Abstract: Grau-Pujol et al. Trials (2021) 22:808 https://doi.org/10.1186/s13063-021-05758-9 RESEARCH Open Access Pre-exposure prophylaxis with hydroxychloroquine for COVID-19: a double-blind, placebo-controlled randomized clinical trial Berta Grau-Pujol1,2,3*† , Daniel Camprubí-Ferrer1†, Helena Marti-Soler1, Marc Fernández-Pardos1, Clara Carreras-Abad1, Maria Velasco-de Andrés1, Elisabet Ferrer1, Magdalena Muelas-Fernandez1, Sophie Jullien1, Giuseppe Barilaro1, Sara Ajanovic1, Isabel Vera1, Laura Moreno4, Eva Gonzalez-Redondo4, Núria Cortes-Serra1, Montserrat Roldán1, Ana Artes-de Arcos1, Isabel Mur5, Pere Domingo5, Felipe Garcia4,6, Caterina Guinovart1 and Jose Muñoz1 Abstract Background: Pre-exposure prophylaxis (PrEP) is a promising strategy to break COVID-19 transmission. Although hydroxychloroquine was evaluated for treatment and post-exposure prophylaxis, it is not evaluated for COVID-19 PrEP yet. The aim of this study was to evaluate the efficacy and safety of PrEP with hydroxychloroquine against placebo in healthcare workers at high risk of SARS-CoV-2 infection during an epidemic period. Methods: We conducted a double-blind placebo-controlled randomized clinical trial in three hospitals in Barcelona, Spain. From 350 adult healthcare workers screened, we included 269 participants with no active or past SARS-CoV-2 infection (determined by a negative nasopharyngeal SARS-CoV-2 PCR and a negative serology against SARS-CoV-2). Participants allocated in the intervention arm (PrEP) received 400 mg of hydroxychloroquine daily for the first four consecutive days and subsequently, 400 mg weekly during the study period. Participants in the control group followed the same treatment schedule with placebo tablets. Results: 52.8% (142/269) of participants were in the hydroxychloroquine arm and 47.2% (127/269) in the placebo arm. Given the national epidemic incidence decay, only one participant in each group was diagnosed with COVID19. The trial was stopped due to futility and our study design was deemed underpowered to evaluate any benefit regarding PrEP efficacy. Both groups showed a similar proportion of participants experiencing at least one adverse event (AE) (p=0.548). No serious AEs were reported. Almost all AEs (96.4%, 106/110) were mild. Only mild gastrointestinal symptoms were significantly higher in the hydroxychloroquine arm compared to the placebo arm (27.4% (39/142) vs 15.7% (20/127), p=0.041). * Correspondence: berta.grau@isglobal.org † Berta Grau-Pujol and Daniel Camprubí-Ferrer contributed equally to this work. 1 Barcelona Institute for Global Health (ISGlobal), Hospital Clínic - University of Barcelona, Rosselló 132 4rt 1a, 08036 Barcelona, Spain 2 Centro de Investigação em Saúde de Manhiça (CISM), Maputo, Mozambique Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not..