Pooled evidence precision of clinical trials on hydroxychloroquine for Covid-19 treatment was stabilized eight months after the outbreak

Abstract

ABSTRACTOBJECTIVEAt the beginning of 2020, hydroxychloroquine showed promisingin vitroactivity for Covid-19 and several studies were oriented to assess its safety and efficacy. However, after a few months, hydroxychloroquine has proved ineffective. The randomized controlled trials (RCTs) developed quickly and in different settings represent the scientific community’s capacity to assess drug repositioning effectiveness during a sanitary crisis. Therefore, a critical evaluation of the evidence generated can guide future efforts in analogous situations. We aimed to analyze the RCTs assessing the efficacy of hydroxychloroquine in treating Covid-19, describe their internal validity and power, and evaluate their contribution to the precision of the combined evidence for assessing the mortality outcome.STUDY DESIGN AND SETTINGSThis meta-research included RCTs assessing hydroxychloroquine to treat patients diagnosed with Covid-19. It was part of an umbrella systematic review of methods/meta-research (PROSPERO: CRD42022360331) that included a comprehensive search in MEDLINE, EMBASE, Cochrane Library, and the Latin America Database - Lilacs. We retrieved studies published until January 10th, 2022. The risk of bias was assessed using Risk of Bias (RoB) 2.0. We analyzed methodology of the studies, precision and random error change through time from pooled evidence, study comparators, patient important outcome, power in different magnitude of effects proxy.RESULTSA total of 22 RCT were included, from that 17 (77%) assessed hospitalized patients and five (23%) outpatients setting. Mortality was related as primary endpoint in only 4 studies, however half of the studies included composite endpoints including mortality as a component. The internal validity analysis using RoB2 found that eight studies (36%) had a high risk of bias. Only one study had sufficient power to evaluate a moderate magnitude of effect (RR = 0,7 on mortality). The standard error to evaluate efficacy on mortality did not change appreciably after October 2020. From Oct 2020 to Dec 2021, 18 additional studies were published with 2,429 patients recruited.CONCLUSIONThis meta-research highlights the impact that collaborative, and network scientific research have on informing clinical decision-making. Duplicate efforts create research waste as precision analysis shows that after October 2020, there was not appreciably changes in the precision of the pooled RCT evidence to estimate the hydroxychloroquine effect on mortality.What is new?After Oct2020, grouped RCT on the use of hydroxychloroquine in Covid-19 showed that precision estimate has not been appreciably modified in subsequent studies.At least 18 RCT (n=2,429) could potentially be saved through collaborative work.Most individual studies did not have sufficient power to assess the size of moderate effect size on mortality.Strengthening cooperation and integrating research centers can decrease research waste.