Remdesivir in Hospitalized Covid-19 Patients: Individual Patient Data Meta-Analysis

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.

MODELING REMDESIVIR ANTIVIRAL EFFICACY in COVID-19 HOSPITALIZED PATIENTS

Background: Despite several clinical studies, the antiviral efficacy of remdesivir in COVID-19 hospitalized patients remains controversial. Methods: We analyzed nasopharyngeal normalized viral loads collected in the 29 days following randomization from 665 hospitalized patients included in the DisCoVeRy trial, allocated to either standard of care (SoC, N=329) or SoC + remdesivir for 10 days (N=336). We used a mathematical model to reconstruct viral kinetic profiles and estimate the antiviral efficacy of remdesivir in reducing viral production. To identify factors associated with viral kinetics, additional analyses were conducted stratified either on time of treatment initiation (≤ or > 7 days since symptom onset) or viral load at randomization (< or ≥ 3.5 log10 copies/104 cells). Results: In our model, remdesivir reduced viral production by 2-fold on average (95%CI: 1.5-3.2). Using the estimated parameter of the model, simulations predict that remdesivir reduces time to viral clearance by 0.7 day compared to SoC, with large inter-individual variabilities (Inter-Quartile Range, IQR: 0.0-1.3 days). Exploratory analyses suggest that remdesivir had a larger impact on patients with a high viral load at randomization, reducing viral production by 5-fold on average (95%CI: 2.8-25), leading to a predicted median reduction in the time to viral clearance of 2.4 days (IQR: 0.9-4.5 days). Conclusion: Our model shows that remdesivir reduces viral production from infected cells by a factor 2, leading to a median reduction of 0.7 days in the time to viral clearance compared to SoC. The efficacy was larger in patients with high level of viral load at treatment initiation.

Clinical trial protocols of repurposed prophylaxis for COVID-19: A review.

Efficient therapeutic strategies are needed to counter the COVID-19 pandemic, caused by the SARS-CoV-2 virus. In a context where specific vaccines are not yet available, the containment of the pandemic would be facilitated with efficient prophylaxis. We screened several clinical trials repositories and platforms in search of the prophylactic strategies being investigated against COVID-19 in July 2020. Up to July 5, 2020, only one clinical trial result was published, although we found 112 clinical trial protocols targeting medical workers (n=70, 63%), patients relatives (n=20, 18%) or individuals at risk of severe COVID-19 (n=14, 13%). (Hydroxy)chloroquine was the most frequently evaluated treatment (n=69, 62%), before BCG vaccine (n=12, 11%), this followed by numerous antivirals and immune enhancers. Ninety-eight (88%) clinical trials were randomized with a median of planned inclusions of 530 (IQR 258-1299). Both pre- and post-exposure prophylaxes are investigated.

Review of trials currently testing treatment and prevention of COVID-19.

BACKGROUND: As COVID-19 cases continue to rise globally, evidence from large randomized controlled trials is still lacking. Currently, numerous trials testing potential treatment and preventative options are being undertaken all over the world. OBJECTIVES: We summarized all registered clinical trials examining treatment and prevention options for COVID-19. Additionally, we evaluated the quality of the retrieved studies. DATA SOURCES: Clinicaltrials.gov, the Chinese Clinical Trial Registry and the European Union Clinical Trials Register were systematically searched. STUDY ELIGIBILITY CRITERIA: Registered clinical trials examining treatment and/or prevention options for COVID-19 were included. No language, country or study design restrictions were applied. We excluded withdrawn or cancelled studies and trials not reporting therapeutic or preventative strategies for COVID-19. PARTICIPANTS AND INTERVENTIONS: No restrictions in terms of participants' age and medical background or type of intervention were enforced. METHODS: The registries were searched using the term 'coronavirus' or 'COVID-19' from their inception until 26 March 2020. Additional manual search of the registries was also performed. Eligible studies were summarized and tabulated. Interventional trials were methodologically analysed, excluding expanded access studies and trials testing traditional Chinese medicine. RESULTS: In total, 309 trials evaluating therapeutic management options, 23 studies assessing preventive strategies and three studies examining both were retrieved. Finally, 214 studies were methodologically reviewed. Interventional treatment studies were mostly randomized (n = 150/198, 76%) and open label (n = 73/198, 37%) with a median number of planned inclusions of 90 (interquartile range 40-200). Major categories of interventions that are currently being investigated are discussed. CONCLUSIONS: Numerous clinical trials have been registered since the onset of the COVID-19 pandemic. Summarized data on these trials will assist physicians and researchers to promote patient care and guide future research efforts for COVID-19 pandemic containment.