Chloroquine, Hydroxychloroquine or Only Supportive Care in Patients AdmItted With Moderate to Severe COVID-19

Study rationale CQ and HCQ were both employed in the treatment of COVID-19 in China. Based on
unpublished anecdotal positive results in China, CQ is now implemented in China and the
Netherlands in severe COVID-19. HCQ is an analog of CQ with more anti-viral effectivity ex
vivo, better safety and tolerability profile.

Rationale for the employment of CQ and HCQ in China comes from the fact that both reduce
COVID-19 replication ex-vivo. On top of this, both drugs have clear immunomodulating effects
(which is used for various indications to treat rheumatologic diseases) and have shown
promising results in patients with dengue and HIV.

Currently, in the Dutch guidelines, for moderate severely ill patients CQ base is the first
line of therapy for patients admitted in hospital with moderate to severe COVID-19.

The time needed to "load" the body when using CQ and thus the possible late onset of action
suggests that initiation of treatment should be timely. Moreover, the hypothesized mode of
action suggests that both HCQ and CQ inhibit cellular replication of COVID-19 but do not have
an intrinsic effect on the virus, thus could be best employed when the viral load is low
(i.e. early phase of the disease) and thus safe time to improve the subsequent immune
response. This underlines that both drugs should be implemented early rather than late in the
course of SARS-COV-2 infection.

The investigators propose a cluster randomized controlled study evaluating the value of
chloroquine and hydroxychloroquine compared to no antiviral therapy in admitted patients with
moderate to severe COVID-19.

Study design:

Population Adult patients with confirmed COVID-19, with moderate to severe symptoms and
admitted to the hospital and a NEWS-2 score ≤ 5, will be available for the study.

Intervention

All three treatment arms contain standard supportive care during hospital admission with in
two arms an addition with either chloroquine (CQ) or hydroxychloroquine (HCQ) Despite the
inclusion of CQ and HCQ as possible additional treatment for COVID-19 in the Dutch treatment
guideline, there's no conclusion on the best treatment strategy in this population. Based on
pharmacokinetic modelling, and the safety profile, HCQ seems to be more promising than CQ,
but both drugs have to be studied in relation to COVID-19. Furthermore, the availability of
both drugs might differ from country to country; in the Netherlands for instance, chloroquine
is widely available. Therefore, a 1:1:1 trial including standard supportive care with in
addition CQ or HCQ as suggested in the LCI/SWAB guideline, the optimal dosages in the
different treatment arms are as follows:

1. Supportive care + chloroquine base arm: loading dose 600mg, followed by 300mg 12 hours
later, followed by 300mg bid for 4 days; total treatment duration of 5 days

2. Supportive care + hydroxychloroquine arm: loading dose 400mg bid, followed by 200mg bid
for 4 days; total treatment duration of 5 days.

3. Supportive care only. Dosage of chloroquine and Hydroxychloroquine will be adjusted, if
the patients has a renal impairment with an estimated glomerular filtration rate (eGDR)
<10, to 50% of the initial dosage.

If patient will be discharged from hospital before the end of the treatment, treatment is
continued outside of the hospital. The general practitioner will receive note of the
treatment at discharge.

Main studyendpoint Composite endpoint with disease progression defined as a NEWS2score ≥ 7
within 14 days or resulting in admission to Intensive/Medium Care unit or resulting in death
within 14 days.