key: cord-0702336-78pzcggg
authors: Syed, F.; Arif, M. A.; Niazi, R.; Baqar, J. B.; Hashmi, U. L.; Batool, S.; Ashraf, S.; Arshad, J.; Musarrat, S.
title: Pre-Exposure Prophylaxis with Various Doses of Hdroxychloroquine among high-risk COVID 19 Healthcare Personnel: CHEER randomized controlled trial
date: 2021-05-17
journal: nan
DOI: 10.1101/2021.05.17.21257012
sha: 0da0701b01c138d87a25854681aaae28439fc79c
doc_id: 702336
cord_uid: 78pzcggg

Background: Pre-exposure prophylaxis (PrEP) is a promising strategy to break the chain of transmission of novel coronavirus (2019-nCoV). Aims: This trial aimed to evaluate the safety and efficacy of PrEP with various doses of HCQ against a placebo among high-risk healthcare providers (HCPs). Methods: A phase II, randomized, placebo-controlled trial was conducted at a tertiary care hospital. A total of 228 HCPs were screened, we included 200 subjects with no active or past SARS-CoV-2 infection. Subjects of experimental groups 1-3 received HCQ in various doses and those in the control group received 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 also by the end of the 12th week, with PCR or IgM and IgG serology. Results: Overall, 146 of 200 participants reported exposure to a confirmed COVID-19 case in the first month, 189 in the 2nd month and 192 were exposed by the 12th week of the study. Moreover, the precautionary practices, i.e. use of personal protective equipment (PPE), significantly varied; initially more than 80% of the exposed HCPs weren't ensuring the PPE used by the patients treated by them. However, it gradually developed with the increasing knowledge of the virus. As far as safety is concerned, mild treatment-related side effects were observed among the interventional and placebo arm patients. While none of the participants were critical, and a few had mild illness by the end of the 12th week, requiring only outpatient observation with no hospitalization. There was no significant clinical benefit of PrEP with HCQ as compared to placebo (p>0.05). Conclusion: It is concluded from the study findings that the PrEP HCQ does not significantly prevent illness compatible with COVID-19 or confirmed infection among high-risk HCPs.

Novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has by far affected 40 almost all countries. Globally as of February 24, 2021, there have been about 111,593,583 41 confirmed cases of COVID-19 and 2,475,020 deaths, as per World Health Organization 42

(WHO) emergency statistics [1] . For the proper management of this pandemic, the most 43 crucial step is the conservation of workforce safety. As this outbreak holds a heavy toll on the 44 frontline healthcare workers, they are three times more likely to be infected than unexposed 45 [2] . Moreover, this pandemic has affected us physically and psychologically; the exposed 46 frontline workers frequently developed depressive symptoms, anxiety, fear, and stress [3] [4] [5] . 47

Given the healthcare workers exposed to COVID-19 patients are at high risk of viral 48

transmission. Therefore, many of them stayed away from their homes for keeping their 49 families safe [6] . The fight against COVID-19 is in continuance and the success only relies 50 on the adherence to the preventive measures. A series of preventive measures and therapeutic 51 options are being explored for disease containment. In addition to the quarantine of exposed 52 individuals from close ones, the prevention strategies also include the use of personal 53 protection equipment (PPE), hand washing, case identification and isolation [7] [8] [9] . Numerous 54 drugs are undergoing clinical trials for effective mitigation of SARS-CoV-2 transmission 55 [6, 10] . Until now, remdesivir is the only drug approved by the Food and Drug Administration 56

(FDA) to treat . Besides, dexamethasone also improved the disease outcomes 57 among severe COVID-19 patients [11, 12] . 58

In addition, research shows that chloroquine acts as an effective in vitro inhibitor of SARS-59

CoV-2. Furthermore, HCQ, a chloroquine derivate is also identified as a possible 60

prophylactic inhibitor for the entry and post-entry stages of SARS-CoV-2, with better in vitro 61 antiviral activity and safety profile, on the ground of anti-inflammatory as well as antiviral 62 effects [13] [14] [15] . HCQ has been evaluated for the treatment of SARS-CoV-2 (pneumonia) and 63

post-exposure prophylaxis. The available clinical evidence for the use of HCQ among 64 COVID-19 patients seems insufficient and does not fully prove the effectiveness of this 65 therapeutic modality among severely ill COVID-19 patients. Nevertheless, the promising 66 treatment outcomes observed among mildly infected patients and no environmental 67

implications associated with the drug suggest its therapeutic potential. 68 May 2020, and the intervention continued for a total of 12 weeks. 79 80 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 17, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 All healthcare workers at high risk for COVID-19 exposure, primarily those in emergency  81  departments (physicians, nurses, ancillary staff, triage personnel), intensive care units  82  (physicians, nurses, ancillary staff, respiratory therapists), performing aerosol-generating  83  procedures (anesthesiologists, nurse, anesthetists, gastroenterologists performing endoscopy,  84 pulmonologists performing bronchoscopy), first responders (EMTs, paramedics) and those 85 working in the departments of general medicine, pulmonology, infectious disease and 86 isolation wards were included in the study. While active COVID-19 cases, those with 87 existing symptoms like fever, cough, shortness of breath, having prior retinal eye disease, 88

Chronic Kidney Disease (CKD), Stage 4 or 5 or dialysis, Glucose-6 Phosphate 89

Dehydrogenase (G-6-PD) deficiency, recent Myocardial Infarction (MI) and epileptic 90 subjects were excluded. Additionally, also kept under exclusion were pregnant females, 91 subjects weighing < 40 kg, those having contraindication or allergy to chloroquine/ HCQ, 92 already administering HCQ or cardiac medicines like flecainide, amiodarone, digoxin, 93 procainamide, or propafenone, medications with known significant drug-drug interactions 94 like artemether, lumefantrine, mefloquine, tamoxifen or methotrexate and those causing QT 95 interval prolongation like macrolides, antipsychotics, quinolones, antihistamines, SSRIs, 96 tricyclic antidepressants, antifungals. 97 A total of 228 participants were initially enrolled ( Figure 1 ); of them, 28 were ineligible and 98 excluded. Participants fulfilling the eligibility criteria were randomized into the four 99 treatment groups. Group 1 participants (n=48) were intervened with HCQ 400 mg (locally 100 manufactured by Getz Pharma) twice a day on day 1 followed by 400 mg weekly. Group 2 101 (n=51) participants were given HCQ 400 mg once every 3 weeks, group 3 (n=55) 102 administered HCQ 200 mg once every 3 weeks and participants in the control group received 103 placebo (n=46). 104 105 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) and also by the end of the 12th week, with PCR or IgM and IgG serology (as per 118 accessibility). 119 120

Outcomes 121

The primary endpoint was to evaluate the COVID-19-free survival among the participants 122 by the end of the study. The secondary endpoints were to evaluate the proportion of rRT-123 PCR positive COVID-19 cases, the role of exposure and preventive practices, the frequency 124 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 17, 2021. ; https://doi.org/10.1101/2021.05.17.21257012 doi: medRxiv preprint of COVID-related symptoms, treatment-related side effects, the incidence of all-cause 125 study medicine discontinuation, and maximum disease severity during the study treatment. 126 127 128

Statistical Methods 129

The continuous variables were summarized as means and standard deviations (SD) and 130 categorical variables as frequencies and percentages. A comparative analysis was 131 performed between the experimental groups. Chi-square test and analysis of variance 132

(ANOVA) were used to compare the baseline characteristics, COVID-19 exposure, 133

preventive measures, symptomatology, side effects and maximum disease severity. A p-134 value <0.05 was considered significant. 135 136

Ethical Consideration 137

The study protocol was approved by the ethical review board of Shaheed Zulfiqar Ali 138

Bhutto Medical University (Reference no. 1-1/2015/ERB/SZABMU/549; Dated 20 April 139 2020), and written informed consents were acquired from the participants before inclusion. 140

The baseline characteristics of the enrolled healthcare personnel are shown in table 1. The 142

trial included 109 (54.5%) male participants, and the mean age was 30.63 ± 8.075 years. The 143 majority of them were doctors and had no comorbid conditions. 144 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) There was no significant difference in the exposure records between the treatment groups as 151

shown in table 2. Most of these healthcare workers were exposed to a confirmed or probable 152 COVID-19 case. Around 73% of participants were exposed in the first month (baseline), 153

which further increased to 94.5% by the second month (1 st follow-up) and 96% by the end of 154 the 12 th week (2 nd follow-up). Initially, 18.5% of participants weren't using PPE, but with 155 the passage of time, the awareness regarding preparedness developed and by the end of the 156 12 th week, only 4.5% of participants weren't taking precautionary measures. 157 158 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) Of the total, COVID-19 related symptoms appeared in 54.9% participants of experimental 165 group 2, 33.3% of group 1, 30.4% from the placebo group and 23.6% from group 3 (Table 3) . 166

Fever, cough, shortness of breath, rhinorrhea, and diarrhea were the commonly reported 167

symptoms. The frequency of cough was significant among the participants of experimental 168 group 2 receiving HCQ (400 mg once every 3 weeks). 169 170 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 17, 2021. 

Test not 10(20.8) 12(23.5) 13(23.6) 12(26.1) 0.072 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 17, 2021. In this trial, the types and frequency of symptoms reported in the present study were similar 228

to those in previous studies involving HCPs [21, 22] . It was also observed that the treatment-229 related side effects were comparatively more evident among the participants of the 230 interventional arms than placebo, i.e. 10.4%, 2.0% and 5.5% participants from experimental 231 group 1, 2 and 3, respectively, receiving various doses of HCQ vs. 2.2% of the placebo group 232

were observed with treatment-related side effects. However, none of the participants required 233 hospitalization, ICU care or death from COVID-19 in any study groups. A majority reported 234 no illness in response to the provided treatment, and a few had a mild illness (outpatient 235 observation). Our safety data is similar to a randomized clinical trial indicating a higher rate 236 of adverse events reported among the intervention arm patients than those receiving placebo 237

[23]. Moreover, five participants discontinued the HCQ prophylaxis due to side effects and 238 one in the placebo arm; these findings are consistent with a similar study [23] . 239 240

Adding to the existing literature, this trial provided a detailed analysis of the monthly 241 exposure history, intensity of exposures, and the enrolled healthcare personnel's preventive 242

practices. However, we acknowledge the limitations. The small sample size for assessing the 243 efficacy of PrEP with HCQ at the initial stages of analysis among the healthcare workers was 244 one of the major limitations. Based on the findings, the incidence rate of SAR-CoV-2 in 245 healthcare workers declined from the initiation of the study till the end of the analysis. 246

Moreover, it cannot be denied that a lower HCQ dose effectively prevented the COVID-19 247 infection in the studied cohort. Further large-scale prophylaxis trials are required to 248

investigate the antiviral activity of varying HCQ dosing and the differential impact of each 249 therapeutic agent on the body's biochemical profile and the overall disease incidence. 250 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 17, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 Conclusions 251

In conclusion, there was no significant reduction in the SARS-CoV-2 transmission with PrEP 252 administration of Hydrochloroquine among the enrolled healthcare personnel. The safety 253 profile varied among the participants who were intervened with HCQ compared to those 254

given placebo, the presence of treatment related side-effects was higher among the 255 participants of experimental group 1 and 3 receiving different HCQ doses. In contrast, the 256 safety outcome of experimental group 2 was similar to that observed in the placebo arm. As 257 far as the disease severity is concerned, none of the participants were severe/critical enough 258 to require hospitalization and ICU care, and none of them died. Preventing healthcare 259 workers from COVID-19 is critical to control the pandemic. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 17, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 

Covid-19: risks to healthcare workers and their families

The chaos of healing: Risking mental health amid COVID19 in Pakistan. 280

Are countries preparing for a responsible lockdown exit strategy

Psychological Response & Perceived Risk Associated 284 with Coronavirus Disease

National Institute of Health. Therapeutic Management of Adults with COVID-19. 292

Preexposure 298 prophylaxis for the prevention of HIV infection: evidence report and systematic 299 review for the US Preventive Services Task Force

Remdesivir for the treatment of Covid-19-preliminary report

Remdesivir for severe COVID-19 305 versus a cohort receiving standard of care

Remdesivir and chloroquine 307 effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Hydroxychloroquine, a less toxic 310 derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. 311 Cell discovery

In vitro antiviral activity and 313 projection of optimized dosing design of hydroxychloroquine for the treatment of 314 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clinical infectious 315 diseases

Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virology 318 journal

A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-321 19

SARS transmission 323 among hospital workers in Hong Kong. Emerging infectious diseases

Pre-exposure prophylaxis with hydroxychloroquine for high-risk healthcare 327 workers during the COVID-19 pandemic: a structured summary of a study protocol 328 for a multicentre, double-blind randomized controlled trial

Efficacy 330 and safety of hydroxychloroquine vs placebo for pre-exposure SARS-CoV-2 331 prophylaxis among health care workers: a randomized clinical trial. JAMA internal 332 medicine

334 Characteristics of health care personnel with COVID-19-United States

Pharmacokinetics of 337 hydroxychloroquine and its clinical implications in chemoprophylaxis against malaria 338 caused by Plasmodium vivax

Pre-exposure prophylaxis with hydroxychloroquine for COVID-19: 342 initial results of a double-blind, placebo-controlled randomized clinical trial

The authors would like to acknowledge the Medical Affairs department of Getz Pharma for 273 their technical support and assistance in the publication process. 274