Robustness of reported postacute health outcomes in children with SARS-CoV-2 infection: a systematic review.

OBJECTIVE: To systematically assess the robustness of reported postacute SARS-CoV-2 infection health outcomes in children. METHODS: A search on PubMed and Web of Science was conducted to identify studies published up to 22 January 2022 that reported on postacute SARS-CoV-2 infection health outcomes in children (<18 years) with follow-up of ≥2 months since detection of infection or ≥1 month since recovery from acute illness. We assessed the consideration of confounding bias and causality, as well as the risk of bias. RESULTS: 21 studies including 81 896 children reported up to 97 symptoms with follow-up periods of 2.0-11.5 months. Fifteen studies had no control group. The reported proportion of children with post-COVID syndrome was between 0% and 66.5% in children with SARS-CoV-2 infection (n=16 986) and between 2.0% and 53.3% in children without SARS-CoV-2 infection (n=64 910). Only two studies made a clear causal interpretation of an association between SARS-CoV-2 infection and the main outcome of 'post-COVID syndrome' and provided recommendations regarding prevention measures. The robustness of all 21 studies was seriously limited due to an overall critical risk of bias. CONCLUSIONS: The robustness of reported postacute SARS-CoV-2 infection health outcomes in children is seriously limited, at least in all the published articles we could identify. None of the studies provided evidence with reasonable certainty on whether SARS-CoV-2 infection has an impact on postacute health outcomes, let alone to what extent. Children and their families urgently need much more reliable and methodologically robust evidence to address their concerns and improve care.

Effects of remdesivir in patients hospitalised with COVID-19: a systematic review and individual patient data meta-analysis of randomised controlled trials.

BACKGROUND: Interpretation of the evidence from randomised controlled trials (RCTs) of remdesivir in patients treated in hospital for COVID-19 is conflicting. We aimed to assess the benefits and harms of remdesivir compared with placebo or usual care in these patients, and whether treatment effects differed between prespecified patient subgroups. METHODS: For this systematic review and meta-analysis, we searched PubMed, Embase, the Cochrane COVID-19 trial registry, ClinicalTrials.gov, the International Clinical Trials Registry Platform, and preprint servers from Jan 1, 2020, until April 11, 2022, for RCTs of remdesivir in adult patients hospitalised with COVID-19, and contacted the authors of eligible trials to request individual patient data. The primary outcome was all-cause mortality at day 28 after randomisation. We used multivariable hierarchical regression-adjusting for respiratory support, age, and enrollment period-to investigate effect modifiers. This study was registered with PROSPERO, CRD42021257134. FINDINGS: Our search identified 857 records, yielding nine RCTs eligible for inclusion. Of these nine eligible RCTs, individual data were provided for eight, covering 10 480 patients hospitalised with COVID-19 (99% of such patients included in such RCTs worldwide) recruited between Feb 6, 2020, and April 1, 2021. Within 28 days of randomisation, 662 (12·5%) of 5317 patients assigned to remdesivir and 706 (14·1%) of 5005 patients assigned to no remdesivir died (adjusted odds ratio [aOR] 0·88, 95% CI 0·78-1·00, p=0·045). We found evidence for a credible subgroup effect according to respiratory support at baseline (pinteraction=0·019). Of patients who were ventilated-including those who received high-flow oxygen-253 (30·0%) of 844 patients assigned to remdesivir died compared with 241 (28·5%) of 846 patients assigned to no remdesivir (aOR 1·10 [0·88-1·38]; low-certainty evidence). Of patients who received no oxygen or low-flow oxygen, 409 (9·1%) of 4473 patients assigned to remdesivir died compared with 465 (11·2%) of 4159 patients assigned to no remdesivir (0·80 [0·70-0·93]; high-certainty evidence). No credible subgroup effect was found for time to start of remdesivir after symptom onset, age, presence of comorbidities, enrolment period, or corticosteroid use. Remdesivir did not increase the frequency of severe or serious adverse events. INTERPRETATION: This individual patient data meta-analysis showed that remdesivir reduced mortality in patients hospitalised with COVID-19 who required no or conventional oxygen support, but was underpowered to evaluate patients who were ventilated when receiving remdesivir. The effect size of remdesivir in patients with more respiratory support or acquired immunity and the cost-effectiveness of remdesivir remain to be further elucidated. FUNDING: EU-RESPONSE.

Clinical trial research agenda on COVID-19 - the first two years in Germany and beyond.

BACKGROUND: We have followed the COVID-19 clinical trial research agenda from the beginning using the COVID-evidence.org platform. Now, two years after the COVID-19 pandemic started, our aim was to re-examine this research agenda with the latest data to provide a global perspective on the research landscape with a focus on Germany. METHODS: We reviewed and updated previously published data on the COVID-19 clinical research agenda as of 28February 2022 focusing on randomized trials. We used the COVID-evidence.org platform including registry entries from ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform as well as publications from the Living OVerview of Evidence platform for COVID-19 (L·OVE). RESULTS: Two years on from the pandemic outbreak, there were 4,673 registered trials. The majority of these trials have remained small with a median of 120 planned participants (IQR 60-320). In the first hundred days of the pandemic most of them (50%) had been registered in China. More than two years later, the five countries with the most registered trials (alone or within a framework of international collaborations) were the USA (825 trials; 18%), Iran (619 trials; 13%), India (566 trials; 12%), China (353 trials; 8%), and Spain (309 trials; 7%). Only 119 trials were reported to have a study site in Germany (2.5% of the registered trials). Of the 4,673 trials registered, 15% (694 trials) had published their results by February 2022. The clinical research agenda has been marked by both successes, such as the large RECOVERY trial providing evidence on 10 treatments for COVID-19 including over 45,000 patients as of February 2022, and failures: worldwide only 57 randomized trials have been registered over two years that aimed to assess non-pharmaceutical interventions (e.g., face mask policies and lockdown measures) to prevent COVID-19, and only 11 of them had published results informing decisions that have an impact on the life of billions of people worldwide. CONCLUSIONS: The COVID-19 clinical research agenda has highlighted the substantial effort of the research community but also the challenges of the clinical research ecosystem. Most importantly, it has shed light on the ability to circumvent traditional barriers and to make trials more useful even under extraordinary conditions. The time to learn our lessons and apply them is now, and the time to demonstrate how we have improved the system is before the next pandemic.

Clinical trial research agenda on COVID-19 – the first two years in Germany and beyond Klinische Studien zu COVID-19 – die ersten zwei Jahre in Deutschland und darüber hinaus

Background We have followed the COVID-19 clinical trial research agenda from the beginning using the COVID-evidence.org platform. Now, two years after the COVID-19 pandemic started, our aim was to re-examine this research agenda with the latest data to provide a global perspective on the research landscape with a focus on Germany. Methods We reviewed and updated previously published data on the COVID-19 clinical research agenda as of 28February 2022 focusing on randomized trials. We used the COVID-evidence.org platform including registry entries from ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform as well as publications from the Living OVerview of Evidence platform for COVID-19 (L·OVE). Results Two years on from the pandemic outbreak, there were 4,673 registered trials. The majority of these trials have remained small with a median of 120 planned participants (IQR 60-320). In the first hundred days of the pandemic most of them (50 %) had been registered in China. More than two years later, the five countries with the most registered trials (alone or within a framework of international collaborations) were the USA (825 trials;18 %), Iran (619 trials;13 %), India (566 trials;12 %), China (353 trials;8 %), and Spain (309 trials;7 %). Only 119 trials were reported to have a study site in Germany (2.5 % of the registered trials). Of the 4,673 trials registered, 15 % (694 trials) had published their results by February 2022. The clinical research agenda has been marked by both successes, such as the large RECOVERY trial providing evidence on 10 treatments for COVID-19 including over 45,000 patients as of February 2022, and failures: worldwide only 57 randomized trials have been registered over two years that aimed to assess non-pharmaceutical interventions (e.g., face mask policies and lockdown measures) to prevent COVID-19, and only 11 of them had published results informing decisions that have an impact on the life of billions of people worldwide. Conclusions The COVID-19 clinical research agenda has highlighted the substantial effort of the research community but also the challenges of the clinical research ecosystem. Most importantly, it has shed light on the ability to circumvent traditional barriers and to make trials more useful even under extraordinary conditions. The time to learn our lessons and apply them is now, and the time to demonstrate how we have improved the system is before the next pandemic.

Randomized trials on non-pharmaceutical interventions for COVID-19: a scoping review.

OBJECTIVE: We aimed at providing a systematic overview of randomised trials assessing non-pharmaceutical interventions (NPIs) to prevent COVID-19. DESIGN: Scoping review. METHODS: We included all randomised trials assessing NPIs to prevent COVID-19 in any country and setting registered in ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform using the COVID-evidence platform (until 17 August 2021). We searched for corresponding publications in MEDLINE/PubMed, Google Scholar, the Living Overview of Evidence platform, and the Cochrane COVID-19 registry as well as for results posted in registries (until 14 November 2021). Descriptive statistics using numbers and percentages were used in the narrative synthesis of the results. RESULTS: We identified 41 randomised trials. Of them, 12 were completed (29.3%) including 9 with published results. The 41 trials planned to recruit a median of 1700 participants (IQR 588-9500, range 30-35 256 399) with a median planned duration of 8 months (IQR 3-14, range 1-24). Most came from the USA (n=11, 26.8%). The trials mostly assessed protective equipment (n=11, 26.8%), COVID-19-related information and education programmes (n=9, 22.0%), access to mass events under specific safety measures (n=5, 12.2%), testing and screening strategies (n=5, 12.2%) and hygiene management (n=5, 12.2%). CONCLUSIONS: Worldwide, 41 randomised trials assessing NPIs have been initiated with published results available to inform policy decisions for only 9 of them. A long-term research agenda including behavioural, environmental, social and systems level interventions is urgently needed to guide policies and practices in the current and future public health emergencies.

Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). METHODS: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. RESULTS: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. CONCLUSIONS: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.

Challenges and Lessons Learned From COVID-19 Trials: Should We Be Doing Clinical Trials Differently?

The COVID-19 crisis led to a flurry of clinical trials activity. The COVID-evidence database shows 2814 COVID-19 randomized trials registered as of February 16, 2021. Most were small (only 18% have a planned sample size > 500) and the rare completed ones have not provided published results promptly (only 283 trial publications as of February 2021). Small randomized trials and observational, nonrandomized analyses have not had a successful track record and have generated misleading expectations. Different large trials on the same intervention have generally been far more efficient in producing timely and consistent evidence. The rapid generation of evidence and accelerated dissemination of results have led to new challenges for systematic reviews and meta-analyses (eg, rapid, living, and scoping reviews). Pressure to regulatory agencies has also mounted with massive emergency authorizations, but some of them have had to be revoked. Pandemic circumstances have disrupted the way trials are conducted; therefore, new methods have been developed and adopted more widely to facilitate recruitment, consent, and overall trial conduct. On the basis of the COVID-19 experience and its challenges, planning of several large, efficient trials, and wider use of adaptive designs might change the future of clinical research. Pragmatism, integration in clinical care, efficient administration, promotion of collaborative structures, and enhanced integration of existing data and facilities might be several of the legacies of COVID-19 on future randomized trials.

Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials.

Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.

Association of Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis.

Importance: Convalescent plasma is a proposed treatment for COVID-19. Objective: To assess clinical outcomes with convalescent plasma treatment vs placebo or standard of care in peer-reviewed and preprint publications or press releases of randomized clinical trials (RCTs). Data Sources: PubMed, the Cochrane COVID-19 trial registry, and the Living Overview of Evidence platform were searched until January 29, 2021. Study Selection: The RCTs selected compared any type of convalescent plasma vs placebo or standard of care for patients with confirmed or suspected COVID-19 in any treatment setting. Data Extraction and Synthesis: Two reviewers independently extracted data on relevant clinical outcomes, trial characteristics, and patient characteristics and used the Cochrane Risk of Bias Assessment Tool. The primary analysis included peer-reviewed publications of RCTs only, whereas the secondary analysis included all publicly available RCT data (peer-reviewed publications, preprints, and press releases). Inverse variance-weighted meta-analyses were conducted to summarize the treatment effects. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation. Main Outcomes and Measures: All-cause mortality, length of hospital stay, clinical improvement, clinical deterioration, mechanical ventilation use, and serious adverse events. Results: A total of 1060 patients from 4 peer-reviewed RCTs and 10 722 patients from 6 other publicly available RCTs were included. The summary risk ratio (RR) for all-cause mortality with convalescent plasma in the 4 peer-reviewed RCTs was 0.93 (95% CI, 0.63 to 1.38), the absolute risk difference was -1.21% (95% CI, -5.29% to 2.88%), and there was low certainty of the evidence due to imprecision. Across all 10 RCTs, the summary RR was 1.02 (95% CI, 0.92 to 1.12) and there was moderate certainty of the evidence due to inclusion of unpublished data. Among the peer-reviewed RCTs, the summary hazard ratio was 1.17 (95% CI, 0.07 to 20.34) for length of hospital stay, the summary RR was 0.76 (95% CI, 0.20 to 2.87) for mechanical ventilation use (the absolute risk difference for mechanical ventilation use was -2.56% [95% CI, -13.16% to 8.05%]), and there was low certainty of the evidence due to imprecision for both outcomes. Limited data on clinical improvement, clinical deterioration, and serious adverse events showed no significant differences. Conclusions and Relevance: Treatment with convalescent plasma compared with placebo or standard of care was not significantly associated with a decrease in all-cause mortality or with any benefit for other clinical outcomes. The certainty of the evidence was low to moderate for all-cause mortality and low for other outcomes.