Low-Dose Radiation Therapy to Lungs in Moderate COVID-19 Pneumonitis: A Case-Control Pilot Study

Study Overview
=================
Brief Summary
-----------------
This pilot case-control study at Mahatma Gandhi Institute of Medical Sciences (MGIMS), Sevagram, India is designed to evaluate the use of low dose radiotherapy (LDRT) in patients with moderate COVID-19 with specific objectives to abrogate the onset of cytokine storm and thus facilitate their early recovery and reduce mortality.

Detailed Description
-----------------
One of the primary attributes to the mortality in coronavirus disease -19 (COVID-19) is acute respiratory distress syndrome (ARDS) induced by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) mediated cytokine storm (CS).To mitigate the ARDS, an ideal approach would be to diminish the viral load by activating immune cells for CS prevention or to suppress the overactive cytokine-releasing immune cells. The search for ideal pharmaceutical agent/s to take care of SARS-CoV-2 mediated CS is still eluding the clinicians. The only drugs with modest clinical benefit are remdesivir and dexamethasone. The availability of the former is uncertain while an overdependence on steroids could prove counterproductive as evident from increasing incidence of fatal mucormycosis reported in post-COVID patients treated with steroids. The situation for COVID-19 patients successfully treated with steroids is akin to from frying pan into the fire. Thus, concerted efforts are needed to prevent the onset of CS in COVID-19. This, would directly help to lower the mortality. One of the approaches being recently investigated worldwide, is the use of single low dose radiotherapy (LDRT) of 0.5 - 1.5 Gy to the lungs before the onset of CS in moderately affected COVID-19 patients requiring oxygen supplementation. This crucial window of opportunity needs to be exploited with LDRT to mitigate the onset of the fatal CS. LDRT could thus be a potential game changer in the management of COVID-19. LDRT with its multipronged actions may attenuate immune activation and consequently mitigate the production of pro-inflammatory cytokines. A number of centers have reported encouraging outcomes in pilot studies with LDRT. There has been a significant reduction in oxygen requirement within just 72 hours of LDRT, resulting in reduced hospital stay and deaths. This pilot case-control study at MGIMS is designed to evaluate the use of LDRT in patients with moderate COVID-19 with specific objectives to prevent the onset of CS and thus facilitate their early recovery and reduce mortality.

Official Title
-----------------
Low-Dose Radiation Therapy in COVID-19

Conditions
-----------------
COVID-19, Pneumonia

Intervention / Treatment
-----------------
* Radiation: Low dose radiotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Reverse transcription polymerase chain reaction (RT-PCR) / Rapid Ag test positive Signed informed consent Age ≥ 50 yrs Respiratory rate : 25 - 30/min, breathless AND/OR Oxygen saturation by pulse oximetry (SpO2) in 90 - 93% on room air (readings taken after 5 mins of stopping oxygen supplementation) Rising levels of quantitative-CRP and/or D-Dimer and/or Ferritin in 2 consecutive samples taken 24 hours apart Exclusion Criteria: Patient who have received vaccination for COVID-19 (single / both doses of any approved vaccine) Hemodynamic instability in shock and/or systolic BP < 90mm Hg Septicemia Disseminated intravascular coagulation Requiring ventilation Unable to lie down supine Severe acute respiratory distress with Fraction of inspired oxygen (FiO2) < 100mm Hg Cardiac defibrillator/pacemaker in situ Lymphocyte count < 1 x 106/ml Pregnancy and/or lactating mothers HIV and/or HbsAg positive patients

Ages Eligible for Study
-----------------
Minimum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: To explore the role of low dose pulmonary radiotherapy (LDRT) in moderate disease category of COVID-19 patients with pneumonitis in terms of the following primary and secondary objectives. The outcome of LDRT in a pilot group of 10 patients (Study group) would be compared with another 10 patients (Control group) who have not given consent for LDRT and/or would not able to be able to lie down still for the entire treatment duration in the radiotherapy unit. This is not a randomized but a case-control study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Study arm<br>10 patients of confirmed diagnosis of moderate COVID-19 who fulfil the inclusion criteria and give written informed consent would be in study arm. All patients, belong to both study and control groups would receive the same treatment (oxygen support, steroids, anticoagulant therapy, remdesivir and other supportive therapy) as per the Institute guidelines for management of moderate COVID-19 disease. Only low dose radiotherapy would be added to patients in the study arm. | Radiation: Low dose radiotherapy<br>* Patients in study group will receive LDRT to both lungs by two parallel opposed fields, antero-posterior (AP) and postero-anterior (PA) to deliver a midplane dose of 0.5 Gy in a single fraction. As this dose is very less, doses to the critical structures including heart and lungs would be very low. All the patients will be treated on Telecobalt unit (Theratronics Phoenix, Canada) and not on the linear accelerator to avoid risks to cancer patients on treatment with linear accelerator. CT based plan will not be undertaken for logistic issues and is also not felt to be mandatory for this LDRT. Dose computation would be carried out by manual dose calculation for the Telecobalt unit.<br>|
| No Intervention: Control Arm<br>10 patients of confirmed diagnosis of moderate COVID-19 who fulfil the inclusion criteria and have not given written informed consent would be in study arm. These patients would receive the same treatment (oxygen support, steroids, anticoagulant therapy, remdesivir and other supportive therapy) as per the Institute guidelines for management of moderate COVID-19 disease except low dose radiotherapy. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients dying due to COVID-19 | Compare the number of patients whose death could be ascribed to COVID-19 in the two groups | 28 days from the date of diagnosis | 
| Mean duration of hospital stay for surviving patients | Compare the mean duration of hospital stay between the patients surviving in study and control groups | 28 days from the date of diagnosis / discharge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean dose of steroid requirement for surviving patients | Compare the mean total dose of steroid required in between the patients surviving in study and control groups | 28 days from the date of diagnosis | 
| Mean time to completely wean off from Oxygen (02) supplementation for surviving patients | Compare the mean time to completely wean off from Oxygen supplementation in patients between the patients surviving in study and control groups | 28 days from the date of diagnosis / discharge | 
| Changes in the biochemical profiles of Interleukin-6 (IL-6) | IL-6 levels in control vs study group patients | 28 days from the date of diagnosis / discharge | 
| Changes in the biochemical profiles of quantitative C reactive protein (CRP) | Quantitative CRP levels in control vs study group patients | 28 days from the date of diagnosis / discharge | 
| Changes in the biochemical profiles of D-Dimer | D-Dimer levels in control vs study group patients | 28 days from the date of diagnosis / discharge | 
| Changes in the biochemical profiles of Ferritin | Ferritin levels in control vs study group patients | 28 days from the date of diagnosis / discharge | 
| Acute pulmonary toxicities that may be attributable to LDRT | Acute pulmonary toxicities as per the Common Terminology Criteria for Adverse Events (CTCAE) version 5 | 28 days from the date of diagnosis / discharge | 
| Total cost of hospital stay following LDRT for surviving patients | Cost evaluation and comparison between the patients surviving in study and control groups | 28 days from the date of diagnosis / discharge | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
COVID-19, Pneumonia, Low dose radiotherapy, Cytokine storm