The DEFEND trial will be the world's first clinical trial to study the effectiveness ofPaxlovid or Veklury in the prevention of cardiovascular post-acute sequelae of SARS-CoV-2among hospitalized adults. Additionally, this pilot study will inform the design andconduct of a future full-scale multi-centre trial by testing the feasibility and accuracyof this study design.
The overall goal of the DEFEND clinical trial is to study the effectiveness of Paxlovid
or Veklury in preventing cardiovascular post-acute among adults who test positive for
SARS-CoV-2 at admission to hospital. The pilot trial will inform the design and conduct
of a future full-scale multicentre trial by estimating the feasible recruitment rate. Our
secondary aim is to validate the accuracy of hospital-based outcome measures in
administrative data, and to determine the event rate of a composite of any of 4 newly
developed or worsening stroke, heart failure, venous thromboembolism, diabetes or death
within 1 year. The DEFEND trial will be a pragmatic, multicentre, registry-based,
double-blind, two-arm, randomized placebo-controlled internal pilot trial. If no major
protocol changes are required, the data obtained from the pilot will be included in the
future large trial; if major protocol changes are required, the results from the pilot
trial will still be published and will be useful to inform future research in this area.
The approach is pragmatic to include as many participants as possible that could benefit
from treatment with Paxlovid or Veklury using broad eligibility criteria for enrolment
and reflecting the real world practice of treating physicians. The DEFEND trial will
enrol participants aged ≥18 who have a positive polymerase chain reaction test for
SARS-CoV-2 at admission to 4 hospitals in Ontario. If they meet the inclusion/exclusion
criteria they will be randomized to either the experimental or control arm of the trial.
Those in the experimental arm will receive either Paxlovid orally twice daily for 5 days
or Veklury intravenously once daily for 5 days (as well as standard of care). Those in
the control arm will receive the placebo at the same schedule and frequency for 5 days
(as well as standard of care). Randomization will be at a 1:1 allocation, stratified by
hospital. The DEFEND trial seeks to enrol 118 participants at 4 committed pilot trial
sites that are representative of acute care hospitals across Ontario over a 12 month
period. This will be followed by a 12 month follow-up period. The DEFEND trial will be
the world's first clinical trial to study the effectiveness of Paxlovid or Veklury in the
prevention of cardiovascular post-acute sequelae of SARS-CoV-2 among hospitalized adults.
Drug: Nirmatrelvir/ritonavir
Paxlovid PO BID for 5 days + standard of care
Other Name: Paxlovid
Drug: Remdesivir
Veklury IV daily for 5 days + standard of care
Other Name: Veklury
Inclusion Criteria:
- ≥18 years old
- Positive PCR test for SARS-CoV-2 within 5 days of admission to hospital
- Normoxic (not receiving supplemental oxygen)
- Able to provide informed written consent (or, if patient is unable, have substitute
decision maker available)
Exclusion Criteria:
- Absolute contraindications to Paxlovid or Veklury (any of the following): Severe
allergy to Paxlovid or Veklury (e.g. anaphylaxis), co-administration with drugs
highly dependent on CYP3A for clearance, co-administration with potent CYP3A
inducers
- Exposure to Paxlovid or Veklury within previous 14 days;
- Receiving supplemental oxygen;
- Known positive SARS-CoV-2 PCR or rapid antigen test 5-90 days prior to admission;
- Limited life expectancy estimated to be ≤3 months;
- Pregnant and breastfeeding women
Kingston Health Sciences Centre
Kingston, Ontario, Canada
Niagara Health System
St. Catharines, Ontario, Canada
Mount Sinai Hospital, Sinai Health System
Toronto, Ontario, Canada
St. Joseph's Health Centre, Unity Health Toronto
Toronto, Ontario, Canada
Dr. Kieran Quinn
416-843-8403
kieran.quinn@mail.utoronto.ca
Not Provided