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.
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.
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.
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.
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). There is 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).
Preprints became a major source of research communication during the COVID-19 pandemic. We aimed to evaluate whether summary treatment effect estimates differ between preprint and peer-reviewed ...journal trials.
A meta-epidemiological study. Data were derived from the COVID-NMA living systematic review (covid-nma.com) up to July 20, 2022. We identified all meta-analyses evaluating pharmacological treatments vs. standard of care or placebo for patients with COVID-19 that included at least one preprint and one peer-reviewed journal article. Difference in effect estimates between preprint and peer-reviewed journal trials were estimated by the ratio of odds ratio (ROR); ROR <1 indicated larger effects in preprint trials.
Thirty-seven meta-analyses including 114 trials (44 preprints and 70 peer-reviewed publications) were selected. The median number of randomized controlled trials (RCTs) per meta-analysis was 2 (interquartile range IQR, 2–4; maximum, 11), median sample size of RCTs was 199 (IQR, 99–478). Overall, there was no statistically significant difference in summary effect estimates between preprint and peer-reviewed journal trials (ROR, 0.88; 95% CI, 0.71–1.09; I2 = 17.8%; τ2 = 0.06).
We did not find an important difference between summary treatment effects of preprints and summary treatment effects of peer-reviewed publications. Systematic reviewers and guideline developers should assess preprint inclusion individually, accounting for risk of bias and completeness of reporting.
Efficacy and safety of COVID‐19 vaccines Boutron, Isabelle; Graña, Carolina; Ghosn, Lina ...
Cochrane database of systematic reviews,
12/2022, Letnik:
2023, Številka:
3
Journal Article
Recenzirano
Odprti dostop
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 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.
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).
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.
Objective
To identify risk factors for perioperative morbidity among a large national cohort of pediatric patients undergoing cochlear implantation.
Study Design
Retrospective study utilizing the ...American College of Surgeons National Surgical Quality Improvement Program Pediatric database (2012–2013).
Methods
Pediatric cochlear implantation cases were identified using current procedural terminology 69930. Patients were categorized by age, and operative characteristics along with 30‐day perioperative outcomes were analyzed.
Results
We identified 1,351 cases of pediatric cochlear implantation. The median age was 3.6 years, and 73 patients were less than 1 year of age. Of 21 complication occurrences (1.55%), superficial incisional surgical site infection (SSI) was the most common (n = 13, 61.9%). Thirty‐nine patients (2.9%) required readmission. The median operative time was 142 minutes, and the mean postoperative length of stay was 0.58 days. When comparing patients younger than 1 year old to those 1 year or older, no significant differences were noted in complication rate, postoperative length of stay, or reoperation rate. Patients less than 1 year of age were more likely to be readmitted (6.9% vs. 2.7%, P = 0.04) and had longer mean operative times (191 minutes vs. 160 minutes, P = 0.0015). Steroid use was a risk factor for unplanned reoperation, SSI, and readmission.
Conclusion
Despite a slight increase in readmission rates and operative times among patients less than 1 year of age, cochlear implantation appears to be safe in this population, with complication rates, reoperation rates, and postoperative lengths of stay similar to children undergoing the procedure at the current U.S. Food and Drug Administration‐approved age of 1 year and older.
Level of Evidence
4. Laryngoscope, 127:720–724, 2017
Researchers worldwide are actively engaging in research activities to search for preventive and therapeutic interventions against coronavirus disease 2019 (COVID-19). Our aim was to describe the ...planning of randomized controlled trials (RCTs) in terms of timing related to the course of the COVID-19 epidemic and research question evaluated.
We performed a living mapping of RCTs registered in the WHO International Clinical Trials Registry Platform. We systematically search the platform every week for all RCTs evaluating preventive interventions and treatments for COVID-19 and created a publicly available interactive mapping tool at https://covid-nma.com to visualize all trials registered.
By August 12, 2020, 1,568 trials for COVID-19 were registered worldwide. Overall, the median (Q1–Q3; range) delay between the first case recorded in each country and the first RCT registered was 47 days (33–67; 15–163). For the 9 countries with the highest number of trials registered, most trials were registered after the peak of the epidemic (from 100% trials in Italy to 38% in the United States). Most trials evaluated treatments (1,333 trials; 85%); only 223 (14%) evaluated preventive strategies and 12 postacute period intervention. A total of 254 trials were planned to assess different regimens of hydroxychloroquine with an expected sample size of 110,883 patients.
This living mapping analysis showed that COVID-19 trials have relatively small sample size with certain redundancy in research questions. Most trials were registered when the first peak of the pandemic has passed.
•Thousands of trials have been planned to identify treatments and preventive interventions for coronavirus disease 2019 (COVID-19).•Decision makers and researchers need to have an overview of all research efforts to avoid overlap.•We create an interactive living mapping of clinical trials of COVID-19 to support these stakeholders in decision-making.
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