Treatment and prevention of early disease before and after exposure to COVID 19 using hydroxychloroquine: A protocol for exploratory re analysis of age and time nuanced effects: Update based on initial dataset review
Abstract BACKGROUND Three companion randomized pragmatic trials were recently published assessing the effect of hydroxychloroquine (HCQ) on pre exposure prophylaxis (PrEP "Rajasingham," NCT04328467) post exposure prophylaxis (PEP "Boulware," NCT04308668) and treatment of early COVID 19 "Skipper," NCT04308668) Respectively, they found non statistically significant reductions in development or persistence of COVID of 17% 27% and 20% and concluded that HCQ did not reduce, prevent or substantially treat COVID 19 illness. With a likely Type 2 error and over ambitious powering (50% effect) these effects may impact trajectory and resource models that drive decisions on lockdowns. All three studies have signals mostly found in the data appendices that suggest useful effects of HCQ in sub groups worthy of re analysis and prospective exploration. HCQ appeared to benefit younger rather than older patients in both the PrEP and PEP studies with respective reductions in COVID 19 of 45% and 36% There was a strong benefit (40% of HCQ in women (PrEP) Response to HCQ appeared to vary by type of exposure, with a large benefit (64% in first responders (PrEP) and in household contacts (31% PEP) Further confounding the data was the undefined, ex protocol use of zinc and ascorbic acid. INTERIM FINDINGS A major impediment in interpreting the PEP and treatment studies concerns the estimation of the time from exposure or symptom onset to treatment. Our initial analysis of the PEP study as published revealed a negative correlation between treatment lag and disease reduction, reaching 49% when HCQ was initiated within one day (RR 0.51, CI 0.176 1.46, p=0.249) However, our initial review (pursuant to this protocol, v1.1) of the publicly released PEP dataset revealed that, contrary to the study's conclusion, this four day period referred not to the time from exposure to treatment as we (and others) had understood, but to the time from exposure and enrollment, a difference of up to 3.5 days. Our re stratification of new data we had requested revealed that HCQ may reduce the development of COVID 19 by as much as 65% (RR 0.35, CI 0.13 0.93, p=0.044) when received within 3 days of exposure (RR 0.83 at 3 5 days; RR 1.37 at 5 7 days) There remains ambiguity in these estimates addressable by further data we have requested. This same issue appears shared by the Treatment study. Further, patients in the PEP study were likely exposed to a series, rather than a single, "index" exposure, an issue possibly shared with the PrEP study. In the treatment study, there may be a bimodal effect of responders and non responders, in whom symptoms may actually worsen. All three studies share the confounding effect of a possibly active folate placebo. OBJECTIVES To conduct a post hoc exploratory re analyses of the de identified raw datasets from randomized studies of the use of HCQ for pre and post exposure prophylaxis, and treatment of early of COVID 19 with view to further defining: (a) The time dependent effect of HCQ, on post exposure prophylaxis and treatment of COVID 19; (b) The age dependent effect of HCQ, on pre and post exposure prophylaxis and treatment of COVID 19; (c) The sub stratification of gender, time and age dependent effects by exposure type and risk level, as well as by the use of zinc and ascorbic acid; (d) The design of prospective clinical trials designed to test the hypotheses generated by this study. These analyses will be expanded should datasets from similarly designed Spanish studies involving PEP or treatment of (both NCT04304053) COVID 19, with directionally similar results, become available. This protocol was devised using the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) incorporating the WHO Trial Registration Data Set. Study Status: Protocol version 1.2 (September 27 2020) registered at: OSF Registries September 27 2020 https:/osf.io/fqtnw https:/doi.org/10.17605/OSF.IO/FQTNW First submitted to medrxiv 9/30/20 as version1.2a, with format revisions requested by medrxiv Supplemental file: Detailed background and rationale Wiseman2020Synechion2001 v1 2aReanalysisHydroxychloroquine092720medrxivREV2 SUPPL.pdf Plain Language Summary Three companion clinical studies from the University of Minnesota examined the effect of hydroxychloroquine (HCQ) when given to treat early cases of COVID 19 or to prevent it from occurring either before or just after exposure to someone with coronavirus. Although reductions in COVID 19 between 17% and 27% were found when HCQ was used before or just after exposure to COVID 19, because the studies had too few patients in them and because they were designed to find larger differences, these effects were not statistically significant, even though, they may have been clinically meaningful. Furthermore, larger reductions of COVID 19 were found within sub groups, reaching for example in one study 45% for younger patients In our initial review of the publicly released data from one of the studies, we discovered an issue that fundamentally alters its interpretation as well as one of its companion studies. According to their published reports, and understood by many others citing this work (including NIH) treatment with HCQ began within four days of either exposure or onset of symptoms. Because shipping schedules were not considered, this delay could have been 7.5 days and many patients may not have received drug in time to have an effect, if there was one. After we requested additional data, we found that HCQ may reduce COVID 19 by as much as 65% when given within 3 days of exposure and we have requested more data to clarify this figure further. We plan therefore to conduct a re analysis of all three studies to explore how the effects of HCQ, if any, might be dependent on time, age, gender, and type of exposure to COVID 19. This will enable us to conduct clinical studies to confirm or refute what we think we have learned from this work.