Effective post-exposure prophylaxis of Covid-19 associated with hydroxychloroquine: Prospective dataset re-analysis incorporating novel, missing data

BACKGROUND A key trial ([NCT04308668][1]) of post-exposure prophylaxis found hydroxychloroquine-associated (HCQ) reductions of Covid-19 by 17% overall and 31% to 49% in subgroups. To understand these trends, we re-analyzed the dataset. METHODS Our protocol conformed to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT). We compared the incidence of Covid-19 after HCQ or placebo, stratifying by intervention lag, age, and gender. RESULTS Newly requested data missing from the dataset revealed that 52% and 19% of subjects received medication 1-2 days after intended and assumed overnight delivery or four-day intervention lag respectively. After re-analysis, we found reduced HCQ-associated incidence of Covid-19 with Early (up to 3 days post-exposure) (RR 0.58, 95%CI 0.35 - 0.97; p =0.044; NNT 14.5) but not Late (RR 1.22, 95%CI 0.72 - 2.04) prophylaxis. We found a significant HCQ-associated Covid-19 reduction in subjects 18 to 45 years old with Early (RR 0.54, 95%CI 0.29-0.97; p =0.0448, NNT 11.5) but not Late (RR 1.02, 95%CI 0.55-1.89) prophylaxis, attenuated in older subjects (RR 0.75, 95%CI 0-27-2.05) and by co-morbidities. Although, we did not detect effects of gender, folate, zinc, or ascorbate, confounding effects cannot be excluded. CONCLUSIONS Using novel data and prospective re-analysis, hydroxychloroquine, in an age-dependent manner, was associated with reduced Covid-19 compatible illness when supplied for post-exposure prophylaxis between 1 and 3 days after high- or moderate-risk exposure, at higher loading and maintenance doses than in similar studies. The original study conclusions are controverted, and our finding warrants prospective confirmation. Protocol registered at Open Science Framework: [osf.io/fqtnw][2] (last revised September 27, 2020, Highlights ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT04308668 ### Clinical Protocols ### Funding Statement There is no external support for this study. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: No IRB approval was required for this work. This is a re-analysis of a de-identified, publicly released dataset obtained from an IRB-supervised study. Additional requested data were de-identified data and provided after we had been advised that the Privacy Officer of the University of Minnesota would be consulted to ensure regulatory compliance. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Microsoft Excel files will be available on reasonable request up to one year after publication to qualified investigators subject to an agreed upon data sharing agreement. The source dataset is available from the original authors. * HCQ : Hydroxychloroquine (and its salts) HCW : Health Care Worker ITT : Intent to Treat mITT : Modified Intent to Treat NNT : Number Needed to Treat PCR : Polymerase Chain Reaction PEP : Post-Exposure Prophylaxis PET : Post Exposure Treatment PPE : Personal Protective Equipment PrEP : Pre-Exposure prophylaxis RCT : Randomized Clinical Trial [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04308668&atom=%2Fmedrxiv%2Fearly%2F2021%2F07%2F05%2F2020.11.29.20235218.atom [2]: http://osf.io/fqtnw