This Phase IIB study will evaluate the efficacy of hydroxychloroquine (HCQ) and azithromycin (Azithro) to prevent hospitalization or death in symptomatic adult outpatients with COVID-19 caused by SARS-CoV-2 infection.

Participants will be randomized 1:1 to receive active/placebo study treatment as follows: HCQ/Placebo 400 mg orally twice a day on Day 0 followed by 200 mg orally twice a day for 6 days, and Azithro/Placebo 500 mg once on Day 0, followed by 250 mg daily for 4 days.

Stratification will be by "high" versus "low" risk of progression to severe COVID-19, where "high risk" is defined as a person age ≥60 years or having at least one of several specified comorbidities.

Participants will receive study treatment for 7 days and will be followed for an additional 23 weeks 13 days. Assessments on a subset of 200 participants will include blood collection, self-collected nasal swabs, and nasopharyngeal swabs.

Inclusion Criteria:

• Documentation of confirmed active severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection.
• Experiencing at least one of the following SARS-CoV-2 infection symptoms within 24 hours of screening: fever screening ( can be subjective symptom(s) OR cough OR shortness of breath. must be new or worse compared to pre-COVID-19 health status:
• Fever (can be subjective) or feeling feverish
• Cough
• Shortness of breath or difficulty breathing at rest or with exertion
• Sore throat
• Body pain or muscle pain
• Fatigue
• Headache
• Agrees to not participate in another clinical trial for the treatment of COVID-19 or SARS-CoV-2 during the study period up until reaching hospitalization or 21 20 days, whichever is earliest.
• Agrees to not obtain study medications outside of the A5395 study.

Exclusion Criteria:

• Need for hospitalization or immediate medical attention in the clinical opinion of the study investigator.
• History of or current hospitalization for COVID-19.
• History of ventricular arrhythmia or using antiarrhythmics within the past 30 days.
• Personal or family history of Long QT syndrome.
• History of kidney disease.
• History of ischemic or structural heart disease.
• History of hypokalemia or hypomagnesemia or taking potassium supplementation or magnesium supplementation
• Personal medical history of porphyria, retinopathy, severe hepatic impairment, or glucose-6-phosphate dehydrogenase (G6PD) deficiency.
• Use of drugs with possible anti-SARS-CoV-2 activity within 30 days prior to study entry, e.g., remdesivir, lopinavir/ritonavir fixed dose combination, ribavirin, chloroquine, hydroxychloroquine, and azithromycin, or participation in a clinical trial involving any of these drugs whether for treatment or prophylaxis.
• Requirement or expected requirement for a medication that significantly prolongs QT intervals or increases risk for QT prolongation.
• Loop diuretics are exceptions to above exclusion criterion but these cannot be used within 30 days prior to study entry.
• Participating in a study where co-enrollment is not allowed.
• Receipt of a SARS-CoV-2 vaccination prior to study entry.
• Known allergy/sensitivity or any hypersensitivity to components of HCQ, azithromycin, or their formulation.
• More than 10 days of any of the following symptoms attributed to the SARS-CoV-2 infection at study entry:
  • Fever (can be subjective) or feeling feverish
  • Cough
  • Shortness of breath or difficulty breathing at rest or with exertion
  • Sore throat
  • Body pain or muscle pain
  • Fatigue
  • Headache
  • Chills
  • Nasal obstruction or congestion
  • Loss of taste or smell
  • Nausea or vomiting
  • Diarrhea