Low-Dose Radiotherapy For Patients With SARS-COV-2 (COVID-19) Pneumonia

The authors propose a two-step randomized Phase II study to determine if single fraction low dose whole thorax megavoltage radiotherapy (LD-WTRT) can produce meaningful clinical benefit in COVID-19 patients. In Step 1, patients would be randomized 1:2 to standard of care without or with LD-WTRT. Patients randomized to LD-WTRT would be further randomized to either 35 cGy or 100 cGy. After 20 patients have been enrolled on each low-dose radiotherapy arm, they will be evaluated to determine the selection of the "best radiotherapy dose-arm" for the remainder of the patients. This will be done by analyzing clinical benefit, risk profile, and the dynamics of biomarker change, specifically focusing on IL-6

• If the rate of Grade 4 toxicity is lower by an absolute rate of 15% when comparing the 35 cGy and 100 cGy arms, the arm with the lower toxicity rate will be used for Step 2 of the trial.
• If the crude clinically meaningful event rate (CMER) which is a composite endpoint, is lower by an absolute rate of 20% when comparing the 35 cGy and 100 cGy arms, the lower CMER rate arm will be used for Step 2. CMER is defined as a composite of :

• Rate of mechanical ventilation (MV)
• Rate of prolonged hospital stay >10 days (PHS)
• Crude all-cause mortality rate at the time of analysis
• If the crude CMER is < 20% difference between the 35 cGy and 100 cGy arms, the investigators will determine whether there is a trend suggesting less Facility Resource Utilization Rate (FRUR). If the FRUR is 20% lower in either the 35 cGy or 100 cGy arms, that dose will be used for Step 2. The FRUR is based upon:

• Days of mechanical ventilation
• Days of hospitalization.
• If both crude CMER and FRU rates do not differ by at least 20%, the investigators will evaluate the area under the curve (AUC) for IL-6 levels drawn within 24 hours before LD-WTRT and at 48 hours (2d) and 168 hours (7d) after radiation. If one of the two arms has a 20% lower serum IL-6 AUC one week after radiotherapy, the investigators will select that arm for Step 2.
• If none of the parameters in numbers 1-4 above differ in the criteria listed, the investigators will use the lower dose of 35 cGy for Step 2.

Inclusion criteria

• Laboratory-confirmed diagnosis of SARS-CoV-2 pneumonia
• Currently hospitalized with COVID-19
• Symptomatic fever, cough and/or dyspnea for < 9 days
• Patient or legal/authorized representative can understand and sign the study informed consent document
• Able to be positioned on a linear-accelerator couch for Radiation Therapy delivery
• And at least one of the following risk factors for significant pulmonary compromise:

• Fever > 102 degrees Fahrenheit during index admission
• Respiratory rate of ≥ 26 / minute within 24 hours of screening
• SpO2 ≤ 95% on room air within 24 hours of screening
• Any patient requiring 4 L/min oxygen therapy to maintain SpO2 >93% within 24 hours of screening
• Ratio of partial pressure of arterial oxygen to fraction of inspired air < 320.
• Patients may be enrolled on this trial while concurrently enrolled on other COVID-19 clinical trials.

Exclusion criteria

• Currently requiring mechanical ventilation
• Prior thoracic radiotherapy, with the exception of the following:

• Breast or post-mastectomy chest wall radiation (without regional nodal irradiation) may be included at the discretion of the site primary investigator, and
• Thoracic skin radiation therapy (without regional nodal irradiation) is allowed.
• Known hereditary syndrome with increased sensitivity to radiotherapy, including ataxia-telangiectasia, xeroderma pigmentosum, and Nijmegen Breakage Syndrome
• Known prior systemic use of the following drugs: Bleomycin, Carmustine, Methotrexate, Busulfan, Cyclophosphamide, or Amiodarone
• History of or current diagnosis of pulmonary fibrosis, or an alternative pulmonary condition responsible for significant lung compromise at the discretion of the site primary investigator
• History of lung lobectomy or pneumonectomy
• Known history of pulmonary sarcoidosis, Wegener's granulomatosis, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, polymyositis/dermatomyositis, Sjögren's syndrome, mixed connective tissue disease, Churg-Strauss syndrome, Goodpasture's syndrome, or ankylosing spondylitis.
• Symptomatic congestive heart failure within the past 6 months including during current hospitalization
• History of recent or current malignancy receiving any cytotoxic chemotherapy or immunotherapy within the past 6 months.
• History of bone marrow transplantation.
• History of any solid organ transplant (renal, cardiac, liver, lung) requiring immunosuppressive therapy.
• Females who are pregnant or breast feeding.
• Inability to undergo radiotherapy for any other medical or cognitive issues.