Dataset Information

Finding the Dose for Hydroxychloroquine Prophylaxis for COVID-19: The Desperate Search for Effectiveness.

ABSTRACT: Hydroxychloroquine is an antimalarial drug being tested as a potential treatment for the novel coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2. Although the efficacy of hydroxychloroquine for COVID-19 remains uncertain, it may serve as a potential prophylactic agent especially in those at high risk, such as healthcare workers, household contacts of infected patients, and the immunocompromised. Our aim was to identify possible hydroxychloroquine dosing regimens through simulation in those at high risk of infections by optimizing exposures above the in vitro generated half maximal effective concentration (EC50 ) and to help guide researchers in dose-selection for COVID-19 prophylactic studies. To maintain weekly troughs above EC50 in > 50% of subjects at steady-state in a pre-exposure prophylaxis setting, an 800 mg loading dose followed by 400 mg twice or 3 times weekly is required. In an exposure driven, post-exposure prophylaxis setting, 800 mg loading dose followed in 6 hours by 600 mg, then 600 mg daily for 4 more days achieved daily troughs above EC50 in > 50% subjects. These doses are higher than recommended for malaria chemoprophylaxis, and clinical trials are needed to establish safety and efficacy.

SUBMITTER: Al-Kofahi M

PROVIDER: S-EPMC7267462 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Finding the Dose for Hydroxychloroquine Prophylaxis for COVID-19: The Desperate Search for Effectiveness.

Al-Kofahi Mahmoud M Jacobson Pamala P Boulware David R DR Matas Arthur A Kandaswamy Raja R Jaber Mutaz M MM Rajasingham Radha R Young Jo-Anne H JH Nicol Melanie R MR

Clinical pharmacology and therapeutics 20200601 4

Hydroxychloroquine is an antimalarial drug being tested as a potential treatment for the novel coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2. Although the efficacy of hydroxychloroquine for COVID-19 remains uncertain, it may serve as a potential prophylactic agent especially in those at high risk, such as healthcare workers, household contacts of infected patients, and the immunocompromised. Our aim was to identify possible hydroxychlo ...[more]

PMID: 32344449

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Project description:The impact of the COVID-19 pandemic worldwide has led to a desperate search for effective drugs and vaccines. There are still no approved agents for disease prophylaxis. We thus decided to use a drug repositioning strategy to perform a state-of-the-art review of a promising but controversial drug, hydroxychloroquine (HCQ), in an effort to provide an objective, scientific and methodologically correct overview of its potential prophylactic role. The advantage of using known drugs is that their toxicity profile is well known and there are fewer commercial interests (e.g., expired patents), thus allowing the scientific community to be freer of constraints. The main disadvantage is that the economic resources are almost always insufficient to promote large multinational clinical trials. In the present study, we reviewed the literature and available data on the prophylactic use of HCQ. We also took an in-depth look at all the published clinical data on the drug and examined ongoing clinical trials (CTs) from the most important CT repositories to identify a supporting rationale for HCQ prophylactic use. Our search revealed a substantial amount of preclinical data but a lack of clinical data, highlighting the need to further assess the translational impact of in vitro data in a clinical setting. We identified 77 CTs using a multiplicity of HCQ schedules, which clearly indicates that we are still far from reaching a standard of care. The majority of the CTs (92%) are randomized and 53% are being conducted in a phase 3 or 2/3 setting. The comparator is placebo or control in 55 (77%) of the randomized studies. Forty-eight (62%) CTs expect to enroll up to 1,000 subjects and 50 (71%) plan to recruit healthcare workers (HCW). With regard to drug schedules, 45 (58.5%) CTs have planned a loading dose, while 18 (23.4%) have not; the loading dose is 800 mg in 19 trials (42.2%), 400 mg in 19 (42.2%), 600 mg in 4 (8.9%) and 1,200 mg in 1 (2.2%). Forty trials include at least one daily schedule, while 19 have at least one weekly schedule. Forty-one (53.2%) will have a treatment duration of more than 30 days. Awaiting further developments that can only derive from the results of these prospective randomized CTs, the take-home message of our review is that a correct methodological approach is the key to understanding whether prophylactic HCQ can really represent an effective strategy in preventing COVID-19.

Project description:BackgroundCoronavirus disease 2019 (Covid-19) occurs after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For persons who are exposed, the standard of care is observation and quarantine. Whether hydroxychloroquine can prevent symptomatic infection after SARS-CoV-2 exposure is unknown.MethodsWe conducted a randomized, double-blind, placebo-controlled trial across the United States and parts of Canada testing hydroxychloroquine as postexposure prophylaxis. We enrolled adults who had household or occupational exposure to someone with confirmed Covid-19 at a distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure). Within 4 days after exposure, we randomly assigned participants to receive either placebo or hydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 additional days). The primary outcome was the incidence of either laboratory-confirmed Covid-19 or illness compatible with Covid-19 within 14 days.ResultsWe enrolled 821 asymptomatic participants. Overall, 87.6% of the participants (719 of 821) reported a high-risk exposure to a confirmed Covid-19 contact. The incidence of new illness compatible with Covid-19 did not differ significantly between participants receiving hydroxychloroquine (49 of 414 [11.8%]) and those receiving placebo (58 of 407 [14.3%]); the absolute difference was -2.4 percentage points (95% confidence interval, -7.0 to 2.2; P = 0.35). Side effects were more common with hydroxychloroquine than with placebo (40.1% vs. 16.8%), but no serious adverse reactions were reported.ConclusionsAfter high-risk or moderate-risk exposure to Covid-19, hydroxychloroquine did not prevent illness compatible with Covid-19 or confirmed infection when used as postexposure prophylaxis within 4 days after exposure. (Funded by David Baszucki and Jan Ellison Baszucki and others; ClinicalTrials.gov number, NCT04308668.).

Dataset Information

Finding the Dose for Hydroxychloroquine Prophylaxis for COVID-19: The Desperate Search for Effectiveness.

Publications

Finding the Dose for Hydroxychloroquine Prophylaxis for COVID-19: The Desperate Search for Effectiveness.

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