Systematic review of registered trials of Hydroxychloroquine prophylaxis for COVID-19 health-care workers at the first third of 2020

In the absence of a vaccine the medical and scientific community is looking intensely at utilizing a pre or post exposure drug that could decrease viremia. The search for a medication that could reduce risk of serious disease, and ideally of any manifestation of disease from SARS-CoV2, and of asymptomatic shedding of SARS-CoV2 is of urgent interest. Repurposing existing pharmaceuticals is among the approaches to achieve these ends. We performed a systematic review of all interventional studies registered in ClinicalTrials.gov with a focus on one repurposed drug, Hydroxychloroquine (HCQ). The detailed analysis of these studies, some of them already recruiting, provide an overall picture of HCQ use as a COVID-19 prophylaxis around the world. Among the included studies, all but three were randomized and parallel and most of them (74%, 23/31) were double-blinded to quadruple-blinded studies. We found a great diversity in dosing and nearly all the possible scientifically reasonable regimens are under evaluation. This diversity offers benefits as well as challenges. Importantly, the final analysis of these trials should be done through an extensive reading of the results in regard to the clinical design, it will be crucial to carefully read and evaluate the results of each study in regards to the clinical design rather than quickly glancing a 140 characters-based social media message announcing the failure or success of a drug against a disease.


Introduction
In the absence of a vaccine the medical and scientific community is looking intensely at utilizing a pre or post exposure drug that could decrease viremia. The search for a medication that could reduce risk of serious disease, and ideally of any disease and of asymptomatic shedding of SARS-CoV2 is of urgent interest, particularly to decrease the risk to health care workers, first responders, and others with high risk of exposure to patients with COVID19. The prospect of protecting healthcare workers against COVID-19 based on repurposing of existing pharmaceuticals is among one of the recent scientific debates [1,2]. The value of hydroxychloroquine (HCQ) as a prophylactic needs careful documented, empirical research in this context [3]. In order to obtain strong clinical evidence, a large number of scientists and teams have launched prospective studies that were registered on ClinicalTrials.gov over a short period of time. The detailed analysis of these studies, some of them already recruiting, will give an overall picture of HCQ use as a COVID-19 prophylaxis around the world. This will help to identify the gaps to be fulfilled with the idea of getting definitive evidence on the positioning of HCQ for COVID-19 prophylaxis in exposed health-care workers.

Material and methods
We performed a systematic review of all interventional studies registered in ClinicalTrials.gov on the 27th of April under the disease "COVID" and "hydroxychloroquine prophylaxis" as other terms [4]. No other filter was used. Studies using hydroxychloroquine (HCQ) as treatment, studies that did not record details about HCQ regimen, as well as those using HCQ in combination with other drugs, were not included. ClinicalTrials.gov is a Web-based resource maintained by the National Library of Medicine that provides patients, their family members, health care professionals, researchers, and the public with access to information on clinical studies. Information on ClinicalTrials. gov is provided and updated by the sponsor or principal investigator of the clinical study.
Two independent authors (ALB, SP) performed the screening of the study record detail to assess eligibility. Data were extracted by Information collected included ClinicalTrials.gov identifier, official title, recruitment status, starting and completion dates, estimated enrolment, allocation, location, intervention model, masking, and HCQ regimen. To ensure reproducibility and completeness of data extraction, an Excel spreadsheet (Microsoft Corp., Redmond, WA, USA) compiling all variables to be extracted was used. Disagreements over eligibility or data extraction were resolved by discussion. Data were centrally checked by an independent operator for completeness, plausibility, and integrity before synthesis.

Results
All interventional clinical trials that studied the use of HCQ for COVID-19 prophylaxis were included in the qualitative analysis. Fortyone (n = 41) studies were identified through ClinicalTrials.gov on the 27th of April (Fig. 1). After screening for eligibility record details of the selected studies, 31 studies were included in the qualitative analysis.  absence of details about HCQ regimen (n = 1), the use of HCQ as indication other than prophylaxis (n = 3), and the combination of HCQ to other drugs or vitamins (n = 6). The qualitative analysis focussed on HCQ drug regimens of the 31 included studies as recorded in ClinicalTrials.gov from the 17th of March to the 24th of April. (See Table 1.) Among the included studies, all but three were randomized and parallel and most of them (74%, 23/31) were double-blinded to quadruple-blinded studies. On the 27th of April, 55% (17/31) of them were recruiting. Estimated enrolment in HCQ arm was from 45 to 20.000 participants, with a median of 380 participants and a total of 45.728 persons receiving HCQ.
Regarding HCQ regimen, 61% (19/31) of the included studies used an HCQ loading dose, followed by daily (14/19) or weekly (5/19) doses. The range of the loading doses was from 400 to 1400 mg on day 1. The most common daily doses were 400 mg (12/31 (39%)) and 200 mg (9/31 (29%)); a 600 mg daily dose was less common and was recorded for only 13% (4/31) of the studies. The remaining six studies used weekly doses of 400 mg. Regarding the duration of prophylaxis, it was highly variable, ranging from 5 to 180 days (median = 40 days) for daily regimen, and 3 to 24 weeks for weekly regimen (median = 12 weeks). Of note, the most frequent prophylactic regimen (6/31 (19%)) was an HCQ loading dose of 800 mg on day 1, followed by HCQ 400 mg for four additional days. Among the studies (n = 5) that did not use a loading dose but a 400 mg daily dose, duration of prophylaxis was highly diverse from 4 to 180 days (median = 60). For the studies (n = 2) that reported a 200 mg daily dose, one study used a loading dose of 800 mg on day 1 and 2, followed by 90 days of 200 mg HCQ, and the other one used a loading dose of 400 mg from day 1 to 3, followed by 14 days of 200 mg HCQ.

Discussion
More than 40 randomized clinical trials have been registered in less than 2 months from 13 different countries to answer the same question: should we used HCQ to protect health-care workers from the COVID-19 consequences? This very active recording in ClinicalTrials.gov demonstrates the huge interest of the scientific community regarding this question. Indeed, the debate continues to rage regarding the use of HCQ for COVID-19 and we need to shed more light based on clinical evidence. At the present time, the debate is still a non-documented speculation that will be ended in the next few months.

Editorial Commentary
One Health 10 (2020) 100141 Table 1 Description of interventional studies registered in ClinicalTrials.gov on the 27th of April under the disease "COVID" and "hydroxychloroquine prophylaxis". The positive point regarding the high diversity of HCQ regimen among recorded clinical studies is that nearly all the possible regimens are under evaluation. The negative point of the high diversity in HCQ dosage and duration of prophylaxis could be that the conclusion of these different studies may be conflicting. Indeed, it would be surprising that a 200 mg daily dose during one month would have the same efficacy and the same ratio benefit/risk than a 600 mg daily dose during three months. As a consequence, the final analysis of these trials should be done through an extensive reading of the results in regards to the clinical design, rather than quickly glancing a 140 characters-based social media message announcing the failure or success of a drug against a disease.

NCT
The authors declare no conflict of interest.