Randomized controlled trial of hydroxychloroquine versus placebo for the treatment of adult patients with acute coronavirus disease 2019 – COVID-19

Chloroquine is perhaps one of the most prescribed drugs in the world and in the past
Europeans visiting malaria-endemic areas for decades received chloroquine prophylaxis and
continued it for 2 months after their return. The recommended weight-adapted dose of
hydroxychloroquine (sulfate) for autoimmune diseases is a loading dose of 400-600 mg/day,
followed by 200-400 mg/day with two-monthly controls of laboratory and neurological
parameters. Hydroxychloroquine is used off-label in doses of up to 600 mg/day for the
treatment of several disease including autoimmune diseases (Lee et.al 2011), chronic Q Fever
(600 mg/day) (Van Roeden SE et.al 2018, Raoult D. et.al 1999), Whipple’s disease (600
mg/day for 12 months) (Lagier J.-C & Raoult) and it has been used in amebiasis at similar
doses.
Experiments confirm SARS-CoV-2 uses the angiotensin converting enzyme 2 receptor (ACE2)
as a cellular entry receptor. The anti-malarial and anti-rheumatic drug hydroxychloroquine
seems to be a potential candidate for the treatment of COVID-19 since it is able to block virus
infection by increasing the endosomal pH, required for virus/cell fusion (Wang et.al 2020), it
affects the activation of p38 mitogen-activated protein kinase (MAPK), involved in the
replication of HCoV-229E (Kono et.al. 2008) and can interfere with the terminal glycosylation
of ACE2, thus inhibiting SARS-CoV-2 infection (Vincent et al. 2005). Chloroquine, at an EC50
of 1.1 μM, was found to be effective in preventing replication of this virus (Wang et.al 2020).
Following the in vitro results, several studies on the use of hydroxychloroquine or chloroquine were launched in Chinese hospitals. Supposedly, the first results obtained from more than 100 patients showed the superiority of chloroquine compared with treatment of the control group in terms of reduction of exacerbation of pneumonia, duration of symptoms and delay of viral clearance, all in the absence of severe side effects (Gao et al. 2020). To date, the claimed findings have not been published and it is unclear on what data this is based (e.g. prospective or retrospective). Nonetheless, the multicenter collaboration group in China has recommended chloroquine phosphate tablet, 500 mg twice per day for 10 days for patients diagnosed as mild, moderate and severe cases of novel coronavirus pneumonia and without contraindications to chloroquine (Gao et al. 2020). The drug is recommended to be included in the next version of the Guidelines for the Prevention, Diagnosis, and Treatment of Pneumonia Caused by COVID-19 issued by the National Health Commission of the People's Republic of China for treatment of COVID-19 infection in larger populations in the future (Gao et al. 2020). From France, the results of an open-label non-randomized clinical trial using hydroxychloroquine and azithromycin as a treatment of COVID-19 showed that hydroxychloroquine treatment is
significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin (Gautret et al. 2020).
A total of 30 clinical trials are ongoing in China for the use of chloroquine or hydroxychloroquine as a therapeutic option in the treatment of SARS-CoV-2 infection causing COVID-19. However, no trial findings have been published and, with rapid reduction in new cases, it is unclear whether these studies will be completed.
Patients will be randomized in a 1:1 ratio to either hydroxychloroquine or placebo.
Randomization will be done with variable block sizes and allocated to the patient following screening, immediately before the first dose.
Patients and investigators, as well as treating physicians will be blinded to treatment-allocation.