Abstract: Open Access Original Article DOI: 10.7759/cureus.20572 Pre-exposure Prophylaxis With Various Doses of Hydroxychloroquine Among Healthcare Personnel With High-Risk Exposure to COVID-19: A Randomized Controlled Trial Review began 12/04/2021 Review ended 12/16/2021 Published 12/21/2021 © Copyright 2021 Syed et al. This is an open access article distributed under the terms of the Creative Fibhaa Syed 1 , Muhammad Hassan 2 , Mohammad Ali Arif 1 , Sadia Batool 1 , Rauf Niazi 1 , Ume E. Laila 1 , Sadia Ashraf 1 , Junaid Arshad 3 Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 1. Internal Medicine, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, PAK 2. Neurology, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, PAK 3. Cardiology, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, PAK Corresponding author: Muhammad Hassan, drhassaanshafqat2011@gmail.com Abstract Objective This trial aimed to evaluate the safety and efficacy of pre-exposure prophylaxis (PrEP) with various hydroxychloroquine (HCQ) doses against a placebo among healthcare personnel (HCP) with high-risk exposure to coronavirus disease 2019 (COVID 19). Methods A phase II, randomized, placebo-controlled trial was conducted including 200 subjects with no active or past severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (antibody testing and reverse transcription-polymerase chain reaction (RT-PCR) were taken at the time of enrollment). Subjects of experimental groups one to three received HCQ in various doses and the control group received a placebo. The study outcomes in terms of safety and efficacy were monitored. Participants exhibiting COVID-19 symptoms were tested for SARS-CoV-2 during the study and by the end of week 12 with RT-PCR or serology testing (COVID-19 IgM/IgG antibody testing). Results Out of the total participants, 146 reported exposure to a confirmed COVID-19 case in the first month, and 192 were exposed by week 12 of the study. Moreover, the precautionary use of personal protective equipment (PPE) significantly varied; initially more than 80% of the exposed HCPs were not ensuring PPE being used by the patients treated by them, which gradually developed over time. Mild treatment-related side effects were observed among the interventional and placebo arm patients. There was no significant clinical benefit of PrEP with HCQ as compared to placebo (p>0.05). Conclusion It is concluded that the PrEP HCQ does not significantly prevent COVID-19 among high-risk HCPs. Categories: Preventive Medicine, Infectious Disease Keywords: hydroxychloroquine., healthcare personnel, covid-19, pre-exposure prophylaxis, sars-cov-2