This phase III trial compares low dose whole lung radiation therapy to best supportive care plus physicians choice in treating patients with COVID-19 infection. Low dose whole lung radiation therapy may work better than the current best supportive care and physician's choice in improving patients' clinical status, the radiographic appearance of their lungs, or their laboratory blood tests.

PRIMARY OBJECTIVE:

I. Intubation-free survival (IFS) and (2) time to clinical recovery (TTCR) based on weaning off supplementary oxygenation or hospital discharge in COVID 19 patients.

SECONDARY OBJECTIVES:

I. To investigate (1) other clinical, (2) radiographic, (3) serologic markers, and (4) immune marker response to best supportive care plus provider's choice of pharmaceutical treatment either with or without whole-lung LD-RT

II. Secondary clinical improvements will look at time to hospital discharge, prevention of ICU admissions, and overall survival.

OUTLINE: Patients are blindly randomized to 1 of 2 arms.

ARM I: Patients receive best supportive care plus physician choice of treatment

ARM II: Patients receive best supportive care plus LDRT (experimental arm).

After completion of study, patients are followed up for 14 days.

Inclusion Criteria:

• Be age 50 or over; Not pregnant (will undergo pregnancy testing if below age 55);
• Have had a positive PCR-based test confirming the diagnosis of COVID-19 within 5 days (+/-2 day)of study enrollment*
• Have had clinical signs of severe acute respiratory syndrome or pneumonia (ie. dyspnea, cough,fever) that primary team feels like patient needs rescuing with LD-RT.**
• Have visible bilateral consolidations/ground glass opacities on chest imaging
• Require supplemental oxygen at the time of enrollment, defined by inability to wean from supplemental oxygen within 24 hours prior to enrollment.
• Not require intubation within 12 hours of randomization (ie, not screen fail). Intubation after enrollment but within 12 hours of randomization will be defined as a screen failure for both the LD-RT and control cohorts.
• Be enrolled within 5 days (+/- 2) of first hospitalization for COVID-19. Prior hospitalization for COVID-19 will be an exclusion criteria (prior ED visits are permissible).
• Willingness and ability of the subject to comply with scheduled visits, protocol-specified laboratory tests, other study procedures, and study restrictions
• Evidence of a signed informed consent/assent indicating that the subject is aware of the infectious nature of the disease and has been informed of the procedures to be followed, potential risks and discomforts, potential benefits, and other pertinent aspects of study participation

Exclusion Criteria:

• Pregnant and/or planned to be pregnant within in next 6 months
• Age 49 or younger at time of enrollment
• Prior inpatient hospitalization for COVID-19 (prior emergency department [ED] visits are not an exclusion criteria)
• Prior enrollment on a separate COVID-19-related therapeutric trial (subsequent co-enrollment is permitted for patinets randomized to the control arm).
• Notably, concurrent use of COVID-directed therapies is no longer an exclusion criteria for this trial. This includes azithromycin, dexamethasone, remdesevir, convalescent plasma, or any other COVIDdirected drug therapy.

Results of the trial and not individual patient data will be shared. The study protocol, consent, and investigator's brochure will be available. The statistical plan is incorporated into the protocol, along with inclusion and exclusion criteria.