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. Additionally, this pilot study will inform the design and conduct of a future full-scale multi-centre trial by testing the feasibility and accuracy of 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.

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