COVID-19 has rapidly evolved into a generalized global pandemic. Post-exposure prophylaxis (PEP) against on COVID-19 was identified as an urgent research priority by the WHO, and lopinavir/ritonavir (LPV/r) is a promising candidate for both COVID-19 treatment and PEP, with a good safety profile and global availability. This is a cluster randomized controlled trial (RCT) of oral LPV/r as PEP against COVID-19, that will address the immediate need for preventive interventions, generate key data on COVID-19 transmission, and serve as a research platform for future vaccines and preventive agents.

Inclusion Criteria:

1. High risk close contact with a confirmed COVID-19 case during their symptomatic period, including one day before symptom onset, within the past 1-7 days. High risk close contact is defined as any of the following exposures without the consistent appropriate use of recommended personal protective equipment:

   1. Provided direct care for the index case
   2. Had close physical contact with the index case
   3. Lived with the index case
   4. Had close contact (within 2 metres), without direct physical contact, for a prolonged period of time
   5. Had direct contact with infectious body fluids, including oral secretions, respiratory secretions, or stool.

2. Successfully contacted by the study team within 24 hours of study team notification of the relevant index COVID-19 case. This time window is necessary because the efficacy of PEP may be dependent on the timing of its initiation, and because randomization of a ring cannot be delayed while awaiting response from contacts that cannot be rapidly reached.

3. Age ≥6 months, since the safety and pharmacokinetic profiles of LPV/r in pediatric patients below the age of 6 months have not been established.

4. Ability to communicate with study staff in English

Exclusion Criteria:

1. Known hypersensitivity/allergy to lopinavir or ritonavir.

2. Current use of LPV/r for the treatment or prevention of HIV infection.

3. Receipt of LPV/r in the context of this trial or any other trial of COVID-19 PEP within 2 days or less prior to the last known contact with the index COVID-19 case. The two day time window is intended to ensure that exposure would not have occurred in the presence of clinically relevant drug levels (five times the elimination half-life of LPV/r, which is estimated at 4-6 hours with prolonged use).

4. Baseline respiratory tract specimen positive for COVID-19. Randomized participants whose baseline samples subsequently show COVID-19 will have study drug discontinued but still remain under observation.

5. Current breastfeeding, due to potential for serious adverse reactions in nursing infants exposed to LPV/r

6. Concomitant medications with prohibited drug interactions with LPV/r that cannot be temporarily suspended/replaced, including but not restricted to: 37

   • alfuzosin (e.g. Xatral®)

   • amiodarone (e.g. Cordarone™)

   • apalutamide (e.g. Erleada™)

   • astemizole*, terfenadine*

   • cisapride*

   • colchicine, when used in patients with renal and/or hepatic impairment

   • dronedarone (e.g., Multaq®)

   • elbasvir/grazoprevir (e.g., ZepatierTM)

   • ergotamine* (e.g. Cafergot®*), dihydroergotamine (e.g. Migranal®), ergonovine, methylergonovine*

   • fusidic acid (e.g., Fucidin®), systemic*

   • lurasidone (e.g., Latuda®), pimozide (e.g., Orap®*)

   • neratinib (e.g., Nerlynx®)

   • sildenafil (e.g., Revatio®)

   • triazolam (e.g. Halcion®), midazolam oral*

   • rifampin (e.g. Rimactane®*, Rifadin®, Rifater®*, Rifamate®*)

   • St. John's Wort

   • Tadalafil (e.g. Adcirca®)

   • venetoclax (e.g. Venclexta®)

   • lovastatin (e.g., Mevacor®*), lomitapide (e.g., JuxtapidTM) or simvastatin (e.g., Zocor®)

   • vardenafil (e.g., Levitra® or Staxyn®)

   • salmeterol (e.g., Advair® or Serevent®)

     • denotes products not marketed in Canada

TBA