Hydroxychloroquine Post-Exposure Prophylaxis for Coronavirus Disease (COVID-19) Among Health-Care Workers

BACKGROUND:

A novel coronavirus referred to as severe acute respiratory syndrome coronavirus 2
(SARS-CoV2) was identified as the causative agent for the pandemic coronavirus disease 2019
(COVID-19). While in most cases, COVID-19 is a mild disease, in almost 15% of cases it may
cause a severe disease leading to respiratory failure, septic shock, multi-organ failure and
death. The relatively high ratios of severe morbidity and mortality that occurs during a
short period led to an extremely high burden on health systems as expected in pandemics.
Health care personnel work long hours in a highly intensive work environment, increasing the
risk of exposure to SARS CoV-2 infection. In China, almost 4% of COVID-19 cases were of
health care staff, having severe disease in 15% of them. In Italy, more than two thousands
health care workers (HCWs) were diagnosed with COVID-19 consisting 9% of total confirmed
cases up to 15 of March, 2020.

Accumulating data suggest that the most likely mode of transmission of SARS CoV-2 is by
droplets, either by inhalation or by contact. Person to person transmission was identified
from asymptomatic infected cases that were redefined recently as pre-symptomatic cases. Most
health agencies suggest a careful approach regarding the protection of HCWs. Still,
accidental exposure of HCWs to COVID-19 cases occurs. Such exposure may occur in many
scenarios, either in the context of unprotected contact with unsuspected cases or
inappropriate protection in contact with suspected or confirmed cases of COVID-19. Exposure
of HCW to a COVID-19 case necessitates risk stratification of disease transmission. The CDC
defines the risk as high if a prolonged contact ("few minutes in a distance of 6 feet)
happened while the patient and the HCW did not wear a facemask. A medium risk is defined if
either the patient did not wear a facemask but HCW was with facemask but without eye
protection or a patient was wearing a facemask but the HCW was not. In both situations of
high and medium risk exposures, exclusion from work for 14 days after last exposure is
recommended.

Both HCWs safety and the critical demand for human resources in COVID-19 pandemic makes the
possibility of effective post exposure prophylaxis highly important.

Chroloquine/hydroxychloroquine for prophylaxis of SARS-CoV2:

Although the focus of chloroquine/HCQ in use for COVID-19 is mainly for treatment, a
potential additional use may be for prophylaxis. Chloroquine is in use for many years as
prophylaxis for malaria. In addition, in Zika virus infection it was evaluated and found
effective in transmission reduction in animal model. In SARS-CoV2, chloroquine/HCQ has
in-vitro activity that interferes with virus entry to host cells by the inhibition of
pre-entry step of the virus to host cells, interfering with viral particles binding to cell
surface receptor as well as reduces virus replication[8]. Such activity in the early stage of
infection may play a role in prevention of disease progression, making these drugs
hypothetically an optional effective post exposure prophylaxis (PEP). The theoretical effects
in such context include reduction of virus transmission, reduction of progression to lower
respiratory infection following infection and therefore preventing clinical disease and
finally reduction of intensity and duration of virus shedding. Given the safe profile of
these drugs and the low collateral damage, makes them a favorable PEP drugs.

The investigators plan in the present study to assess the effect of chloroquine/HCQ PEP given
for a restricted duration following a recognized event of a significant risk exposure among
HCWs in hospitals to prevent symptomatic infection and documented COVID-19.

OBJECTIVES The objective of this trial is to evaluate the efficacy of HCQ as PEP in reduction
of virus transmission among HCWs following unprotected close contact to patients with
COVID-19. The investigatots aim to demonstrate a decrease in clinical disease as well as
ameliorating disease severity and shortening virological shedding among HCW participants
developing COVID-19.

METHODS Study design: randomized controlled, superiority open label trial. Setting: The study
will be conducted in Rambam health Care Campus (RHCC)

Randomization:

Participants who meet eligibility criteria will be randomized in a 1:1 ratio. Randomization
will be done using a computer-generated list of random numbers allocated centrally through a
web site, stratified by hospital.

Intervention:

The intervention group will receive oral hydroxychloroquine. In the first day 400 mg twice
daily, followed by 200mg twice daily on days 2-10.

The control group will not receive treatment.

Criteria for discontinuing study drug include development of any of the following:

- Serious adverse event related to the drug

- Participant request

Sample size:

The trial will test for HDQ's superiority (1-sided alpha) assuming a primary outcome
incidence of 20% in the control group and a reduction of 50% in the intervention group. With
a 1-sided 5% alpha a fixed sample of 291 patients per group will provide 80% power to reject
the null hypothesis of no difference between study groups.

Follow-up and data collection:

Participants will be actively followed-up by phone call at days 7 and 14 and 30 days after
randomization. In addition, they will be asked to fulfill a diary on daily basis of
temperature and development of respiratory symptoms. Participants will be guided to contact
the research team if any signs or symptoms of disease or adverse effects appear.

If COVID-19 is suspected according to clinical signs and symptoms, participants will be
evaluated by physician by a phone call in order to decide if he/she needs hospital transfer
or additional outpatient tests. For all clinically suspected COVID-19 cases a nasal and
throat PCR tests will be taken within 48 hours from symptoms start. If positive, the test
will be repeated on day 14 and thereafter weekly up to 2 consecutive negative tests taken 24
hours apart. If first set of PCR tests was negative and symptoms continue for more than 72
hours a second set of PCR tests will be performed.

For participants admitted to hospital with a confirmed COVID-19, daily clinical and
laboratory follow up will be performed. Blood count, electrolytes and creatinine levels will
be taken on admission and repeated on days 5+/-2. Other tests will be performed as clinically
indicated. Chest x-ray or other chest imaging will be performed at recruitment if not
performed previously and repeated as necessary according to clinical judgment. PCR from
respiratory or body samples will be obtained on day 5 (or discharge if prior to day 5) and
otherwise as clinically indicated. Blood samples for serology will be taken at recruitment
and at day 14 (or at discharge if before day 14). Samples will be frozen and batch analyzed
at the end of the study.

All participants will be followed up to 30 days after inclusion. The data will be entered
anonymously into a central case report form (CRF). The investigatots will document the
follow-up, participants' virological tests and medical course data, including complications
and adverse events.

Study monitoring:

Trial follow-up and monitoring will be performed by The Rambam-Technion ID research team
using a risk-based monitoring approach with adaptive on-site monitoring.

Trial flow and recruitment follow-up: Recruitment reports will be collected monthly,
detailing the number of eligible participants, excluded participants, reason for exclusion
and number of included participants, in a structured table. The recruitment status vs.
expected recruitment rate will be reported monthly, overall and per site.

Remote monitoring: Remote monitoring will be performed continuously throughout the trial to
check for data completion and quality. Critical variables will be defined, based on data
needed for baseline description of the study cohort, information regarding the intervention
and outcome data. Feedback will be provided to local study coordinators via email or
telephone. Data will be completed or corrected in real time with the support of the
monitoring center. Risk thresholds will be defined for onsite monitoring.

Onsite monitoring: will be performed periodically and as required following the remote
monitoring thresholds. The regular onsite monitoring visits will include:

- Inspection of the informed consent forms with dates corresponding to recruitment

- Inclusion criteria confirmed vs. patients' charts

- Confirmation of primary outcome data in source documents Safety monitoring: The trial
will be followed by an independent data and safety monitoring board and a steering
committee. No interim analyses are planned. All serious adverse events will be reported
to the independent monitoring board. Interim analyses and serious adverse events will be
reported to the local ethics committees, as per local good practice guidelines.

Statistical analysis:

The primary analysis will include all randomized participants by intention to treat. A
per-protocol analysis will include participants who received the allocated intervention for
at least 5 calendar days.

Participants' baseline characteristics will be reported as mean with standard deviation, or
median with interquartile based on variable distributions. The relative risk for the primary
outcome will be computed with 95% confidence intervals. Time dependent variables will be
analyzed using Kaplan Meyer curves. The trial will not be powered for subgroup analyses.