To address the need to intervene to prevent the spread of COVID-19 in long-term care homes, we propose a randomized clinical trial of chemoprophylaxis in long-term care homes experiencing COVID-19 outbreaks. LTCH units experiencing an outbreak of COVID-19 will be randomized to chemoprophylaxis with favipiravir or placebo in a 1:1 ratio. Chemoprophylaxis in this setting refers to the use of favipiravir for pre-exposure prophylaxis, post-exposure prophylaxis, pre-emptive therapy, or treatment for established COVID-19. This design mimics the approach to influenza outbreaks, which has proven efficacy for outbreak control. The primary outcome will be control of the outbreak, defined as no new microbiologically confirmed case of COVID-19 for 24 consecutive days up to day 40.
Early in the COVID-19 pandemic, it became apparent that the elderly are disproportionately
bearing the burden of disease and mortality. Many outbreaks are occurring in long-term care
homes (LTCHs), with strikingly high mortality rates: nearly two-thirds of all Canadian COVID-
19 deaths are in LTCH residents. This is unsurprising, as viral respiratory outbreaks in
LTCHs are devastating: before the use of influenza vaccine, case fatality rates during
influenza outbreaks were as high as 55%. Interventions are thus urgently needed to control
LTCH outbreaks to mitigate harms to this vulnerable population and maximize acute care
capacity.
Chemoprophylaxis is the cornerstone of management of LTCH influenza outbreaks and disease
prophylaxis has been deemed a critical COVID-19 research priority by the World Health
Organization. While definitive therapies do not yet exist, there is significant interest in
repurposing existing anti-viral agents against COVID-19. Favipiravir, a broad spectrum
antiviral agent, demonstrates activity against SARS-CoV-2 in vitro, and was associated with
faster viral clearance, radiographic improvement, and clinical recovery in early trials.
Favipiravir is an ideal candidates for chemoprophylaxis, as it is orally available and has a
reasonable safety profile.
To address the need to intervene to prevent the spread of COVID-19 in LTCHs, we propose a
cluster-randomized placebo-controlled trial of chemoprophylaxis in LTCHs experiencing
COVID-19 outbreaks.
This study is a partially blinded, placebo-controlled cluster randomized trial of
chemoprophylaxis to control outbreaks of COVID-19 in LCTHs for the elderly. The unit of
analysis is a ward/unit. An outbreak is defined as ≥ 2 symptomatic
microbiologically-confirmedCOVID-19 cases within 7 days on the LTCH unit. This design is
selected to mimic the current approach to outbreaks of other respiratory viral infections,
both because this approach has proven effective for these other viruses, and because it is
standard practice and therefore feasible to implement.
Eligible LTCHs will be asked to report outbreaks to the study in addition to the
legally-required reporting to their local public health unit; public health units will also
be asked to discuss the study with LTCHs reporting outbreaks. In addition, study staff will
contact the infection control practitioner in each of the screened LTCHs twice weekly, to
ensure the prompt identification of outbreak units.
Residents and staff will be assessed for contraindications to enrollment and informed consent
will be obtained for residents and staff to receive the allocated intervention, and to be
followed up individually for clinical outcomes, adherence and safety during the outbreak.
LTCH units experiencing an outbreak of COVID-19 will be randomized to either favipiravir or
placebo in a 1:1 ratio. Favipiravir or placebo will be offered to all residents and staff who
will be working on the unit during the chemoprophylaxis period, according to the allocation.
Study drug will continue for a duration of 25 days. The dosage for favipiravir to be used in
this study for chemoprophylaxis is 1600 mg (8 x 200 mg tablets) orally twice daily on day 1
followed by 800 mg (4 x 200 mg tablets) orally twice daily on day 2-25. Residents in the LTCH
unit diagnosed with COVID-19 at enrollment will be offered treatment with favipiravir or
placebo for 14 days, according to the LTCH unit allocation. The dose of favipiravir for
treatment is 2000mmg orally twice daily on day 1, then 1000 mg orally twice daily for 13
additional days.
Surveillance for infection will occur as usual for resident illness within each LTCH; staff
will be asked to report symptoms and will be screened for symptoms each time they enter the
building. Consenting residents and staff will be screened at day 0, day 14 and day 40 to
identify asymptomatic infections and to assess duration of viral shedding. The primary
outcome will be control of the outbreak, defined as no new microbiologically confirmed case
of COVID-19 for 24 consecutive days up to day 40.
Drug: Favipiravir
Favipiravir is the experimental drug. The dosage for favipiravir to be used in this study for prophylaxis is 1600 mg (8 x 200 mg tablets) orally twice daily on day 1 followed by 800 mg (4 x 200 mg tablets) orally twice daily on days 2-25. The dose of favipiravir for treatment is 2000 mg orally twice daily on day 1, the 1000 mg orally twice daily for 13 additional days.
Other Name: Avigan
Drug: Favipiravir Placebo
Favipiravir Placebo is the placebo drug. For chemoprophylaxis, the dosage of favipiravir placebo is 8 tablets orally twice daily on day 1, followed by 4 tablets twice daily from days 2-25. The dosage of favipiravir placebo for treatment is 10 tablets orally twice daily on day 1, followed by tablets twice daily from days 2-14.
Inclusion Criteria:
- Inclusion criteria for LTCHs:
1. LTCH in Ontario with >80% of residents being adults ≥65 years of age.
2. Residents are or can be routinely assessed at least daily by staff.
3. LTCH has not previously had a unit enrolled in this study.
4. Outbreak of COVID-19 declared on at least one nursing unit, requiring all of the
following:
1. ≥2 to ≤4 residents who develop PCR-confirmed symptomatic COVID-19 infection
on the same unit within ≤ 7 days at the time when the outbreak is identified
as eligible.
2. ≤21 days from symptom onset in the index case at the time when the outbreak
is identified as eligible.
3. Cumulative attack rate in residents on the affected unit since the beginning
of the pandemic ≤25% at the time when the outbreak is identified as
eligible.
4. ≤20% of residents with microbiologically confirmed COVID-19 or line-listed
as a presumptive case in a COVID-19 outbreak and not tested for COVID-19 in
prior outbreaks within the last six months.
5. Nursing unit with ≥16 and ≤32 residents.
6. Nursing home agrees to work with study coordination to minimize the number
of persons who provide care on the unit.
5. Mechanism exists for delivery of medication and recording of administered
medication for all residents.
6. ≥80% of residents on outbreak unit are eligible and they or their substitute
decision makers consent to participate in the study.
7. Written informed consent of Medical Director, Administrator and a delegate of the
Residents' Council of the LTCH for LTCH to be included in the cluster trial.
- Inclusion criteria for LTCH residents:
1. Informed consent from resident or substitute decision maker (SDM)
- Inclusion criteria for LTCH staff:
1. Expected to work at least two 8-hour shifts, or the equivalent time (16 hours on
the unit) during the outbreak period.
2. Informed consent.
Exclusion Criteria:
- Exclusion criteria for LTCHs:
1. Inability to deliver medication to consenting residents within 96 hours of
identification of the outbreak.
2. Inability to define a physically separate unit with ≤32 residents.
3. Any of facility management, medical advisory committee or resident council do not
approve participation.
- Exclusion criteria for LTCH Residents and Staff:
1. Pregnancy (females < 55 years of age require a negative urine pregnancy test at
enrollment, and either menopause or two concurrent reliable methods of
contraception need to be confirmed)
2. History of abnormalities of uric acid metabolism, other than gout.
3. History of hypersensitivity to remdesivir or favipiravir
4. Previous diagnosis of hepatic cirrhosis
5. Current use of the following medications, which cannot be discontinued for the
duration of the study: pyrazinamide, hydralazine, more than 3000 mg of
acetaminophen per day
Mount Sinai Hospital
Toronto, Ontario, Canada
Allison J McGeer, MD, Principal Investigator
MOUNT SINAI HOSPITAL