Rethinking remdesivir for COVID-19: A Bayesian reanalysis of trial findings.
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ABSTRACT: Background
Following testing in clinical trials, the use of remdesivir for treatment of COVID-19 has been authorized for use in parts of the world, including the USA and Europe. Early authorizations were largely based on results from two clinical trials. A third study published by Wang et al. was underpowered and deemed inconclusive. Although regulators have shown an interest in interpreting the Wang et al. study, under a frequentist framework it is difficult to determine if the non-significant finding was caused by a lack of power or by the absence of an effect. Bayesian hypothesis testing does allow for quantification of evidence in favor of the absence of an effect.Findings
Results of our Bayesian reanalysis of the three trials show ambiguous evidence for the primary outcome of clinical improvement and moderate evidence against the secondary outcome of decreased mortality rate. Additional analyses of three studies published after initial marketing approval support these findings.Conclusions
We recommend that regulatory bodies take all available evidence into account for endorsement decisions. A Bayesian approach can be beneficial, in particular in case of statistically non-significant results. This is especially pressing when limited clinical efficacy data is available.
SUBMITTER: Hoek JM
PROVIDER: S-EPMC8301659 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC8922517 | biostudies-literature
Project description:The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused the Coronavirus Disease 2019 (COVID-19) worldwide pandemic in 2020. In response, most countries in the world implemented lockdowns, restricting their population's movements, work, education, gatherings, and general activities in attempt to "flatten the curve" of COVID-19 cases. The public health goal of lockdowns was to save the population from COVID-19 cases and deaths, and to prevent overwhelming health care systems with COVID-19 patients. In this narrative review I explain why I changed my mind about supporting lockdowns. The initial modeling predictions induced fear and crowd-effects (i.e., groupthink). Over time, important information emerged relevant to the modeling, including the lower infection fatality rate (median 0.23%), clarification of high-risk groups (specifically, those 70 years of age and older), lower herd immunity thresholds (likely 20-40% population immunity), and the difficult exit strategies. In addition, information emerged on significant collateral damage due to the response to the pandemic, adversely affecting many millions of people with poverty, food insecurity, loneliness, unemployment, school closures, and interrupted healthcare. Raw numbers of COVID-19 cases and deaths were difficult to interpret, and may be tempered by information placing the number of COVID-19 deaths in proper context and perspective relative to background rates. Considering this information, a cost-benefit analysis of the response to COVID-19 finds that lockdowns are far more harmful to public health (at least 5-10 times so in terms of wellbeing years) than COVID-19 can be. Controversies and objections about the main points made are considered and addressed. Progress in the response to COVID-19 depends on considering the trade-offs discussed here that determine the wellbeing of populations. I close with some suggestions for moving forward, including focused protection of those truly at high risk, opening of schools, and building back better with a economy.
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Project description:Gautret and colleagues reported the results of a non-randomised case series which examined the effects of hydroxychloroquine and azithromycin on viral load in the upper respiratory tract of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients. The authors reported that hydroxychloroquine (HCQ) had significant virus reducing effects, and that dual treatment of both HCQ and azithromycin further enhanced virus reduction. In light of criticisms regarding how patients were excluded from analyses, we reanalysed the original data to interrogate the main claims of the paper. We applied Bayesian statistics to assess the robustness of the original paper's claims by testing four variants of the data: 1) The original data; 2) Data including patients who deteriorated; 3) Data including patients who deteriorated with exclusion of untested patients in the comparison group; 4) Data that includes patients who deteriorated with the assumption that untested patients were negative. To ask if HCQ monotherapy was effective, we performed an A/B test for a model which assumes a positive effect, compared to a model of no effect. We found that the statistical evidence was highly sensitive to these data variants. Statistical evidence for the positive effect model ranged from strong for the original data (BF+0 ~11), to moderate when including patients who deteriorated (BF+0 ~4.35), to anecdotal when excluding untested patients (BF+0 ~2), and to anecdotal negative evidence if untested patients were assumed positive (BF+0 ~0.6). The fact that the patient inclusions and exclusions are not well justified nor adequately reported raises substantial uncertainty about the interpretation of the evidence obtained from the original paper.
| S-EPMC7894854 | biostudies-literature
Project description:Remdesivir (Veklury®), a nucleotide analogue prodrug with broad-spectrum antiviral activity, is approved for the treatment of coronavirus disease 2019 (COVID-19), the illness caused by severe acute respiratory syndrome coronavirus 2 infection. Unlike some antivirals, remdesivir has a low potential for drug-drug interactions. In the pivotal ACTT-1 trial in hospitalized patients with COVID-19, daily intravenous infusions of remdesivir significantly reduced time to recovery relative to placebo. Subsequent trials provided additional support for the efficacy of remdesivir in hospitalized patients with moderate or severe COVID-19, with a greater benefit seen in patients with minimal oxygen requirements at baseline. Clinical trials also demonstrated the efficacy of remdesivir in other patient populations, including outpatients at high risk for progression to severe COVID-19, as well as hospitalized paediatric patients. In terms of mortality, results were equivocal. However, remdesivir appeared to have a small mortality benefit in hospitalized patients who were not already being ventilated at baseline. Remdesivir was generally well tolerated in clinical trials, but pharmacovigilance data found an increased risk of hepatic, renal and cardiovascular adverse drug reactions in the real-world setting. In conclusion, remdesivir represents a useful treatment option for patients with COVID-19, particularly those who require supplemental oxygen.
| S-EPMC10474216 | biostudies-literature
Project description:Human coronaviruses (HCoV) were discovered in the 1960s and were originally thought to cause only mild upper respiratory tract diseases in immunocompetent hosts. This view changed since the beginning of this century, with the 2002 SARS (severe acute respiratory syndrome) epidemic and the 2012 MERS (Middle East respiratory syndrome) outbreak, two zoonotic infections that resulted in mortality rates of approximately 10% and 35%, respectively. Despite the importance of these pathogens, no approved antiviral drugs for the treatment of human coronavirus infections became available. However, remdesivir, a nucleotide analogue prodrug originally developed for the treatment of Ebola virus, was found to inhibit the replication of a wide range of human and animal coronaviruses in vitro and in preclinical studies. It is therefore not surprising that when the highly pathogenic SARS-CoV-2 coronavirus emerged in late 2019 in China, causing global health concern due to the virus strong human-to-human transmission ability, remdesivir was one of the first clinical candidates that received attention. After in vitro studies had shown its antiviral activity against SARS-CoV-2, and a first patient was successfully treated with the drug in the USA, a number of trials on remdesivir were initiated. Several had encouraging results, particularly the ACTT-1 double blind, randomized, and placebo controlled trial that has shown shortening of the time to recovery in hospitalized patients treated with remdesivir. The results of other trials were instead negative. Here, we provide an overview of remdesivir discovery, molecular mechanism of action, and initial and current clinical studies on its efficacy.
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Project description:ObjectivesTo perform a Bayesian reanalysis of a recent trial of psilocybin (COMP360) versus escitalopram for Major Depressive Disorder (MDD) in order to provide a more informative interpretation of the indeterminate outcome of a previous frequentist analysis.DesignReanalysis of a two-arm double-blind placebo controlled trial.ParticipantsFifty-nine patients with MDD.InterventionsTwo doses of psilocybin 25mg and daily oral placebo versus daily escitalopram and 2 doses of psilocybin 1mg, with psychological support for both groups.Outcome measuresQuick Inventory of Depressive Symptomatology-Self-Report (QIDS SR-16), and three other depression scales as secondary outcomes: HAMD-17, MADRS, and BDI-1A.ResultsUsing Bayes factors and 'skeptical priors' which bias estimates towards zero, for the hypothesis that psilocybin is superior by any margin, we found indeterminate evidence for QIDS SR-16, strong evidence for BDI-1A and MADRS, and extremely strong evidence for HAMD-17. For the stronger hypothesis that psilocybin is superior by a 'clinically meaningful amount' (using literature defined values of the minimally clinically important difference), we found moderate evidence against it for QIDS SR-16, indeterminate evidence for BDI-1A and MADRS, and moderate evidence supporting it for HAMD-17. Furthermore, across the board we found extremely strong evidence for psilocybin's non-inferiority versus escitalopram. These findings were robust to prior sensitivity analysis.ConclusionsThis Bayesian reanalysis supports the following inferences: 1) that psilocybin did indeed outperform escitalopram in this trial, but not to an extent that was clinically meaningful--and 2) that psilocybin is almost certainly non-inferior to escitalopram. The present results provide a more precise and nuanced interpretation to previously reported results from this trial, and support the need for further research into the relative efficacy of psilocybin therapy for depression with respect to current leading treatments.Trial registration numberNCT03429075.
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Project description: Not available
| S-EPMC8406992 | biostudies-literature
Project description:BackgroundImmunocompromised patients are at high risk of severe COVID-19 and death, yet treatment strategies for immunocompromised patients hospitalized for COVID-19 reflect variations in clinical practice. This comparative effectiveness study investigated the effect of remdesivir treatment on inpatient mortality among immunocompromised patients hospitalized for COVID-19 across all variants of concern (VOC) periods.MethodsData for immunocompromised patients hospitalized for COVID-19 between December 2020 and April 2022 were extracted from the US PINC AI Healthcare Database. Patients initiating remdesivir within two days of hospitalization were matched 1:1 using propensity score matching with replacement to patients who did not receive remdesivir during their hospitalization for COVID-19. Additional matching criteria included admission month, age group, and hospital. Cox Proportional Hazards models were used to examine the effect of remdesivir on risk of 14- and 28-day mortality during VOC periods.ResultsA total of 19,184 remdesivir patients were matched to 11,213 non-remdesivir patients. Overall, 11.1% and 17.7% of remdesivir patients died within 14 and 28 days, respectively, compared with 15.4% and 22.4% of non-remdesivir patients. Remdesivir was associated with a reduction in mortality at 14 days (hazard ratio [95% confidence interval]: 0.70 [0.62-0.78]) and 28 days (0.75 [0.68-0.83]). Survival benefit remained significant during the Pre-Delta, Delta, and Omicron time-periods.ConclusionsPrompt initiation of remdesivir in immunocompromised patients hospitalized for COVID-19 is associated with significant survival benefit across all variant waves. These findings provide much-needed evidence relating to the effectiveness of a foundational treatment for hospitalized COVID-19 patients among a high-risk population.
| S-EPMC10724457 | biostudies-literature