Table 3.

Suggested Parameters for the Study Protocol, if Low Dose Radiation Therapy (LDRT) is Planned to be Tested for COVID-19

Section	Protocol Content/Stipulation		Comments/Concerns to Address
Background	Rationale for the use of LDRT for COVID-19		Biology of disease and radiation Specific biological rationale for use and timing of LDRT
Objectives of LDRT
Primary	Presumably anti-inflammatory or this can be immunomodulatory (therapeutic effect of vaccine)		Address anti-inflammatory effect(s)
Secondary	Development of biomarker panels in the context of LDRT use, to aid in acute clinical management and in the analysis of late clinical trajectories of COVID-19 (55–66)		Address any anti-viral effect(s) as well as potential immune enhancement of disease Address coagulopathy effect(s)
Patient Selection
Eligibility	Clinical condition and measurable parameters; Specify clinical criteria in terms of respiratory status, overall performance status, and laboratory parameters of immune and inflammatory status. Adapt criteria with IRB approval as natural history and other treatments of COVID19 evolve. Carefully track number of eligible patients consented to the study receiving treatment Intent-to-treat analysis essential		Stratification much like the PREVENT trial likely useful to match controls better. Examples are the Charlson Comorbidity Index (67) and the Wuhan/Guangdong Risk Score (68) Assess both rate of clinical decline in addition to net scores Randomize patients to LDRT or control arm a few hours prior to availability of linear accelerator to deliver radiation. This will reduce number of patients randomized to LDRT that deteriorate without receiving the experimental LDRT
Exclusion	Criteria should be clearly specified Some discussants felt that trials of LDRT are currently not indicated, due to lack of data on mechanism and shifting standard care (e.g., Dexamethasone use making value of immune markers potentially challenging)		Ethical review- Institutional Review Board or another similar panel necessary
Gender & minority inclusion	Inclusion particularly relevant with the epidemiology of infection. Data should be collected regarding social and economic status, living conditions, co-morbidities and patient geography (e.g., pollution and lung disease correlations, etc.)		Underlying disparities in genetics or biology may impact outcome
Trial type and projected number of patients, duration of study
Phase 1	Generally, this is a specified Phase 1 trial or a run-in part of a Phase 2		Intent-to-treat analysis is essential
Phase 2, single arm or randomized	Run-in and randomization favored		Phase 2 run-in favored when there are Phase 1 safety data available
Phase 3	Felt to be insufficient evidence at present for a Phase 3 trial
Treatment
Radiation, target, dose, and schedule	Dose range of 0.35– 1.5 Gy (or up to 2 Gy); Single dose due to complex logistics Need to standardize definition of low, ultra-low, etc.		Megavoltage recommended Needs better biological assessment of intention of chosen dose because different doses may affect different subsets of the COVID-19 immune response and may vary from person to person
Concomitant drugs required as part of treatment	Critical to include data on corticosteroids,; other antivirals, and other inflammatory agents Consider anticoagulants, oxygen use and status, cardiac inotropes, history of prior and current use of ACE inhibitors, diabetes Complex geographic and environmental interactions linked to lung disease in addition to smoking and mining(69)		Describe/examine course of drugs in relation to LDRT because the relative timing of interventions could theoretically cause different therapeutic maneuvers to block each other. This may vary by economic situation (e.g., Low to Middle Income Country)
	Remdesivir(70) and Dexamethasone(10) are baseline for all patients at present
Other drugs	Details of prior/ current medications		Timing of course in relation to LDRT
Excluded	In this early phase it was felt that recruitment of pediatric/juvenile/middle-age and pregnant patients be avoided		No formal age cut-off was selected. Risk for secondary cancers made most feel age consideration to be reasonable
Drug - if randomized	Radiation was felt to be the primary agent to randomize (e.g., comparing different radiation doses or “standard of care” +/− radiation) Steroid dose could be added if necessary (or frequency of its use)		Radiation (dose) +/− steroids vs. steroids without radiation More than one radiation dose could be tested vs. arm without radiation
Drug #1	One participant mentioned concomitant use of antibodies to reduce selected cell populations and minimize cytokine storm as a possible treatment		No specific recommendation by workshop
Response criteria
Circulating blood counts	Include granulocytes and lymphocytes, with a focus on subtyping via flow cytometry to evaluate subtypes (exhaustion, etc.) Mast cell populations are also of interest T cell lymphopenia and exhaustion, N:L ratio, HLA-DR + monocytes, CD14+:CD16+ monocytes, TF+ monocytes		Neutrophil/lymphocyte ratio may be a helpful biomarker Dexamethasone may reset current trial designs in this context
Immunological- general	Pre- and post-treatment evaluation		Involvement with appropriate expertise. Dexamethasone may reset the current trial designs in this context
	Fibrosis biology felt to be important for both control and treatment patient cohorts
	Evidence of: Pro: antifibrotic effect	Con - no anti- fibrotic effect
	Normalization: IL-6, ratio of IL-10: TNF-α, CRP, IL-10/23, IL-1β, IFN-type I, IL-2, fibrinogen, TPA, PAI-1, ferritin, albumin, D-dimer, LDH, prothrombin, C3/C5 complement	Further rise in systemic proinflammatory markers, coagulopathy and immune paralysis
Immunological- SARS-CoV-2 related (See Table 2)	As above, other factors to be collected from the same samples as allowed (complement, IL-6, other IL factors, TNF-factors, etc.)		As above-appropriate expertise
	Evidence of: Pro: improvement of viral disease	Con: no improvement
	Normalization: IFN-α (or IP-10), Ab titers, S-protein tetramers	Rising angiotensin II (viral load and lung injury)
Chemistry	AST, ALT and others per routine care
Imaging
Chest (CT, X-ray)	Chest X-ray, unilateral or bilateral changes or 3-D ultrasound if no X-ray available CT-scans likely difficult due to logistics involving movement of patients, possible contamination of equipment and staff exposures		Lung infiltration may impact radiation lung dose
Other organs	Liver, mediastinal content, scatter dose to the thyroid, stomach, colon, the great vessels, the bones of the chest including their marrow, and potentially other organs.		Not known if LDRT would be equally effective if blocking at the diaphragm is used rather than at the true inferior limit of the lungs
Symptomatic response
System	Subjective and objective measures		Some felt symptomatic relief useful but not sufficient endpoint
Patient outcomes
ICU-care required, or no longer required	Outcome measurements that are validated for the acute phase of therapy.		Hospital costs and outcomes related to ICU admission timing will vary situationally Acute medical management phase measurements like more rapid ICU discharge need to be used cautiously as it is unknown how these may correlate with severe late effects; i.e., early “benefits” that alter hospital management may not predict late functional outcome which may be more important
Duration in ICU (pre- and post LDRT)	Important parameter to consider as a primary trial efficacy endpoint		Changing acute management with LDRT might not correlate with ultimate pulmonary function
Alive, duration	Long-term data should be sought
Death, when post LDRT	Possible co-primary endpoint with ICU duration
Long-term survivors	For survivors, evaluation of the long-term symptoms from viral infection, treatment, and the neutralizing capacity of antibodies		Can LDRT degrade development and maintenance of long-term immunity for survivors? Research subjects should be followed for the development of cancer and cardiovascular disease