ABSTRACT
Background: The interpretation of the evidence from randomized clinical trials (RCTs) on remdesivir for hospitalized patients with coronavirus disease 2019 (COVID-19) is conflicting. We conducted a systematic review and individual patient data meta-analysis (IPDMA) of RCTs to assess the benefit and harm of remdesivir compared to placebo or usual care in hospitalized patients and whether treatment effects differed between prespecified subgroups. Method(s): We systematically searched electronic databases and registries through April 11th 2022 and contacted authors of eligible trials to share individual patient data. The primary outcome was all-cause mortality at day 28. We used multivariable hierarchical regression adjusting for respiratory support, age, and enrollment period to investigate effect modifiers. The study was registered in PROSPERO (CRD42021257134). Result(s): Out of nine eligible RCTs, eight provided individual data for 10480 hospitalized COVID-19 patients (99% of global IPD) recruited between February 2020 and April 2021. Within 28 days of randomization, 662 of 5317 patients (12.5%) assigned to remdesivir and 706 of 5005 (14.1%) assigned to no remdesivir died (adjusted odds ratio [aOR] 0.88;95% confidence interval [CI], 0.78-1.00;p=0.045). We found evidence for a credible subgroup effect according to respiratory support at baseline (interaction p=0.019). Of those ventilated including high-flow oxygen, 253/844 (30.0%) assigned to remdesivir died versus 241/846 (28.5%) assigned to no remdesivir (aOR 1.10 [0.88-1.38];low certainty evidence). Of those receiving no or low flow oxygen, 409/4473 (9.1%) assigned to remdesivir died versus 465/4159 (11.2%) assigned to no remdesivir (aOR 0.80 [0.70-0.93];high certainty evidence). There was no credible subgroup effect with respect to time to start of remdesivir after symptom onset, age, presence of comorbidities, enrollment period or corticosteroid use. Remdesivir did not increase the frequency of severe or serious adverse events. Table 1 summarizes the findings according to GRADE (Grading of Recommendations, Assessment, Development and Evaluations). Conclusion(s): This IPDMA, summarizing the evidence of 99% patients ever randomized on the topic, demonstrated that remdesivir reduced mortality in hospitalized COVID-19 patients requiring no or conventional oxygen support, but patients requiring more respiratory support may not benefit. These findings may inform clinical guidelines, especially due to increasing resistance to current monoclonal antibodies.
ABSTRACT
Background: Since January 2021, the two in Switzerland approved severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines tozinameran (Pfizer/Biontech) and elasomeran (Moderna) have been used to vaccinate the Swiss population. These vaccines were found to be safe in licensing trials with excellent efficacy of 95% and 94% in terms of preventing COVID-19 illness 14 days after the second vaccination. However, randomized evidence on the comparative effectiveness of both vaccines in immunocompromised patients is currently lacking. Methods: We conducted a parallel, two-arm (allocation 1:1) open-label, non-inferiority randomized clinical trial (RCT) nested into the Swiss HIV Cohort Study (SHCS) and the Swiss Transplant Cohort Study (STCS). Patients living with HIV and solid organ transplant recipients (i.e. lung and kidney) from these cohorts were randomized to receive either tozinameran or elasomeran. The primary endpoint was an antibody response to SARS-CoV-2 spike (S1) protein receptor binding domain using Elecsys® Anti-SARS-CoV-2 S assay from Roche (binary, cut-off ≥0.8 Units/ml) 12 weeks after first vaccination (8 weeks after second vaccination). Secondary outcomes were immune response measured with the Antibody CORonavirus Assay (ABCORA), clinical and safety outcomes. Results: A total of 430 patients were randomized and 412 were included in the intention-to-treat analysis (341 HIV patients and 71 solid organ transplant recipients). Antibody response was for elasomeran 92.1% (95% CI 88.4-95.8%;186/202) and for tozinameran 94.3% (95% CI 91.2-97.4%;198/210;difference:-2.2%;95% CI-7.1-2.7%), fulfilling non-inferiority of elasomeran. Overall, neutralization activity to SARS-CoV-2 Wuhan HU-1 strain was estimated to 96.5% (95% CI 94.5-98.4%) in HIV patients and 21.1% (95% CI 11.6-30.6%) in solid organ transplant recipients. 5 SARS-CoV-2 infections occurred (3 elasomeran;2 tozinameran) and 18 serious adverse event occurred (9 elasomeran;9 tozinameran). Conclusion: In immunocompromised patients the antibody response of elasomeran was comparable to tozinameran. People living with HIV had in general a sufficient immune response while a high proportion of transplant recipients had no immune response. Nearly 80% of patients with solid organ transplant have not developed neutralizing activity and need booster vaccination.
ABSTRACT
Background: Never before have clinical trials drawn as much public attention as those testing interventions for COVID-19. We aimed to describe the worldwide COVID-19 clinical research response and its evolution over the first 100 days of the pandemic. Methods: Descriptive analysis of planned, ongoing or completed trials by April 9, 2020 testing any intervention to treat or prevent COVID-19, systematically identified in trial registries, preprint servers, and literature databases. A survey was conducted of all trials to assess their recruitment status up to July 6, 2020. Results: Most of the 689 trials (overall target sample size 396,366) were small (median sample size 120;interquartile range [IQR] 60-300) but randomized (75.8%;n=522) and were often conducted in China (51.1%;n=352) or the USA (11%;n=76). 525 trials (76.2%) planned to include 155,571 hospitalized patients, and 25 (3.6%) planned to include 96,821 health-care workers. Treatments were evaluated in 607 trials (88.1%), frequently antivirals (n=144) or antimalarials (n=112);78 trials (11.3%) focused on prevention, including 14 vaccine trials. No trial investigated social distancing. Interventions tested in 11 trials with >5,000 participants were also tested in 169 smaller trials (median sample size 273;IQR 90-700). Hydroxychloroquine alone was investigated in 110 trials. While 414 trials (60.0%) expected completion in 2020, only 35 trials (4.1%;3,071 participants) were completed by July 6. Of 112 trials with detailed recruitment information, 55 had recruited <20% of the targeted sample;27 between 20-50%;and 30 over 50% (median 14.8% [IQR 2.0-62.0%]). Conclusions: The size and speed of the COVID-19 clinical trials agenda is unprecedented. However, most trials were small investigating a small fraction of treatment options. The feasibility of this research agenda is questionable, and many trials may end in futility, wasting research resources. Much better coordination is needed to respond to global health threats.