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 COVID- 19. 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 permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Grau-Pujol et al. Trials (2021) 22:808 Page 2 of 10 Conclusions: Although the efficacy of PrEP with hydroxychloroquine for preventing COVID-19 could not be evaluated, our study showed that PrEP with hydroxychloroquine at low doses is safe. Trial registration: ClinicalTrials.gov NCT04331834. Registered on April 2, 2020. Keywords: Hydroxychloroquine, COVID-19, Pre-exposure prophylaxis, Prevention, Health-care workers, Control, SARS-CoV-2 Background and Medical Products (AEMPS). It was registered at The novel severe acute respiratory syndrome coronavirus clinicaltrials.gov (NCT04331834) on April 2, 2020. 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19) [1]. Currently, the worldwide Participants prevention strategies for SARS-CoV-2 infection are We recruited healthcare workers from three hospitals in vaccines, although self-protection equipment use, hand Barcelona, Spain, (Hospital Clínic, Hospital de la Santa washing, case identification, case isolation, contact tracing, Creu i Sant Pau and Hospital Plató). and exposed people quarantine of close contacts are still We included adult healthcare workers working at least recommended [2–4]. However, vaccines were still under 3 days a week in a trial hospital with a negative result of development at the time of the trial. In these circum- SARS-CoV-2 polymerase chain reaction (PCR) assay in stances, secondary attack rate estimates of COVID-19 nasopharyngeal swab within 4 days before enrolment. ranged from 3 to 15% in the community [5–7], which can Serological testing to detect antibodies against SARS- reach 26% in healthcare professionals [8]. Prevention of CoV-2 was evaluated in all candidates with a rapid healthcare workers’ infection is crucial for protecting the diagnostic test (VivadiagTM COVID-19 IgM/IgG Rapid workforce during pandemic management. Pre-exposure Test©, Hangzhou, China) and confirmed with Enzyme- prophylaxis (PrEP) is a promising strategy, which proved Linked ImmunoSorbent Assays (VITROS Anti-SARS- effective in preventing other infectious diseases such as CoV-2 Total© Ortho-Clinical Diagnostics, 2020). Those HIV [9]. Thus, several trials with repurposed drugs to individuals with a positive COVID-19 serological testing evaluate PrEP effectiveness in mitigating SARS-CoV-2 by any method were excluded. Participants with any of transmission are under development [10–12]. the following conditions were also excluded: pregnancy, Chloroquine was observed to effectively inhibit SARS- breastfeeding, ongoing antiviral, antiretroviral or cortico- CoV-2 in vitro [13, 14]. Its derivate, hydroxychloroquine, steroids treatment, chloroquine or hydroxychloroquine shows a better in vitro antiviral activity and safety profile intake the last month, or any contraindication to [15, 16]. Hydroxychloroquine potentially inhibits entry hydroxychloroquine. and post-entry stages of SARS-CoV-2 [13, 15]. While hydroxychloroquine was evaluated for the treatment of Intervention and comparator SARS-CoV-2 pneumonia and post-exposure prophylaxis, Randomization was generated using a computer random it is not evaluated for PrEP yet. The aim of this study is number generator. We used sequentially numbered to compare the efficacy and safety of PrEP with hydroxy- sealed envelopes of identical appearance containing ei- chloroquine against placebo in healthcare workers in ther hydroxychloroquine or placebo, ensuring allocation reducing the risk of COVID-19 disease during an concealment. Participants allocated to the intervention epidemic period. arm (PrEP) received 400 mg of hydroxychloroquine (two tablets of 200 mg) daily the first four consecutive days, Methods followed by 400 mg weekly during the study period, ini- Trial design tially scheduled to be 6 months. Participants in the con- We conducted a multicentre double-blind, placebo- trol group followed the same treatment schedule with controlled randomized clinical trial. We allocated partici- placebo tablets that were indistinguishable from hydro- pants to one of the two study arms in a 1:1 ratio by simple xychloroquine tablets. randomization. Randomization list was generated prior to Participants took the first two tablets at the recruit- enrolment. The trial protocol was described elsewhere [17]. ment visit under direct observation by a physician, who Screening of candidates was initiated on April 3, 2020, then provided the needed tablets to complete the first and the first recruitment was on April 4, 2020. month of treatment. This trial was approved by the Drug Research Ethics Participants, investigators assessing participant eligibil- Committee of the Hospital Clinic of Barcelona (CEIm), ity and recruitment, assessing outcomes and follow-up, Barcelona, Spain, and the Spanish Agency of Medicines and/or dealing with data management and analysis were Grau-Pujol et al. Trials (2021) 22:808 Page 3 of 10 all blinded to arm allocation. Only one person unrelated during the participant’s follow-up visits with a standard- to participant recruitment and follow-up, clinical assist- ized CRF for each participant, performing an electrocar- ance, data management, and analysis had access to this diogram to evaluate possible cardiac rhythm alterations information. and if they contacted the provided phone number for as- sistance. AEs were recorded in a specific adverse event Outcome reporting form and were measured based on the ICH- The primary outcome was the incidence of COVID-19 GCP guidelines, determining the severity of the event, confirmed cases (defined by compatible symptoms with the relationship to study intervention, and expectedness COVID-19 with seroconversion or a positive PCR for of the adverse event. All these classifications were per- SARS-CoV-2) in the hydroxychloroquine arm compared formed by blinded physicians unaware of the trial arm to the placebo arm at any time during the study follow- assignments. up. Medical assistance was ensured for all participants di- The secondary outcomes included (i) the SARS-CoV-2 agnosed with SARS-CoV-2 infection following hospital seroconversion in the hydroxychloroquine group com- guidelines. pared to the placebo group in both asymptomatic and Although the protocol was designed to follow partici- symptomatic participants; (ii) the occurrence of any ad- pants for 6 months, this manuscript only includes partic- verse event (AE) related with hydroxychloroquine treat- ipants’ first-month analysis. ment; (iii) the incidence of SARS-CoV-2 infection and COVID-19 in healthcare workers in the placebo group Sample size during the study period; and (iv) the risk ratio for the We estimated sample size assuming an expected inci- different clinical, analytical and microbiological condi- dence of 10% of COVID-19 in healthcare workers in the tions to develop COVID-19. control group and 2% in the hydroxychloroquine group, with a hazard ratio of 0.2. Thus, we required a total of Participant’s follow-up 440 subjects (220 per group) for a significance level of Passive and active surveillance was conducted on all 5%, statistical power of 90%, and assuming a rate of lost- participants to detect SARS-CoV-2 infections and any to-follow-up of 10% [18]. AE. Active surveillance of each participant was conducted Interim analysis monthly by blinded physicians unaware of the trial arm Interim analyses of the efficacy and safety of hydroxy- assignments, which completed a standardized case chloroquine were planned monthly, with the option of report form (CRF) for each participant. Follow-up visits early stopping the trial for futility. We planned to re- included (i) assessment of compliance with PrEP; (ii) estimate incidence and lost to follow-up rate at the first physical examination and detailed evaluation of symp- month, since these data were unknown when we esti- toms to either detect past and current symptoms and mated sample size. After the first interim analysis, the signs related to COVID-19, as well as possible adverse trial was halted on the basis of a very low incidence rate events; (iii) venepuncture for blood determinations, among study participants. Thus, results were only pro- including SARS-CoV-2 serology test (VITROS Anti- vided for the first month. SARS-CoV-2 Total© Ortho-Clinical Diagnostics, 2020); (iv) assessment of COVID-19 risk factors such as known Statistical analysis close contacts with suspected and/or confirmed COVID- We conducted an intention-to-treat analysis, with all pa- 19 cases or the number of weeks during which they were tients fulfilling inclusion criteria and not presenting ex- managing COVID-19 patients; (v) standardized ques- clusion criteria. Categorical variables were expressed as tions to collect past and current common side effects absolute frequency and percentage and were compared along with open free text; and (vi) electrocardiogram to with Fisher’s exact test. Continuous variables were evaluate possible cardiac rhythm alterations. expressed as mean and standard deviation (SD) or me- During this study period, a medical doctor was avail- dian and interquartile range (IQR). We conducted all able by phone 24 h a day for passive surveillance. All analyses with R [19]. participants were provided with this contact number in case of presenting any COVID-19 related symptom or Results AE. In that instance, a standardized CRF was filled out Participants to collect the information. A nasopharyngeal swab was Screening performed on all those participants presenting with We assessed 350 healthcare workers for eligibility; 269 COVID-19-related symptoms to detect SARS-CoV-2 in- of them fulfilled the study criteria and were recruited fection by PCR. Adverse events were thus assessed after signing the informed consent form. Participants Grau-Pujol et al. Trials (2021) 22:808 Page 4 of 10 were randomly assigned to the hydroxychloroquine studied risk factors were similar between groups. Table 2 group (n= 142, 52.8%) and to the placebo group (n= describes participants’ risk factors for COVID-19 127, 47.2%). The trial had to be stopped due to the low exposure. recruitment rate, and the estimated sample size was not Included participants did not present any relevant reached. Figure 1 describes participants’ enrolment and abnormality in the blood test (Table 3) neither in the randomization. electrocardiogram. Median QTc did not differ between The participants’ demographic characteristics are groups (383 ms [IQR: 357–400] in the hydroxychloro- shown in Table 1. The trial included 197/269 (73.2%) fe- quine group and 384 ms [IQR: 368–405] in the placebo male participants and the median age was 39 years [IQR: group). 30–50]. Eighty-three (30.9%) had some underlying med- ical condition and 74 (25.5%) were under chronic Withdrawal and lost to follow-up treatment. On June 12th, a total of 253 (94.1%) participants had Almost half of the recruited individuals (44.6%, 120/ completed the first month of follow-up. In the hydroxy- 269) were medical doctors. 33.1% referred contact with chloroquine group, 137 (96.5%) completed follow-up at at least one confirmed or probable COVID-19 case first month. The reasons for no completion were with- without wearing a mask, 34.6% (44/127) in the hydroxy- drawal of consent (n=1, 0.7%), AEs (n=1, 0.7%), and chloroquine, and 30.2% (43/142) in the placebo group others (n=3, 2.1%). In the placebo group, 116 (91.3%) (p value=0.526). From them, the median number of completed the course of prophylaxis. Their reasons of contacts per participant was 2.5 [IQR: 2–3]. Partici- no completion were withdrawal of consent (n=3, 2.4%), pants were living with a median number of 2 co- participant unable to receive study drug as per protocol habitants [IQR: 1–3] and 28.3% (76/269) of the (n=1, 0.8%), AEs (n=5, 3.9%), SARS-CoV-2 infection participants were living with healthcare workers. All (n=1, 0.8%), and others (n=1, 0.8%) (Fig. 1). Fig. 1 Flow diagram of trial participants at screening, recruitment, and follow-up Grau-Pujol et al. Trials (2021) 22:808 Page 5 of 10 Table 1 Participants’ baseline characteristics for both the hydroxychloroquine and placebo group Placebo Hydroxychloroquine (n = 127) (n = 142) n % n % Sex, female 93 73.2 104 73.2 Age (mean, SD) 40.3 (12.8) 39.6 (11.2) Country of origin Spain 112 88.2 126 88.7 Other European countries 0 4 2.8 Latin America 14 11.0 12 8.5 North Africa 1 0.8 0 Professional category Medical Doctor 53 42.1 67 47.2 Nurse 35 27.8 40 28.2 Nurse Assistant 12 9.5 12 8.5 Administrative 10 7.9 10 7.0 Other 16 12.7 13 9.2 Smoking 17 13.8 21 14.9 Comorbidities Any 42 33.1 41 28.9 Diabetes mellitus 1 0.8 0 Hypertension 3 2.4 2 1.4 Chronic respiratory condition 2 1.6 5 3.5 Dyslipidemia 4 3.1 3 2.1 Hyperthyroidism 6 4.7 7 4.7 Allergy 3 2.4 2 1.4 Dermatological condition 5 3.9 2 1.4 Gastrointestinal/liver conditions 2 1.6 5 3.5 Gynecological conditions 2 1.6 4 2.8 Psychological disease 2 1.6 2 1.4 Neurological disease 1 0.8 3 2.1 Other 16 12.6 8 5.6 Immunosuppression 0 0 Chronic treatment Any 34 26.8 40 28.2 Antidiabetics 0 1 0.7 Antihypertensives 1 0.8 2 1.4 Statins 3 2.4 1 0.7 Bronchodilators 2 1.6 1 0.7 Contraceptives 9 7.1 11 7.7 Levothyroxine 6 4.7 9 6.3 Proton pump inhibitors 2 1.6 5 3.5 Other 5 3.9 4 2.8 History of vaccination Haemophilus 9 7.8 8 6.2 Pneumococcal 5 4.2 9 6.7 Influenza 85 68.5 92 64.8 SD standard deviation Grau-Pujol et al. Trials (2021) 22:808 Page 6 of 10 Table 2 Participant’s risk factors of COVID-19 exposure at screening and the first month of follow-up Screening Month 1 Placebo Hydroxychloroquine Placebo Hydroxychloroquine (n=127) (n=142) (n=116) (n=137) Number of cohabitants (median, IQR) 2 [1–3] 1.5 [1–3] 1 [1–3] 2 [1–3] Confirmed cases (median, IQR) 1 [1–1] 1 [1–1] 1 [1–1] 1 [1–1] Suspected cases (median, IQR) 3 [3–3] 3 [3–3] 3 [3–3] 3 [3–3] a Used public transportation 54 43.2 55 38.7 56 48.7 58 42.3 Close contact with animalsa 26 20.8 36 25.5 39 33.6 52 38.0 a,b Use of COVID-19 recommended PPE at work Always 107 86.3 117 82.4 111 95.7 135 98.5 Almost always 8 6.5 11 7.7 4 3.4 2 1.5 Sometimes 2 1.6 5 3.5 1 0.9 0 0.0 Occasionally 2 1.6 1 0.7 0 0.0 0 0.0 Never 5 4.0 8 5.6 0 0.0 0 0.0 Close contact with a confirmed COVID-19 case 35 28.0 34 23.9 17 14.7 7 5.1 without using PPEa If yes, how many 1 20 57.1 11 32.4 9 56.2 3 42.9 2–3 10 28.6 18 59.2 7 43.8 3 42.9 ≥4 5 14.3 5 14.7 0 0 1 14.3 If yes, how frequently Every day 16 48.5 13 38.2 2 11.8 0 0.0 ≥ 1/week 8 24.2 10 29.4 8 47.1 5 83.3 < 1/week 9 27.3 13 38.2 9 42.1 1 16.7 Close contact with a suspected COVID-19 case 19 15.2 15 10.6 5 4.3 6 4.4 without using PPEa If yes, how many 1 7 36.8 6 40.0 1 20.0 3 50.0 2–3 6 31.6 7 46.7 2 40.0 2 33.3 ≥4 6 31.6 2 13.3 2 40.0 1 16.7 If yes, how frequently Every day 8 44.4 3 20.0 1 20.0 1 16.7 ≥ 1/week 6 33.3 8 53.3 2 40.0 4 67.7 < 1/week 4 22.2 4 26.7 2 40.0 1 16.7 Sometimes defined as not using the proper PPE 1-2 times/week. Occasionally defined as not using the proper PPE > 2 times/week PPE personal protection equipment a During the last 20 days b Almost always defined as not using the proper PPE protection 1–2 times in the last 20 days COVID-19 risk factors at month 1 confirmed COVID-19 cases without using PPE com- After a month of follow-up, 39.4% (65/165) of partici- pared to the placebo (5.1% (7/137) vs 14.7% (17/116), re- pants ceased to work in a COVID-19 hospital unit, with spectively, p value=0.018) (Table 2). a similar proportion between both groups. In addition, only seven participants denied having always used PPE Efficacy when assisting patients. The proportion of participants During the first month of follow-up, the cumulative inci- in contact with a confirmed and/or a suspected COVID- dence of COVID-19 among the study participants was 19 case showed to be lower compared with the screening 0.4%. Among all trial participants at the end of the first visit (p value< 0.001 in the hydroxychloroquine group, p month (n = 253), only one participant from the placebo value=0.002 in the placebo group). Participants from the arm (1/116, 0.8%), tested positive forSARS-CoV-2 PCR and hydroxychloroquine group had lower contact with for a SARS-CoV-2 serology test. The participant presented Grau-Pujol et al. Trials (2021) 22:808 Page 7 of 10 Table 3 Comparison of adverse events (AE) between study groups after 1 month of follow-up Placebo Hydroxychloroquine (n=142) (n = 127) n % n % p value At least 1 adverse event 42 33.1 53 37.3 0.548 Syndromic approach General symptoms 9 7.7 10 7.0 > 0.999 Fever 6 4.7 4 2.8 0.553 Chills 0 0.0 2 1.4 0.552 Sweating 0 0.0 0 0.0 Malaise 4 3.1 4 2.8 > 0.999 Myalgia 2 1.6 3 2.1 > 0.999 Arthralgia 0 0.0 0 0.0 Gastrointestinal symptoms 20 15.7 39 27.4 0.041 Nausea 3 2.4 10 7.0 0.160 Abdominal pain 11 8.3 15 10.9 0.825 Diarrhea 8 6.3 24 16.9 0.028 Dysgeusia 0 0.0 0 0.0 Dermatological symptoms 2 1.6 3 2.2 > 0.999 Itching 0 0.0 2 1.4 0.546 Rash 2 1.6 2 1.4 > 0.999 Respiratory symptoms 9 7.1 5 3.7 0.257 Rhinorrea 3 2.4 0 0.0 0.190 Sore throat/odynophagia 5 3.9 3 2.2 0.556 Cough 3 2.4 2 1.5 0.851 Pleuritic pain 0 0.0 0 0.0 Dyspnea 0 0.0 0 0.0 Neurological symptoms 12 9.4 14 9.9 > 0.999 Headache 12 9.4 13 9.1 0.987 Visual disturbances 0 0.0 1 0.7 >0.999 Cardiovascular symptoms 2 1.6 2 1.4 0.999 Other symptoms 10 8.0 7 4.9 0.427 Severity 0.249 Mild 43 33.8 63 44.4 Moderate 3 2.4 1 0.7 Severe 0 0.0 0 0.0 Potential relationship with the study drug Related (at least one AE) 33 26.0 49 34.5 0.206 Non related (at least one AE) 17 13.4 14 9.9 0.476 Withdrawal due to AE 5 3.9 1 0.7 0.270 % according to available data with fever, respiratory symptoms, and headache 6 days after Safety randomization. The participant did not receive specific A total of 95 participants experienced at least one AE treatment for COVID-19 or required hospitalization. during the first month of follow-up, posing an overall The risk ratio of collected risk factors and clinical and accumulated prevalence of 35.3%. The proportion of analytical conditions for developing COVID-19 could participants experiencing at least one AE was similar in not be calculated due to low COVID-19 incidence. both groups. Eighty-two events (34.5% (49/142) in the Grau-Pujol et al. Trials (2021) 22:808 Page 8 of 10 hydroxychloroquine group and 26.0% (33/127) in the hydroxychloroquine at the study doses had an excellent placebo group, p=0.206) were judged to be related to the safety profile. Nevertheless, the community incidence of study intervention (hydroxychloroquine or placebo). No SARS-CoV-2 events decreased during the first month of serious AEs were reported. Almost all AEs (96.4%, 106/ follow-up as a consequence of the country’s control and 110) were considered mild. Only four were reported as mitigation strategies. Thus, the overall incidence in the co- moderate: prostate adenocarcinoma in the hydroxychlor- hort was 0.8%, the trial was stopped due to futility, and the oquine group and dental infection, hypertensive crisis, study design was deemed underpowered to answer the and myalgia in the placebo group. main objective. Although the SARS-CoV-2 incidence found Gastrointestinal symptoms (diarrhea, abdominal pain, in study participants was low, seroprevalence studies show and nausea) were the most common AEs, and they were that healthcare workers are at high risk of being infected by more commonly reported in the hydroxychloroquine SARS-CoV2 [20]. Thus, major efforts should be made to group. The median number of days from the first dose protect these essential workers from the infection, primarily to intake to AE appearance was 2.5 in the hydroxychlor- by prophylactic measures (chemoprophylaxis or vaccin- oquine group [IQR 0–10.5] and 6 in the placebo group ation). These strategies should also be evaluated in other [IQR 2–18]. populations that are likely to be at high risk of exposure, Headache, rash, respiratory, and general symptoms such as patients and staff at long-term care facilities or were also observed. They appeared similarly in time be- people in other congregate living situations. tween both groups; the median number of days to ap- In this trial, AEs were similar between the hydroxy- pearance was 4.5 [IQR: 0–17] in the hydroxychloroquine chloroquine and the placebo group. Mild gastrointestinal group and 5 [IQR: 1–18] in the placebo group. events were higher in the hydroxychloroquine group Four cardiovascular AEs (two in each study group) than in the placebo group. Our safety data contrast with were detected during the first month of treatment: two available data from a recently published placebo- pre-excitation syndromes (Wolf-Parkinson-White), one controlled clinical trial post-exposure prophylaxis with with hypertensive crisis, and two participants presenting hydroxychloroquine to prevent COVID-19, in which the with heart palpitations. The only moderate cardiovascu- intervention arm had a higher rate of AEs (40.1%) com- lar AE was the hypertensive crisis; the rest were mild pared to the placebo arm (16.8%) [21]. The reasons for and none of them was considered related to the study these discrepancies may include the high loading doses drug. None of the participants presented prolonged QTc of hydroxychloroquine required for the post-exposure intervals at first month (388 ms [IQR: 365–402] in the prophylaxis strategies (3200 mg compared to 1200 mg in hydroxychloroquine group and 393 ms [IQR: 371–405] 4 days in our intervention). Moreover, the loading dose in the placebo group). during 4 consecutive days in PrEP strategies could be Only one participant in the hydroxychloroquine group avoided since the patient has not yet been exposed to presented mild visual disturbances. the virus, potentially decreasing the number of AEs. One participant discontinued the prophylaxis due to Large observational studies evaluating the hydroxy- AEs in the hydroxychloroquine group and five in the chloroquine effect on SARS-CoV-2 pneumonia showed placebo group. Table 3 shows a detailed description of that higher doses of the drug could be associated with the AEs presented in both study groups. QTc interval prolongation and death due to cardiovascu- No relevant laboratory abnormalities occurred. Most lar events; especially when administered with other abnormalities were transient, with no significant changes drugs which favor QT interval prolongation [22, 23]. in the two groups (Supplementary Table 1). The relationship of high doses of hydroxychloroquine with severe AEs was also supported by a recent study Discussion evaluating high doses of hydroxychloroquine (up to 600 Although the SARS-CoV-2 incidence found in study bid during 10 days) for treating COVID-19 patients. This participants was low, seroprevalence studies show that study showed that 15% of participants had prolonged healthcare workers are at high risk of being infected by QTc interval and two of them presented ventricular SARS-CoV-2 [20]. Thus, major efforts should be made tachycardia. In this specific case, the authors suggested to protect these essential workers from the infection, that this outcome could have been influenced by most of primarily by prophylactic measures (chemoprophylaxis their participants receiving oseltamivir, which also pro- or vaccination). We conducted a multicentre double- longs QT, and the older age of them [24]. In our case, blind placebo-controlled randomized clinical trial to no cardiovascular events related to the study drug were evaluate whether PrEP with hydroxychloroquine was an observed. effective intervention for preventing COVID-19 among The adequate safety profile of the preventive (low) healthcare workers during a COVID-19 epidemic doses of hydroxychloroquine found in our study is sup- period. These data showed that prophylaxis with ported by many studies on hydroxychloroquine short- Grau-Pujol et al. Trials (2021) 22:808 Page 9 of 10 term use as antimalarial and long-term use for rheum- Supplementary Information atic diseases demonstrated to be safe as well [25–28]. The online version contains supplementary material available at https://doi. org/10.1186/s13063-021-05758-9. As mentioned above, this trial has some limitations. The main one is a low power in our study design to as- Additional file 1. sess the efficacy of PrEP with hydroxychloroquine in healthcare workers at the first interim analysis. The prin- Acknowledgements cipal reason was the low incidence of COVID-19 during We thank the commitment of all participants who, apart from facing the the study follow-up in the study area. The analysis pre- COVID-19 epidemic with their daily work, decided to get involved in this study. We thank all investigators and other personnel for their commitment to the sented in this manuscript was conducted during April, work, which was carried out with enthusiasm despite the minimal financial May, and June 2020 in Barcelona. During that period, support. In particular, we would like to acknowledge at ISGlobal, Spain, María COVID-19 reported cases were already decreasing in José Cavallín, Natalia Rodríguez-Valero, Almudena Legarda, Pere Millat, Alejandro Almuedo, Carlos Ratia, Carme Subirà, Alberto Ayllon, Andrea Aira Catalunya: while 1208 cases were reported on April 3rd, and Teresa de Alba; at the International Health and Tropical Medicine 77 cases were reported on June 12th. Accordingly, Department of Hospital Clínic de Barcelona, Eva Chicharro and Dolors Soy; at SARS-CoV-2 attack rate declined from 0.9 at the initi- Hospital de la Santa Creu i Sant Pau, Maria Ema Molas, Noemí Corbacho and Jessica Muñoz. ation of the study to 0.77 at the end of the analysis [29]. We are particularly grateful to María Jesús Pinazo, Quique Bassat, Elena Arbelo, In addition, we noticed that healthcare workers' risk per- and Gerard Espinosa, the clinical trial Data Safety and Monitoring Board. ception decreased as the national epidemic vanished. We acknowledge support from the Spanish Ministry of Science, Innovation and Universities through the “Centro de Excelencia Severo Ochoa 2019-2023” That had an impact not only on participants’ recruit- Program (CEX2018-000806-S), and support from the Generalitat de Catalunya ment but also on participants’ adherence and follow-up. through the CERCA Program”. Moreover, other factors influenced their participation. Authors’ contributions Some study candidates had already self-prescribed Grau-Pujol and Camprubí-Ferrer contributed equally to this manuscript. hydroxychloroquine assuming its role on COVID-19 Concept and design: Muñoz, Grau-Pujol, Camprubí-Ferrer, Marti-Soler, Fernán- prevention, so although displaying interest, they were ex- dez-Pardos, Guinovart, Garcia. Acquisition or interpretation of data: Grau- Pujol, Camprubí-Ferrer, Martí-Soler, Carerras-Abad, Muelas-Fernández, Jullien, cluded to participate. In addition, a fraction of recruited Barilaro, Ajanovic, Ferrer, Vera, Moreno, González-Redondo, Roldán, Artes-de participants dropped out from the study the following Arcos, Mur. Drafting of the manuscript: Grau-Pujol, Camprubí-Ferrer. Critical day of test results notification. Hence, this set of circum- revision: Muñoz, Camprubí-Ferrer, Grau-Pujol, Jullien, Carreras-Abad, Do- mingo, Mur, Barilaro, Guinovart, Martí-Soler. Statistical analysis: Martí-Soler, stances prompted us to stop trial recruitment by the 8th Grau-Pujol, Camprubí-Ferrer, Muñoz. Obtained funding: Muñoz. Administra- of May even though we had not reached our estimated tive or technical support: Fernández-Pardos, Grau-Pujol, Velasco-de Andrés, sample size. Consequently, both study groups were un- Cortes-Serra, Ferrer, Vera, González-Redondo, Moreno, Roldán, Artes-de Arcos. Supervision: Muñoz. The authors read and approved the final manuscript. evenly distributed (52.8% vs 47.2%). Funding Conclusions This work was supported by funds from ISGlobal and Hospital Clínic’s This trial displayed that administering 400 mg of hydroxy- International Health’s department. Laboratorios Rubió has partially contributed to the funding of this project and with hydroxychloroquine chloroquine during 4 consecutive days followed by 400 doses (Dolquine®). The funding body did not participate on the study design mg of hydroxychloroquine weekly in adults during a and collection, analysis, data interpretation or manuscript writing. month was safe. The question if COVID-19 could be pre- Availability of data and materials vented with hydroxychloroquine PrEP was unanswered. Data will be available from the author on reasonable request (jose. Since the epidemiological situation happening in our munoz@isglobal.org). country is expected to be reproduced in other areas where similar trials are being conducted, our group will make all Declarations efforts to share databases with clinical trials with a similar Ethics approval and consent to participate design, doses of hydroxychloroquine, and similar study This trial was approved by the Drug Research Ethics Committee of the Hospital Clinic of Barcelona (CEIm), Barcelona, Spain, and the Spanish Agency endpoints, in an effort to answer the main question that of Medicines and Medical Products (AEMPS). initially fostered the design of this and similar studies. Pre- The study was performed according to the Declaration of Helsinki (version of venting healthcare workers from contracting COVID-19 is Fortaleza, Brazil, October 2013), current ICH-GCP guidelines, and all applicable national and local regulatory requirements (Spanish Royal Decree 1090/2015). critical to control the pandemic. Thus, further studies in Informed consent was signed by all participants before their inclusion in the countries in the peak of the pandemic are needed to inves- study. Participation in this study was voluntary, and under no circumstances tigate effective preventive measures. the clinical management of the participants was affected by the decision to participate or not in the study. The participant was free to withdraw at any Abbreviations time of the study. AE: Adverse event; AEMPS: Spain and the Spanish Agency of Medicines and Medical Products; CEIm: Drug Research Ethics Committee of the Hospital Consent for publication Clinic of Barcelona; CRF: Case report form; CT : Cycle threshold; Not applicable. IQR: Interquartile range; PCR: Polymerase chain reaction; PrEP: Pre-exposure prophylaxis; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; Competing interests SD: Standard deviation; WHO: World Health Organization The authors declare that they have no competing interests. Grau-Pujol et al. Trials (2021) 22:808 Page 10 of 10 Author details healthcare workers during the COVID-19 pandemic: A structured summary 1 Barcelona Institute for Global Health (ISGlobal), Hospital Clínic - University of of a study protocol for a multicentre, double-blind randomized controlled Barcelona, Rosselló 132 4rt 1a, 08036 Barcelona, Spain. 2Centro de trial. 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