On 11 March 2020, the World Health Organization declared SARS-CoV-2 (commonly called COVID-19) a global pandemic. As in any pandemic, maintaining the health and safety of the healthcare workforce is of great importance as health care workers (HCW) remain a critical line of defence against the spread of COVID-19 and play a vital role in the recovery of those already infected. Frontline HCW, such as those in the emergency department (ED), are at high risk of contracting COVID-19 due to their close proximity to patients who may have the virus. The impact of frontline HCW becoming ill and thus unable to go to work is equally high, and of grave risk to the function of the healthcare system and the ability to minimize the impact of the current pandemic. This study aims to evaluate whether hydroxychloroquine (HCQ), a well-tolerated drug typically used in the prevention of malaria transmission and rheumatic disease, taken before and during exposure to patients with COVID-19, is effective at reducing COVID-19 infections among ED health care workers.
On March 11th, 2020, the World Health Organization (WHO) declared coronavirus disease
(COVID-19) caused by severe acute respiratory virus coronavirus 2 (SARS-CoV-2) a pandemic. As
of March 22, 2020 there have been over 267,013 confirmed cases and 11,201 deaths in 185
different countries or regions; it is quickly overwhelming health care systems worldwide to
detrimental effect. Even with current moderate interventions imposed, estimates predict that
10-18% of the Canadian population will be infected with the virus by its peak in July. Health
care workers (HCWs) remain a critical line of defence in the fight against this pandemic and
maintaining their health is not only an important social responsibility of the government,
but it is also of vital national interest to treat and control others infected with this
virus or sick with other disease.
Estimates from China indicate that HCWs make up 3.8% of cases, while in Italy it is reported
to be much higher - 8.3%. Early numbers from front-line workers in Italy suggested up to 20%
of HCWs become infected with COVID-19, and these rates are approximately 3 times higher than
the general population. When HCWs become sick, not only do they risk dying, but they also
must take weeks away from work limiting the ability of the health care system to function.
The fear associated with becoming ill also causes higher rates of missed work and higher
rates of burnout, as seen with previous outbreaks. It is also now clear that asymptomatic
transmission of COVID-19 not only occurs, but may even be the most important factor in spread
of the virus. HCWs may therefore become vectors of viral spread to those who are the most
vulnerable in other areas of the hospital. Preventing HCWs from acquiring SARS-CoV-2 should
therefore be of the utmost importance to national interests.
Repurposing drugs already known to be safe and tolerable in humans provides a major advantage
in a pandemic where time is critical. Of candidate drugs, chloroquine (CQ) and its derivative
hydroxychloroquine (HCQ), have shown some promise. Originally an anti-malarial medication, CQ
exerts direct antiviral effects by inhibiting pH-dependent steps of the replication of
several viruses, including coronaviruses. It also has immunomodulatory effects, suppressing
the release of TNFα and IL-6, which are involved in the inflammatory complications of several
viral diseases. In vitro data has shown that CQ potently blocks virus infection at low
micromolar concentrations with a high selectivity index. CQ is also widely distributed
throughout the body, including the lungs, after oral administration. An early clinical trial
of more than 100 COVID-19 patients in China reported that CQ was superior to placebo in
inhibiting pneumonia, improving lung imaging, promoting viral seroconversion, and shortening
the disease course, although data was not released. Based on those results experts in China
recommended CQ 500mg twice daily for ten days in all patients with COVID-19. HCQ has also
been shown to also have anti-SARS-CoV-2 activity in vitro and may actually be more potent. It
has a better safety profile than CQ (during long term use), and allows a higher daily dose,
with fewer concerns of drug-drug interactions. Preliminary clinical data also suggests that
HCQ may lead to significantly faster viral clearance in COVID-19 patients as assessed by
nasopharyngeal swab (70% vs. 12.5%, p=0.001).
Pre-exposure prophylaxis (PrEP) offers the ability to protect front-line HCWs from illness,
decrease nosocomial spread of SARS-CoV-2, and prevent loss of work force due to illness.
Rigorous testing of HCQ for this purpose is critical at this time. The investigators
therefore aim to conduct the first randomized placebo-controlled trial of HCQ to prevent
COVID-19 infections in emergency departments (ED) as they prepare for escalating rates of
COVID-19 in Toronto, Canada.
Drug: Hydroxychloroquine
Oral Hydroxychloroquine, 400 mg taken once daily, for three months as pre-exposure prophylaxis to prevent COVID-19 in health care workers in the emergency department.
Drug: Placebo oral tablet
Placebo pill (same formula as Hydroxychloroquine without active ingredient) taken once daily, for three months.
Inclusion Criteria:
- Health care worker (HCW) in the emergency department who is anticipated to work at
least 10 shifts over the duration of the study period (minimum 6 hours per shift) and
anticipated to remain in the emergency department for the duration of the study (i.e.,
not transferring to another unit). For the purposes of the study, "health care
workers" are physicians (including residents), nurses, nurse practitioners, physician
assistants, respiratory therapists, X-ray technicians, social workers and support
staff (including but not limited to house-keeping, and porters).
- Age ≥18 years.
- Ability to communicate with study staff in English
Exclusion Criteria:
- Currently pregnant, planning to become pregnant during the study period, and/or breast
feeding
- Known hypersensitivity/allergy to hydroxychloroquine or to 4-aminoquinoline compounds.
- Current use of hydroxychloroquine for the treatment of a medical condition.
- Known prolonged QT syndrome, or concomitant medications which simultaneously may
prolong the QTC that cannot be temporarily suspended/replaced. These are including but
not limited to Class IA, IC and III antiarrhythmics; certain antidepressants,
antipsychotics, and anti-infectives; domperidone; 5-hydroxytryptamine (5-HT)3 receptor
antagonists; kinase inhibitors; histone deacetylase inhibitors beta-2 adrenoceptor
agonists.
- Known pre-existing retinopathy.
- Disclosure of self-administered use of hydroxychloroquine or chloroquine within 12
weeks prior to study. This window allows five half-lives of HCQ (i.e. 21 days) to pass
before being reintroduced to the drug.
- Confirmed symptomatic COVID-19 at time of enrollment, i.e. symptom of COVID-19 at
enrollment with confirmation of SARS-CoV-2 infection by viral detection as performed
according to local guidelines for symptomatic HCWs. All participants with COVID-19
symptoms at enrollment will be directed to have confirmatory testing (within the
department or occupational health as per the site guidelines). Participants who are
negative for SARS-CoV-2 will be redirected to enrollment procedures; those testing
positive will be excluded.
University Health Network
Toronto, Ontario, Canada