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. Keywords: COVID-19, Randomized controlled trial, Selective outcome reporting, Selection bias, Quality of reporting, Peer review; Completeness of reporting, CONSORT, Transparency
Healthcare decisions are ideally based on clinical trial results, published in study registries, as journal articles or summarized in secondary research articles. In this research project, we ...investigated the impact of academically and commercially sponsored clinical trials on medical practice by measuring the proportion of trials published and cited by systematic reviews and clinical guidelines.
We examined 691 multicenter, randomized controlled trials that started in 2005 or later and were completed by the end of 2016. To determine whether sponsorship/funding and place of conduct influence a trial's impact, we created four sub-cohorts of investigator initiated trials (IITs) and industry sponsored trials (ISTs): 120 IITs and 171 ISTs with German contribution compared to 200 IITs and 200 ISTs without German contribution. We balanced the groups for study phase and place of conduct. German IITs were funded by the German Research Foundation (DFG), the Federal Ministry of Education and Research (BMBF), or by another non-commercial research organization. All other trials were drawn from the German Clinical Trials Register or ClinicalTrials.gov. We investigated, to what extent study characteristics were associated with publication and impact using multivariable logistic regressions.
For 80% of the 691 trials, results were published as result articles in a medical journal and/or study registry, 52% were cited by a systematic review, and 26% reached impact in a clinical guideline. Drug trials and larger trials were associated with a higher probability to be published and to have an impact than non-drug trials and smaller trials. Results of IITs were more often published as a journal article while results of ISTs were more often published in study registries. International ISTs less often gained impact by inclusion in systematic reviews or guidelines than IITs.
An encouraging high proportion of the clinical trials were published, and a considerable proportion gained impact on clinical practice. However, there is still room for improvement. For publishing study results, study registries have become an alternative or complement to journal articles, especially for ISTs. IITs funded by governmental bodies in Germany reached an impact that is comparable to international IITs and ISTs.
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).
This study describes access to individual patient-level data from randomized clinical trials during the COVID-19 pandemic to determine whether the intent to share what was reported in the registry, ...publication, or preprint was consistent with actual data access.
Up-to-date systematic reviews (SRs) are essential for making evidence-based decisions. During the 2019 coronavirus (COVID-19) pandemic, there was a particular need for up-to-date evidence, making the ...living systematic review (LSR) approach an appropriate review type. However, this approach poses certain challenges.
We aim to provide practice insights and report challenges that we faced while conducting two Cochrane LSRs on COVID-19 treatments with (i) convalescent plasma and (ii) systemic corticosteroids. We address our objective with an experience report and share challenges of the following components based on Iannizzi et al. (2022): study design, publication types, intervention/comparator, outcomes, search strategy, review updates and transparent reporting of differences between review updates.
Regarding the study design, the plasma LSR included different study designs because RCT data were not available at the beginning of the pandemic, whereas for the corticosteroids LSR, which started several months later, RCT data were already available. The challenges in both LSRs included the publication types (preprints were included with caution) and the intervention/comparator, for instance the unavailability of standard of care for either LSR, or SARS-CoV-2 variants occurrence. Further challenges in both LSRs occurred in the components “outcome sets” (which had to be adjusted) and “literature search”. The decision criteria for updating were based on important studies and available resources in both LSRs and policy relevance in the plasma LSR. Transparent reporting of the differences between the various update versions were discussed for both LSRs.
In summary, there are similarities and differences regarding challenges of review components for both LSRs. It is important to keep in mind that the two LSR examples presented here were conducted in the wake of the COVID-19 pandemic. Therefore, many of the challenges are attributable to the pandemic and are not specific to LSRs, such as constant adjustments of the outcome sets or changes in the database search. Nevertheless, we believe that some of these aspects are helpful for LSR authors and are applicable to other LSRs outside the pandemic context, particularly in areas where new evidence is rapidly emerging.
Aktuelle systematische Reviews (SRs) sind für evidenzbasierte Entscheidungen unerlässlich. Während der Coronavirus-Pandemie 2019 (COVID-19) bestand ein besonderer Bedarf an aktueller Evidenz, sodass der Ansatz der Living Systematic Reviews (LSRs) einen geeigneten Reviewtyp darstellt. Allerdings bringt der Ansatz einige Herausforderungen mit sich.
Unser Ziel ist es, im Folgenden über die Herausforderungen zu berichten, die bei der Durchführung zweier Cochrane LSRs zu COVID-19-Behandlungen mit (i) Rekonvaleszentenplasma und (ii) systemischen Kortikosteroiden zur COVID-19-Behandlung aufgetreten sind. In unserem Erfahrungsbericht gehen wir auf die folgenden Komponenten, basierend auf Iannizzi et al. (2022) ein: Studiendesign, Publikationstypen, Intervention/Vergleich, Outcomes, Suchstrategie, Updates der LSRs und transparente Darstellung der Unterschiede zwischen den Updates der Reviews.
Bezüglich der Komponente Studiendesign wurden im Plasma-LSR Studien mit unterschiedlichen Designs eingeschlossen, da zu Beginn der Pandemie keine Daten aus RCTs vorlagen. Das Kortikosteroide-LSR wurde erst Monate später initiiert, als bereits RCT-Daten vorlagen. Bei beiden LSRs gab es Herausforderungen hinsichtlich der Publikationsarten (Preprints wurden mit Vorsicht eingeschlossen) und der Intervention/Vergleich, z.B. Nichtverfügbarkeit eines Behandlungsstandards oder dem Auftreten von SARS-CoV-2-Varianten. Weitere Herausforderungen in beiden LSRs lagen in den Komponenten: Endpunkte (die fortlaufend angepasst werden mussten), und der Literaturrecherche. Die Entscheidungskriterien für die Aktualisierung basierten in beiden LSRs auf wichtigen Studien und verfügbaren Ressourcen und im Plasma-LSR zusätzlich auf der politischen Relevanz. In beiden LSRs standen wir vor der Herausforderung, die Leser*innen über den Stand der Reviews zu informieren. Transparente Darstellung der Änderungen wurden für beide LSRs diskutiert.
Zusammenfassend lässt sich sagen, dass es sowohl Gemeinsamkeiten als auch Unterschiede bei den Herausforderungen der einzelnen Komponenten in beiden LSRs gibt. Es ist jedoch zu bedenken, dass beide von uns vorgestellten Beispiele im Zuge der COVID-19-Pandemie entstanden sind. Daher sind viele Herausforderungen der Pandemie nicht spezifisch dem LSR-Ansatz zuzuschreiben, wie z. B. die ständige Anpassung der Outcome-Sets, Unterschiede in den Studiendesigns oder Änderungen der durchsuchten Datenbanken. Dennoch sind wir der Meinung, dass einige dieser Aspekte auch auf LSRs außerhalb des Pandemiekontextes anwendbar sind, insbesondere in Bereichen, in denen rasch neue Evidenz gewonnen wird.
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).
Various epidemiological studies suggest a positive association between exposure to cow's milk A1 β-casein protein and risk for noncommunicable chronic diseases. The consumption of A2 cow's milk is ...increasing, likely because A2 milk is postulated to have positive effects on digestive health.
A systematic review was conducted to investigate associations between A1 β-casein and health-related outcomes in humans.
Five electronic databases, 3 clinical trial registries, and the internet were searched systematically.
Using predefined inclusion criteria, 2 authors independently selected studies investigating the effect of A1 β-casein or β-casomorphin-7 intake/exposure on any health-related outcome in humans. Discrepancies were resolved by consensus.
Two authors independently extracted data and assessed risk of bias. The certainty of evidence per outcome was evaluated using the GRADE approach. Discrepancies were resolved by consensus.
Fifteen randomized controlled trials, 2 case-control studies, and 8 ecological studies were included. Most randomized controlled studies and case-control studies investigating a potential effect on various outcomes were based on intermediate markers and found no significant difference between the 2 milk types. In contrast, most ecological studies reported that population-level A1 β-casein exposure is associated with adverse health outcomes. The certainty of the evidence for the included outcomes, as assessed by the GRADE approach, was rated as moderate for digestive symptoms and as low to very low for all other outcomes.
Human-based evidence from clinical trials and epidemiological studies published prior to October 2017 provides moderate certainty for adverse digestive health effects of A1 β-casein compared with A2 β-casein but low or very low certainty for other health effects. These conclusions may change in the future, given the emergent nature of this topic and the ongoing research in this area.
PROSPERO registration number CRD42016043795.
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.
Background
Worldwide approximately 360 million people suffer from hearing impairment, 328 million of whom are adults. Up to now there has been no systematic evaluation of any representative ...epidemiological data on the prevalence of hearing loss among adults in Germany. The present paper is intended to investigate this within the framework of a systematic review.
Methods
A systematic literature search was carried out in electronic databases as well as by means of hand-searching. Studies published after 1975 and indicating the prevalence or incidence of hearing impairment among German adults were included. Study selection, data extraction and additional quality assessments were made by two independent reviewers.
Results
By means of a systematic literature search it was possible to identify 6 sources, which provided solely cross-sectional data, whereby the reported data are based on a study population of between some hundred and 10 million people living in Germany. The prevalences ascertained showed a broad range of between 16% and 25% and varied according to age, study setting, definition of hearing loss and method of data capture. At present there are no utilizable data on the extent of the use of hearing aids.
Discussion
The present review demonstrates clearly that evidence-based information relating to Germany can only be made on the basis of a clear definition of hearing loss within the framework of an up-to-date and representative epidemiological study carried out with appropriate methodology. In view of the high prevalence of illnesses causing hearing impairment and of the risks to health associated with untreated hearing impairment as well as of socio-economic costs, such an epidemiological study is of great social significance.
We report on the case of an elderly patient with persisting diarrhea. Few weeks previous of admission the patient had received antibiotic therapy because of respiratory infection. On admission he ...seemed exsiccated and feeble.
Macroscopic findings in colonoscopy showed proctosigmoiditis and membranous exsudations. Stool culture provided the evidence for an antibiotic-associated infection with pseudomonas aeruginosa.
The recommended oral therapy with ciprofloxacin proved to be effective.
Complications with elderly patients are multimorbidity and diarrhea-induced prerenal failure. Frail patients can react strongly to antibiotic therapy with enteritis and dysbacteriosis.
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