: We included and analyzed 41 RCTs assessing 12 different vaccines, including homologous and heterologous vaccine schedules and the effect of booster doses. Thirty-two RCTs were multicentre and five were multinational. The sample sizes of RCTs were 60 to 44,325 participants. Participants were aged: 18 years or older in 36 RCTs; 12 years or older in one RCT; 12 to 17 years in two RCTs; and three to 17 years in two RCTs. Twenty-nine RCTs provided results for individuals aged over 60 years, and three RCTs included immunocompromized patients. No trials included pregnant women. Sixteen RCTs had two-month follow-up or less, 20 RCTs had two to six months, and five RCTs had greater than six to 12 months or less. Eighteen reports were based on preplanned interim analyses. Overall risk of bias was low for all outcomes in eight RCTs, while 33 had concerns for at least one outcome. We identified 343 registered RCTs with results not yet available.  This abstract reports results for the critical outcomes of confirmed symptomatic COVID-19, severe and critical COVID-19, and serious adverse events only for the 10 WHO-approved vaccines. For remaining outcomes and vaccines, see main text. The evidence for mortality was generally sparse and of low or very low certainty for all WHO-approved vaccines, except AD26.COV2.S (Janssen), which probably reduces the risk of all-cause mortality (risk ratio (RR) 0.25, 95% CI 0.09 to 0.67; 1 RCT, 43,783 participants; high-certainty evidence). Confirmed symptomatic COVID-19 High-certainty evidence found that BNT162b2 (BioNtech/Fosun Pharma/Pfizer), mRNA-1273 (ModernaTx), ChAdOx1 (Oxford/AstraZeneca), Ad26.COV2.S, BBIBP-CorV (Sinopharm-Beijing), and BBV152 (Bharat Biotect) reduce the incidence of symptomatic COVID-19 compared to placebo (vaccine efficacy (VE): BNT162b2: 97.84%, 95% CI 44.25% to 99.92%; 2 RCTs, 44,077 participants; mRNA-1273: 93.20%, 95% CI 91.06% to 94.83%; 2 RCTs, 31,632 participants; ChAdOx1: 70.23%, 95% CI 62.10% to 76.62%; 2 RCTs, 43,390 participants; Ad26.COV2.S: 66.90%, 95% CI 59.10% to 73.40%; 1 RCT, 39,058 participants; BBIBP-CorV: 78.10%, 95% CI 64.80% to 86.30%; 1 RCT, 25,463 participants; BBV152: 77.80%, 95% CI 65.20% to 86.40%; 1 RCT, 16,973 participants). Moderate-certainty evidence found that NVX-CoV2373 (Novavax) probably reduces the incidence of symptomatic COVID-19 compared to placebo (VE 82.91%, 95% CI 50.49% to 94.10%; 3 RCTs, 42,175 participants). There is low-certainty evidence for CoronaVac (Sinovac) for this outcome (VE 69.81%, 95% CI 12.27% to 89.61%; 2 RCTs, 19,852 participants). Severe or critical COVID-19 High-certainty evidence found that BNT162b2, mRNA-1273, Ad26.COV2.S, and BBV152 result in a large reduction in incidence of severe or critical disease due to COVID-19 compared to placebo (VE: BNT162b2: 95.70%, 95% CI 73.90% to 99.90%; 1 RCT, 46,077 participants; mRNA-1273: 98.20%, 95% CI 92.80% to 99.60%; 1 RCT, 28,451 participants; AD26.COV2.S: 76.30%, 95% CI 57.90% to 87.50%; 1 RCT, 39,058 participants; BBV152: 93.40%, 95% CI 57.10% to 99.80%; 1 RCT, 16,976 participants). Moderate-certainty evidence found that NVX-CoV2373 probably reduces the incidence of severe or critical COVID-19 (VE 100.00%, 95% CI 86.99% to 100.00%; 1 RCT, 25,452 participants). Two trials reported high efficacy of CoronaVac for severe or critical disease with wide CIs, but these results could not be pooled. Serious adverse events (SAEs) mRNA-1273, ChAdOx1 (Oxford-AstraZeneca)/SII-ChAdOx1 (Serum Institute of India), Ad26.COV2.S, and BBV152 probably result in little or no difference in SAEs compared to placebo (RR: mRNA-1273: 0.92, 95% CI 0.78 to 1.08; 2 RCTs, 34,072 participants; ChAdOx1/SII-ChAdOx1: 0.88, 95% CI 0.72 to 1.07; 7 RCTs, 58,182 participants; Ad26.COV2.S: 0.92, 95% CI 0.69 to 1.22; 1 RCT, 43,783 participants); BBV152: 0.65, 95% CI 0.43 to 0.97; 1 RCT, 25,928 participants). In each of these, the likely absolute difference in effects was fewer than 5/1000 participants. Evidence for SAEs is uncertain for BNT162b2, CoronaVac, BBIBP-CorV, and NVX-CoV2373 compared to placebo (RR: BNT162b2: 1.30, 95% CI 0.55 to 3.07; 2 RCTs, 46,107 participants; CoronaVac: 0.97, 95% CI 0.62 to 1.51; 4 RCTs, 23,139 participants; BBIBP-CorV: 0.76, 95% CI 0.54 to 1.06; 1 RCT, 26,924 participants; NVX-CoV2373: 0.92, 95% CI 0.74 to 1.14; 4 RCTs, 38,802 participants). For the evaluation of heterologous schedules, booster doses, and efficacy against variants of concern, see main text of review. AUTHORS' CONCLUSIONS: Compared to placebo, most vaccines reduce, or likely reduce, the proportion of participants with confirmed symptomatic COVID-19, and for some, there is high-certainty evidence that they reduce severe or critical disease. There is probably little or no difference between most vaccines and placebo for serious adverse events. Over 300 registered RCTs are evaluating the efficacy of COVID-19 vaccines, and this review is updated regularly on the COVID-NMA platform (covid-nma.com). Implications for practice Due to the trial exclusions, these results cannot be generalized to pregnant women, individuals with a history of SARS-CoV-2 infection, or immunocompromized people. Most trials had a short follow-up and were conducted before the emergence of variants of concern. Implications for research Future research should evaluate the long-term effect of vaccines, compare different vaccines and vaccine schedules, assess vaccine efficacy and safety in specific populations, and include outcomes such as preventing long COVID-19. Ongoing evaluation of vaccine efficacy and effectiveness against emerging variants of concern is also vital.

Patients' Perspectives on Transforming Clinical Trial Participation: Large Online Vignette-based Survey.

BACKGROUND: Patients' participation is crucial to the success of randomized controlled trials (RCTs). However, recruiting and retaining patients in trials remain a challenge. OBJECTIVE: This study aims to describe patients' preferences for the organization of RCTs (visits on- site or remotely) and evaluate the potential impact of fulfilling preferences on their willingness to participate in a clinical trial. METHODS: This was a vignette-based survey. Vignettes were case scenarios of real clinical trials assessing pharmacological treatments. These RCTs evaluated 6 prevalent chronic diseases (ie, osteoporosis, osteoarthritis, asthma, cardiovascular diseases, diabetes, and endometriosis). Each vignette described (1) the RCT and characteristics of the treatment tested (ie, doses, administration routes) and (2) the trial procedures and different options (on-site or remotely) for how the trial was organized for informed consent, follow-up visits, and communication of results when the trial was completed. We recruited 628 participants from ComPaRe (www.compare.aphp.fr), a French e-cohort of patients with chronic diseases. The outcomes were the participants' preferences for the way the trial was organized (on-site or remotely) and their willingness to participate in the trial. RESULTS: Of the 628 participants who answered the vignettes, 491 (78.2%) were female (median age 55 years), with different chronic diseases ranging from endometriosis in 59 of 491 (12%) patients to asthma in 133 of 628 (21.2%) patients. In addition, 38 (6.1%) participants wanted to provide informed consent and all trial visits on-site, 176 (28%) wished to participate in the trial entirely remotely, and 414 (65.9%) wanted to combine remote-based and hospital-based visits. Considering the trial as a whole, when the trial was organized in a way that the patients preferred, the median (Q1-Q3) likelihood of participation in the trial was 90% (80-100) versus 60% (30-80) if the trial followed the patients' nonpreferred model. Furthermore, 256 (40.8%) patients responded to open-ended questions expressing their experience with trial participation and visits to the hospital and providing suggestions for improvement. The patients emphasized the need to personalize the way a trial is organized according to each patient's needs and conditions. CONCLUSIONS: There was a significant diversity in the participants' preferences. Most participants preferred hybrid organization involving both on-site and remote visits. Participants were more likely to participate in a trial organized according to their preferences.

[The PRISMA 2020 statement: an updated guideline for reporting systematic reviewsDeclaración PRISMA 2020: una guía actualizada para la publicación de revisiones sistemáticas]. / A declaração PRISMA 2020: diretriz atualizada para relatar revisões sistemáticas.

The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, published in 2009, was designed to help systematic reviewers transparently report why the review was done, what the authors did, and what they found. Over the past decade, advances in systematic review methodology and terminology have necessitated an update to the guideline. The PRISMA 2020 statement replaces the 2009 statement and includes new reporting guidance that reflects advances in methods to identify, select, appraise, and synthesise studies. The structure and presentation of the items have been modified to facilitate implementation. In this article, we present the PRISMA 2020 27-item checklist, an expanded checklist that details reporting recommendations for each item, the PRISMA 2020 abstract checklist, and the revised flow diagrams for original and updated reviews.

La declaración PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses), publicada en 2009, se diseñó para ayudar a los autores de revisiones sistemáticas a documentar de manera transparente el porqué de la revisión, qué hicieron los autores y qué encontraron. Durante la última década, ha habido muchos avances en la metodología y terminología de las revisiones sistemáticas, lo que ha requerido una actualización de esta guía. La declaración PRISMA 2020 sustituye a la declaración de 2009 e incluye una nueva guía de presentación de las publicaciones que refleja los avances en los métodos para identificar, seleccionar, evaluar y sintetizar estudios. La estructura y la presentación de los ítems ha sido modificada para facilitar su implementación. En este artículo, presentamos la lista de verificación PRISMA 2020 con 27 ítems, y una lista de verificación ampliada que detalla las recomendaciones en la publicación de cada ítem, la lista de verificación del resumen estructurado PRISMA 2020 y el diagrama de flujo revisado para revisiones sistemáticas.

The PRISMA 2020 statement: An updated guideline for reporting systematic reviews.

Matthew Page and co-authors describe PRISMA 2020, an updated reporting guideline for systematic reviews and meta-analyses.

Reporting of harms in oncological clinical study reports submitted to the European Medicines Agency compared to trial registries and publications-a methodological review.

BACKGROUND: An accurate and comprehensive assessment of harms is a fundamental part of an accurate weighing of benefits and harms of an intervention when making treatment decisions; however, harms are known to be underreported in journal publications. Therefore, we sought to compare the completeness of reporting of harm data, discrepancies in harm data reported, and the delay to access results of oncological clinical trials between three sources: clinical study reports (CSRs), clinical trial registries and journal publications. METHODS: We used the EMA clinical data website to identify all trials submitted to the EMA between 2015 and 2018. We retrieved all CSRs and included all phase II, II/III or III randomised controlled trials (RCTs) assessing targeted therapy and immunotherapy for cancer. We then identified related records in clinical trial registries and journals. We extracted harms data for eight pre-specified variables and determined the completeness of reporting of harm data in each of the three sources. RESULTS: We identified 42 RCTs evaluating 13 different drugs. Results were available on the EMA website in CSRs for 37 (88%) RCTs, ClinicalTrials.gov for 36 (86%), the European Clinical Trials Register (EUCTR) for 20 (48%) and in journal publications for 32 (76%). Harms reporting was more complete in CSRs than other sources. We identified marked discrepancies in harms data between sources, e.g. the number of patients discontinuing due to adverse events differed in CSRs and clinical trial registers for 88% of trials with data in both sources. For CSRs and publications, the corresponding number was 90%. The median (interquartile range) delay between the primary trial completion date and access to results was 4.34 (3.09-7.22) years for CSRs, 2.94 (1.16-4.52) years for ClinicalTrials.gov, 5.39 (4.18-7.33) years for EUCTR and 2.15 (0.64-5.04) years for publications. CONCLUSIONS: Harms of recently approved oncological drugs were reported more frequently and in more detail in CSRs than in trial registries and journal publications. Systematic reviews seeking to address harms of oncological treatments should ideally use CSRs as the primary source of data; however, due to problems with access, this is currently not feasible.

Risk of bias in observational studies using routinely collected data of comparative effectiveness research: a meta-research study.

BACKGROUND: To assess the completeness of reporting, research transparency practices, and risk of selection and immortal bias in observational studies using routinely collected data for comparative effectiveness research. METHOD: We performed a meta-research study by searching PubMed for comparative effectiveness observational studies evaluating therapeutic interventions using routinely collected data published in high impact factor journals from 01/06/2018 to 30/06/2020. We assessed the reporting of the study design (i.e., eligibility, treatment assignment, and the start of follow-up). The risk of selection bias and immortal time bias was determined by assessing if the time of eligibility, the treatment assignment, and the start of follow-up were synchronized to mimic the randomization following the target trial emulation framework. RESULT: Seventy-seven articles were identified. Most studies evaluated pharmacological treatments (69%) with a median sample size of 24,000 individuals. In total, 20% of articles inadequately reported essential information of the study design. One-third of the articles (n = 25, 33%) raised some concerns because of unclear reporting (n = 6, 8%) or were at high risk of selection bias and/or immortal time bias (n = 19, 25%). Only five articles (25%) described a solution to mitigate these biases. Six articles (31%) discussed these biases in the limitations section. CONCLUSION: Reporting of essential information of study design in observational studies remained suboptimal. Selection bias and immortal time bias were common methodological issues that researchers and physicians should be aware of when interpreting the results of observational studies using routinely collected data.

Interleukin-6 blocking agents for treating COVID-19: a living systematic review.

BACKGROUND: Interleukin 6 (IL-6) blocking agents have been used for treating severe coronavirus disease 2019 (COVID-19). Their immunosuppressive effect might be valuable in patients with COVID-19 characterised by substantial immune system dysfunction by controlling inflammation and promoting disease tolerance. OBJECTIVES: To assess the effect of IL-6 blocking agents compared to standard care alone or with placebo on efficacy and safety outcomes in COVID-19. We will update this assessment regularly. SEARCH METHODS: We searched the World Health Organization (WHO) International Clinical Trials Registry Platform (up to 11 February 2021) and the L-OVE platform, and Cochrane COVID-19 Study Register to identify trials up to 26 February 2021. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating IL-6 blocking agents compared with standard care alone or with placebo for people with COVID-19, regardless of disease severity. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two review authors independently collected data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. We rated the certainty of evidence with the GRADE approach for the critical outcomes such as clinical improvement (defined as hospital discharge or improvement on the scale used by trialists to evaluate clinical progression or recovery) (day (D) 28 / ≥ D60); WHO Clinical Progression Score of level 7 or above (i.e. the proportion of participants with mechanical ventilation +/- additional organ support OR death) (D28 / ≥ D60); all-cause mortality (D28 / ≥ D60); incidence of any adverse events; and incidence of serious adverse events. MAIN RESULTS: We identified 10 RCTs with available data including one platform trial comparing tocilizumab and sarilumab with standard of care. These trials evaluated tocilizumab (nine RCTs including two platform trials; seven were reported as peer-reviewed articles, two as preprints; 6428 randomised participants); and two sarilumab (one platform trial reported as peer reviewed article, one reported as preprint, 880 randomised participants). All trials included were multicentre trials. They were conducted in Brazil, China, France, Italy, UK, USA, and four were multi-country trials. The mean age range of participants ranged from 56 to 65 years; 4572 (66.3%) of trial participants were male. Disease severity ranged from mild to critical disease. The reported proportion of participants on oxygen at baseline but not intubated varied from 56% to 100% where reported. Five trials reported the inclusion of intubated patients at baseline. We identified a further 20 registered RCTs of tocilizumab compared to placebo/standard care (five completed without available results, five terminated without available results, eight ongoing, two not recruiting); 11 RCTs of sarilumab (two completed without results, three terminated without available results, six ongoing); six RCTs of clazakisumab (five ongoing, one not recruiting); two RCTs of olokizumab (one completed, one not recruiting); one of siltuximab (ongoing) and one RCT of levilimab (completed without available results). Of note, three were cancelled (2 tocilizumab, 1 clazakisumab). One multiple-arm RCT evaluated both tocilizumab and sarilumab compared to standard of care, one three-arm RCT evaluated tocilizumab and siltuximab compared to standard of care and consequently they appear in each respective comparison. Tocilizumab versus standard care alone or with placebo a. Effectiveness of tocilizumab for patients with COVID-19 Tocilizumab probably results in little or no increase in the outcome of clinical improvement at D28 (RR 1.06, 95% CI 1.00 to 1.13; I2 = 40.9%; 7 RCTs, 5585 participants; absolute effect: 31 more with clinical improvement per 1000 (from 0 fewer to 67 more); moderate-certainty evidence). However, we cannot exclude that some subgroups of patients could benefit from the treatment. We did not obtain data for longer-term follow-up (≥ D60). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score of level of 7 or above is uncertain at D28 (RR 0.99, 95% CI 0.56 to 1.74; I2 = 64.4%; 3 RCTs, 712 participants; low-certainty evidence). We did not obtain data for longer-term follow-up (≥ D60). Tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo (RR 0.89, 95% CI 0.82 to 0.97; I2 = 0.0%; 8 RCTs, 6363 participants; absolute effect: 32 fewer deaths per 1000 (from 52 fewer to 9 fewer); high-certainty evidence). The evidence suggests uncertainty around the effect on mortality at ≥ D60 (RR 0.86, 95% CI 0.53 to 1.40; I2 = 0.0%; 2 RCTs, 519 participants; low-certainty evidence). b. Safety of tocilizumab for patients with COVID-19 The evidence is very uncertain about the effect of tocilizumab on adverse events (RR 1.23, 95% CI 0.87 to 1.72; I2 = 86.4%; 7 RCTs, 1534 participants; very low-certainty evidence). Nevertheless, tocilizumab probably results in slightly fewer serious adverse events than standard care alone or placebo (RR 0.89, 95% CI 0.75 to 1.06; I2 = 0.0%; 8 RCTs, 2312 participants; moderate-certainty evidence). Sarilumab versus standard care alone or with placebo The evidence is uncertain about the effect of sarilumab on all-cause mortality at D28 (RR 0.77, 95% CI 0.43 to 1.36; 2 RCTs, 880 participants; low certainty), on all-cause mortality at ≥ D60 (RR 1.00, 95% CI 0.50 to 2.0; 1 RCT, 420 participants; low certainty), and serious adverse events (RR 1.17, 95% CI 0.77 to 1.77; 2 RCTs, 880 participants; low certainty). It is unlikely that sarilumab results in an important increase of adverse events (RR 1.05, 95% CI 0.88 to 1.25; 1 RCT, 420 participants; moderate certainty). However, an increase cannot be excluded No data were available for other critical outcomes. AUTHORS' CONCLUSIONS: On average, tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo and probably results in slightly fewer serious adverse events than standard care alone or placebo. Nevertheless, tocilizumab probably results in little or no increase in the outcome clinical improvement (defined as hospital discharge or improvement measured by trialist-defined scales) at D28. The impact of tocilizumab on other outcomes is uncertain or very uncertain. With the data available, we were not able to explore heterogeneity. Individual patient data meta-analyses are needed to be able to identify which patients are more likely to benefit from this treatment. Evidence for an effect of sarilumab is uncertain and evidence for other anti-IL6 agents is unavailable. Thirty-nine RCTs of IL-6 blocking agents with no results are currently registered, of which nine are completed and seven trials were terminated with no results available. The findings of this review will be updated as new data are made available on the COVID-NMA platform (covid-nma.com).