key: cord-0977758-jc9ugexn
authors: Rana, D. R.; Dulal, S.
title: Therapeutic Application of Chloroquine in Clinical Trials for COVID-19
date: 2020-03-27
journal: nan
DOI: 10.1101/2020.03.22.20040964
sha: 5624f7d0ef88d47c5c8e0396a217300060374346
doc_id: 977758
cord_uid: jc9ugexn

The novel corona virus disease -2019 (COVID-19) pandemic has caused a massive global public health havoc. Recent clinical trials carried out in China has found a promising therapeutic application of chloroquine and hydroxychloroquine for COVID-19. This study meticulously evaluated the various dosages of chloroquine and hydroxychloroquine utilized in clinical trials registered in Chinese and US clinical trial registries for the treatment of pneumonia caused by SARS-CoV-2.

species (7) . Chloroquine phosphate can also be replaced with another member of its family, hydroxychloroquine. The active compound chloroquine constitutes 60% in chloroquine phosphate and 77.5% in hydroxychloroquine respectively. The recommended 3-day chloroquine phosphate dosage for malaria treatments for adults is 1 gm orally followed by 500 mg after 6-8 hours in the first day and 500 mg per day for second and the third day (7) . Similarly, the 3-day dosage for hydroxychloroquine is 800 mg orally followed by 400 mg after 6-8 hours in the first day and 400 mg per day for second and third day (8). This study was specifically conducted to examine the various dosages utilized in previous clinical trials registered and underwent for the treatment of pneumonia caused by SARS-CoV-2. The guidelines by the Chinese government has postulated the dose of 500 mg twice a day for 7 days for adults aged 18-65 years and weighing more than 50 kg; and initial dose of 500 mg twice a day for first two days and 500 mg per day for days 3 through 7 for adults of weight less than 50 kg (4).

List of clinical trials registered in China were utilized in this study accessing with a ready-made excel spreadsheet from the Chinese clinical trial registry (9), on 16 th March, 2020 provided in the website. The list of clinical trials registered in the US government clinical trial registry (10) were retrieved by searching "coronavirus" key word on 16 th March, 2020. All the trials were filtered out based on the presence of word "chloroquine" in the title irrespective of the metabolic forms of the molecule (hydroxychloroquine) or tests being carried alone or in combination with other antiviral therapies. Excel spreadsheet file was prepared based on various headings including intervention groups, randomization status, sample sizes, etc. Univariate statistics were used to report the methodologies of the trials.

As of 16 th March 2020, 462 trials were registered in the Chinese clinical trial registry (9) starting from 23 rd January, 2020. 22 (4.8%, 22/462) clinical trials used the word chloroquine in their titles. Three of them were reported to have been canceled, one . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.03.22.20040964 doi: medRxiv preprint was a prophylactic study and another was a duplicate copy. Seventeen (3.7%, 17/462) clinical trials from the Chinese registry were used for the downstream analysis. As of 16 th March 2020, 97 entries were obtained by searching for coronavirus related clinical trials in the US clinical trial registry (10) of which only 65 were registered after 1 st January 2020. Out of 65 registrations, 5 (7.7%, 5/65) were related to use of chloroquine. Two of these were registered from China, one from Thailand, one from the United Kingdom and one form South Korea. The study from United Kingdom Most of the trials used oral chloroquine phosphate (67%, 14/21) as treatment option, followed by hydroxychloroquine (33%, 7/21), aerosolized chloroquine (10%, 2/21) and combination of chloroquine and other antivirals (5%, 1/21) ( Table 1 ). The maximum quantity of chloroquine given was 42 gm in a duration of 42 days and the lowest reported was 4 gm in a duration of 5 days (Table 2) . Similarly, the maximum quantity of hydroxychloroquine given was 12.4 gm in a duration of 14 days and the lowest . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.03.22.20040964 doi: medRxiv preprint amount was 2 gm in a period of 5 days. Only one of the two trials using aerosolized chloroquine phosphate stated the dosage. It was 2.1 gm in a period of 7 days. All 2,602 study patients were planned to be enrolled. Four trials registered in the US registry didn't have details about sample size allocation in different intervention arms. The Chinese government in its 6 th and 7 th guidelines for the treatment of novel coronavirus pneumonia has recommended use of chloroquine phosphate at specific dosages (Table 3) . Modern and robust scientific interventions at national and international level for prevention, containment and treatment has protected mankind from various deadly diseases like Ebola, Severe Acute Respiratory Syndrome, Middle . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.03.22.20040964 doi: medRxiv preprint East Respiratory Syndrome, etc. in the contemporary parameters. The Spanish flu about one hundred years ago claimed about up to 50 million lives (12) as modern scientific knowledge were contemporarily lacking and limited. As predicted, in the absence of these measures, if 60% of global population were infected as forecasted by experts, and approximately 20% required treatment of chloroquine phosphate or hydroxychloroquine sulphate (13) , the cost could range tens of thousands USD per million population (Table 3) . 19 (20,21) . In spite of that, continued efforts to try different dosages in ethically valid clinical trials is required for the assessment of effective and safe dosage administration. This can importantly contribute to guide the medical professionals for prescribing the accurate interventions and also contribute to pharmaceutical companies for deciding appropriate manufacturing pathways. While hydroxchloroquine has low dosage requirements and lesser side effects, the comparative price for complete prescribed treatment is more than five times of chloroquine phosphate. While malaria is endemic in poor parts of the world, the prevalence is still too less than the panic and feared caused by prevalence of COVID-19 prompting pharmaceuticals for scaling up for the production of chloroquine.

As chloroquine has significant adverse events, effective short-course dosing are very important. Moreover, both of these drugs are prescribed for weeks to months for various indications. Other antiviral drugs in pipeline may not be very useful as their productions and supplies to the developing countries may require lengthy timeframe whereas mass production of chloroquine and hydroxychloroquine is already in place in malaria endemic developing countries.

. CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020. 03.22.20040964 doi: medRxiv preprint In conclusion, chloroquine and hydroxchloroquine might have the potential to be the best therapeutic medication for this rampant COVID-19 in the present context. However the corroborating evidences from these undergoing clinical trials are definitely demanded to make the ultimate decision on COVID-19 treatment.

Conflicts of interest: None . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.03.22.20040964 doi: medRxiv preprint

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