Inclusion Criteria: 

• Participants aged 12 years or older and weighing ≥ 40 kg at screening.
• Refer to Appendix 4 for reproductive criteria and contraception requirements for male and female participants.
• Meeting 1 of the 2 categories of COVID-19 risk: ·
  • Category A: Immunocompromised;
  • Category B: Non-Immunocompromised, but with ≥ 2 risk factors;
  • Onset of signs/symptoms attributable to COVID-19 ≤ 10 days prior to the day of randomization for non-immunocompromised participants (Category B).
• Confirmed SARS-CoV-2 infection as determined by RT-PCR or acceptable test method performed by a health care provider in any specimen collected within 48 hours prior to randomization.
• Hospitalized for inpatient care for the treatment of clinical manifestations of severe COVID-19.
• Requirement for oxygen supplementation (via nasal cannula, mask, NIV or high flow oxygen) to maintain SpO2 ≥ 94% at the time of Screening and Randomization. Participants with chronic lung disease requiring home oxygen therapy are eligible if they require a higher than usual oxygen flow rate to maintain their target oxygen saturation.

Exclusion Criteria: 

• Critical illness, defined by ≥ 1 of the following:
  • Requirement for mechanical ventilation or ECMO at randomization, or likely to require IMV or ECMO within 12 hours of randomization in the judgment of the investigator, or clinical need for mechanical ventilation or ECMO, even if not able to be administered due to resource limitation at the time of randomization;
  • Multi-organ dysfunction/failure;
  • Hemodynamically unstable, eg. septic shock, cardiac failure or requiring vasopressors;
  • Participant not expected to survive 24 hours from time of randomization.
• History of severe chronic liver disease.
• Receiving dialysis of any kind or severe renal impairment defined as eGFR in adults < 30 mL/min/1.73 m^2 or eCrCl in adolescents aged 12 to 17 years < 30 mL/min.
• Confirmed concurrent active systemic infection other than COVID-19 that may interfere with the evaluation of response to the study intervention.
• History of hypersensitivity or other contraindication to any of the components of the study intervention, as determined by the investigator.
• Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the patient inappropriate for the study.
• Use of nirmatrelvir/ritonavir as an outpatient to treat the current COVID-19 related illness ≤ 7 days of randomization.
• Current use of any prohibited concomitant medication(s). 
• Inability to closely monitor concentrations of immunosuppressant medications (ie, Calcineurin inhibitors and mTOR inhibitors) and adjust their doses for nirmatrelvir/ritonavir DDI during active treatment, and for at least 5 days after the last dose of study intervention. Prior/Concurrent Clinical Study Experience:
• Previous administration with an investigational product (drug or vaccine-) within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer).
• Known prior participation in this trial.
• Females who are pregnant < 14 weeks gestation. Pregnancy ≥ 14 weeks is not exclusionary.
• Investigator site staff directly involved in the conduct of the study and their family members, site staff otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly involved in the conduct of the study and their family members.

Eligibility last updated 10/13/22. Questions regarding updates should be directed to the study team contact.