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0 0.5 1 1.5 2+ Hospitalization, COVID-19 50% Improvement Relative Risk Hospitalization, all cause 39% Case 27% HCQ  COVID PREP  Prophylaxis  RCT Is pre-exposure prophylaxis with HCQ beneficial for COVID-19? RCT 1,483 patients in the USA (April - July 2020) Trial compares with folic acid, results vs. placebo may differ Fewer cases with HCQ (not stat. sig., p=0.12) Rajasingham et al., medRxiv, September 2020 Favors HCQ Favors folic acid

Hydroxychloroquine as pre-exposure prophylaxis for COVID-19 in healthcare workers: a randomized trial

Rajasingham et al., medRxiv, doi:10.1101/2020.09.18.20197327, COVID PREP, NCT04328467
Sep 2020  
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PrEP RCT showing HR 0.73, p = 0.12. Trial halted after 47% enrollment, p < 0.05 will be reached at ~75% enrollment if similar results continue.
HR 0.66/0.68 for full medication adherence, 0.72/0.74, p = 0.18/0.22 overall (1x/2x dosing). Efficacy for first responders was higher, OR 0.32, p = 0.01. First responders had a much higher incidence, allowing greater power, and reducing the effect of confounders such as misdiagnosis of other conditions or survey issues.
Performance is similar to the control arm for the first 3 weeks. The effect may be greater with a dosage regimen that achieves therapeutic levels faster ~40% of participants suspected they might have had COVID-19 before the trial, the effect in people without prior COVID-19 may be higher.
Research shows the treatment used in the control arm (folic acid) may have significant efficacy for COVID-19 Deschasaux-Tanguy, Farag, so the true effectiveness of HCQ may be higher than observed. Also see
Authors note:
- the trial was underpowered
- investigation into more frequent dosing may be warranted
- insufficient dosing with no participants achieving more than the in vitro EC50
Internet survey RCT subject to survey bias. There were no deaths or ICU admissions. Low risk healthcare workers, median age ~40. 494 1x/week dosing, 495 2x/week dosing, 494 control participants (1x and 2x participants received the same overall dosage). COVID PREP. NCT04328467 (history).
risk of hospitalization, 50.1% lower, RR 0.50, p = 1.00, treatment 1 of 989 (0.1%), control 1 of 494 (0.2%), NNT 987, COVID-19.
risk of hospitalization, 39.0% lower, RR 0.61, p = 0.34, treatment 11 of 989 (1.1%), control 9 of 494 (1.8%), NNT 141, all cause.
risk of case, 27.0% lower, HR 0.73, p = 0.12, treatment 58 of 989 (5.9%), control 39 of 494 (7.9%), NNT 49.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Rajasingham et al., 21 Sep 2020, Randomized Controlled Trial, USA, peer-reviewed, 22 authors, study period 6 April, 2020 - 13 July, 2020, this trial compares with another treatment - results may be better when compared to placebo, trial NCT04328467 (history) (COVID PREP).
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This PaperHCQAll
Hydroxychloroquine as Pre-exposure Prophylaxis for Coronavirus Disease 2019 (COVID-19) in Healthcare Workers: A Randomized Trial
Radha Rajasingham, Ananta S Bangdiwala, Melanie R Nicol, Caleb P Skipper, Katelyn A Pastick, Margaret L Axelrod, Matthew F Pullen, Alanna A Nascene, Darlisha A Williams, Nicole W Engen, Elizabeth C Okafor, Brian I Rini, Ingrid A Mayer, Emily G Mcdonald, Todd C Lee, Peter Li, Lauren J Mackenzie, Justin M Balko, Stephen J Dunlop, Katherine H Hullsiek, David R Boulware, Sarah M Lofgren, Mahsa Abassi, Andrew Balster, Lindsey B Collins, Glen Drobot, Douglas S Krakower, Sylvain A Lother, Dylan S Mackay, Cameron Meyer-Mueller, Stephen Selinsky, Dayna Solvason, Ryan Zarychanski, Rebecca Zash
Clinical Infectious Diseases, doi:10.1093/cid/ciaa1571
Background. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly emerging virus causing the ongoing coronavirus disease 2019 (COVID-19) pandemic with no known effective prophylaxis. We investigated whether hydroxychloroquine could prevent SARS-CoV-2 in healthcare workers at high risk of exposure. Methods. We conducted a randomized, double-blind, placebo-controlled clinical trial of healthcare workers with ongoing exposure to persons with SARS-CoV-2, including those working in emergency departments, intensive care units, COVID-19 hospital wards, and first responders. Participants across the United States and in the Canadian province of Manitoba were randomized to hydroxychloroquine loading dose then 400 mg once or twice weekly for 12 weeks. The primary endpoint was confirmed or probable COVID-19-compatible illness. We measured hydroxychloroquine whole-blood concentrations. Results. We enrolled 1483 healthcare workers, of whom 79% reported performing aerosol-generating procedures. The incidence of COVID-19 (laboratory-confirmed or symptomatic compatible illness) was 0.27 events/person-year with once-weekly and 0.28 events/person-year with twice-weekly hydroxychloroquine compared with 0.38 events/person-year with placebo. For once-weekly hydroxychloroquine prophylaxis, the hazard ratio was .72 (95% CI, .44-1.16; P = .18) and for twice-weekly was .74 (95% CI, .46-1.19; P = .22) compared with placebo. Median hydroxychloroquine concentrations in whole blood were 98 ng/mL (IQR, 82-120) with onceweekly and 200 ng/mL (IQR, 159-258) with twice-weekly dosing. Hydroxychloroquine concentrations did not differ between participants who developed COVID-19-compatible illness (154 ng/mL) versus participants without COVID-19 (133 ng/mL; P = .08). Conclusions. Pre-exposure prophylaxis with hydroxychloroquine once or twice weekly did not significantly reduce laboratoryconfirmed COVID-19 or COVID-19-compatible illness among healthcare workers. clinical Trials Registration. NCT04328467.
Supplementary Data Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author. Notes
Abella, Jolkovsky, Biney, Efficacy and safety of hydroxychloroquine vs placebo for pre-exposure SARS-CoV-2 prophylaxis among health care workers: a randomized clinical trial, JAMA Intern Med, doi:10.1001/jamainternmed.2020.6319
Al-Kofahi, Jacobson, Boulware, Finding the dose for hydroxychloroquine prophylaxis for COVID-19: the desperate search for effectiveness, Clin Pharmacol Ther, doi:10.1002/cpt.1874
Borba, Val, Sampaio, Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial, JAMA Netw Open
Boulware, Pullen, Bangdiwala, A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19, N Engl J Med
Fan, Zhang, Liu, Connecting hydroxychloroquine in vitro antiviral activity to in vivo concentration for prediction of antiviral effect: a critical step in treating COVID-19 patients, Clin Infect Dis, doi:10.1093/cid/ciaa623
Harris, Taylor, Minor, The REDCap consortium: building an international community of software platform partners, J Biomed Inform
Kucirka, Lauer, Laeyendecker, Boon, Lessler, Variation in falsenegative rate of reverse transcriptase polymerase chain reaction-based SARS-CoV-2 tests by time since exposure, Ann Intern Med
Lancet, Expression of concern: hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis, Lancet
Lim, Im, Cho, Pharmacokinetics of hydroxychloroquine and its clinical implications in chemoprophylaxis against malaria caused by Plasmodium vivax, Antimicrob Agents Chemother
Liu, Cao, Xu, Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, Cell Discov
Magagnoli, Narendran, Pereira, Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19, doi:10.1016/j.medj.2020.06.001
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Prevention, Interim, for healthcare personnel with potential exposure to COVID-19
Qu, Brady, Apilado, Capillary blood collected on volumetric absorptive microsampling (VAMS) device for monitoring hydroxychloroquine in rheumatoid arthritis patients, J Pharm Biomed Anal
Rathi, Ish, Kalantri, Kalantri, Hydroxychloroquine prophylaxis for COVID-19 contacts in India, Lancet Infect Dis, doi:10.1016/S1473-3099(20)30313-3
Skipper, Pastick, Engen, Hydroxychloroquine in nonhospitalized adults with early COVID-19: a randomized trial, Ann Intern Med, doi:10.7326/M20-4207
Tett, Cutler, Day, Brown, A dose-ranging study of the pharmacokinetics of hydroxy-chloroquine following intravenous administration to healthy volunteers, Br J Clin Pharmacol
The, Group, Effect of hydroxychloroquine in hospitalized patients with COVID-19, N Engl J Med, doi:10.1056/NEJMoa2022926
Vincent, Bergeron, Benjannet, Chloroquine is a potent inhibitor of SARS coronavirus infection and spread, Virol J
Wang, Cao, Zhang, Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res
Yao, Ye, Zhang, In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Clin Infect Dis
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