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Control of COVID-19 Outbreaks in Long Term Care

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04448119
Recruitment Status : Active, not recruiting
First Posted : June 25, 2020
Last Update Posted : August 13, 2021
Sponsor:
Collaborators:
MOUNT SINAI HOSPITAL
Applied Health Research Centre
Sunnybrook Health Sciences Centre
University Health Network, Toronto
University of Toronto
Information provided by (Responsible Party):
Appili Therapeutics Inc.

Tracking Information
First Submitted Date  ICMJE June 24, 2020
First Posted Date  ICMJE June 25, 2020
Last Update Posted Date August 13, 2021
Actual Study Start Date  ICMJE October 16, 2020
Estimated Primary Completion Date November 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 24, 2020)
Control of Outbreak [ Time Frame: Day 40 ]
Control of outbreak, defined as no new cases of COVID-19 in residents for 24 consecutive days up to day 40 after the start of prophylaxis
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 24, 2020)
  • Mortality (Residents) [ Time Frame: Day 40, Day 60 ]
    The proportion of residents of included LTCH units who die up to day 40, and up to day 60
  • COVID-19 Infection (Residents) [ Time Frame: Day 40 ]
    The proportion of residents of included LTCH units who were uninfected at baseline and develop new symptomatic microbiologically confirmed COVID-19 up to day 40
  • COVID-19 Infection (Staff) [ Time Frame: Day 14, Day 40 ]
    The proportion of exposed staff uninfected at baseline in whom SARS-CoV-2 infection is identified up to day 14 and up to day 40
  • Hospitalization (Residents) [ Time Frame: Day 40 ]
    The proportion of residents of included LTCH units hospitalized up to day 40
  • Medication Discontinuation (Residents) [ Time Frame: Day 40 ]
    The proportion of residents of included LTCH units who discontinue study medication due to adverse events
  • Medication Discontinuation (Staff) [ Time Frame: Day 40 ]
    The proportion of LTCH staff of included LTCH units who discontinue study medication due to adverse events
  • COVID-19 in new LTCH Units (a) [ Time Frame: Day 40 ]
    The occurrence of new microbiologically confirmed COVID-19 infections in residents in other units of the LTCH up to day 40 (dichotomous, at LTCH level)
  • COVID-19 in new LTCH Units (b) [ Time Frame: Day 40 ]
    The proportion of previously unaffected LTCH units of the remainder of the LTCH in which a case of COVID-19 is identified
  • COVID-19 in new LTCH Units (c) [ Time Frame: Day 40 ]
    The proportion of residents in the remainder of the LTCH who develop COVID-19 infections up to day 40
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Control of COVID-19 Outbreaks in Long Term Care
Official Title  ICMJE Control of COVID-19 Outbreaks in Long Term Care (CONTROL-COVID)
Brief Summary

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.

Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE
  • COVID-19
  • SARS-CoV-2
Intervention  ICMJE
  • 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.
Study Arms  ICMJE
  • Experimental: Chemoprophylaxis
    Participants of LTCH units allocated to the chemoprophylaxis arm receive favipiravir for 25 days. Residents in the LTCH unit diagnosed with COVID- 19 at enrollment will be offered treatment with favipiravir for 14 days.
    Intervention: Drug: Favipiravir
  • Placebo Comparator: Placebo
    Participants of LTCH units allocated to the control arm receive placebo for 25 days. Residents in the LTCH unit diagnosed with COVID-19 at enrollment will be offered treatment with placebo for 14 days.
    Intervention: Drug: Favipiravir Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: June 24, 2020)
760
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 2021
Estimated Primary Completion Date November 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 65 Years and older   (Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04448119
Other Study ID Numbers  ICMJE CONTROL-COVID-Favipiravir-1
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party Appili Therapeutics Inc.
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Appili Therapeutics Inc.
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • MOUNT SINAI HOSPITAL
  • Applied Health Research Centre
  • Sunnybrook Health Sciences Centre
  • University Health Network, Toronto
  • University of Toronto
Investigators  ICMJE
Principal Investigator: Allison J McGeer, MD MOUNT SINAI HOSPITAL
PRS Account Appili Therapeutics Inc.
Verification Date August 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP