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

• ClinicalTrials.gov Identifier: NCT04466683
• Recruitment Status: Unknown
• First Posted: July 10, 2020
• Last Update Posted: March 15, 2021
• Sponsor: Ohio State University Comprehensive Cancer Center
• Collaborator: Varian Medical Systems
• Information provided by (Responsible Party): Arnab Chakravarti, Ohio State University Comprehensive Cancer Center

Study Description

Brief Summary:

Low doses of radiation in the form of chest x-rays has been in the past to treat people with pneumonia. This treatment was thought to reduce inflammation and was found to be effective without side effects. However, it was an expensive treatment and was eventually replaced with less expensive treatment options like penicillin.

The COVID-19 virus has emerged recently, causing high rates of pneumonia in people. The authors believe that giving a small dose of radiation to the lungs may reduce inflammation and neutralize the pneumonia caused by COVID-19. For this study, the x-ray given is called radiation therapy. Radiation therapy uses high-energy X-ray beams from a large machine to target the lungs and reduce inflammation. Usually, it is given at much higher doses to treat cancers.

The purpose of this study is to find out if adding a single treatment of low-dose x-rays to the lungs might reduce the amount of inflammation in the lungs from COVID-19 infection, which could reduce the need for a ventilator or breathing tube.

Condition or disease	Intervention/treatment	Phase
Covid-19; Sars-CoV2; Pneumonia	Radiation: Low dose radiation 35 cGy; Radiation: High dose radiation 100 cGy	Phase 2

Detailed Description:

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

1. 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.

2. 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 :

   1. Rate of mechanical ventilation (MV)
   2. Rate of prolonged hospital stay >10 days (PHS)
   3. Crude all-cause mortality rate at the time of analysis

3. 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:

   1. Days of mechanical ventilation
   2. Days of hospitalization.
4. 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.
5. 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Subjects will be randomized 2:1 to receive radiation therapy (2 different doses) or control (no radiation). Sixty subjects will be enrolled to 3 arms and the best dose chosen after enrolling 60 subjects. Randomization of an additional 40 subjects will be randomized 2:1 to receive radiation therapy (best dose) versus control with no radiation.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Protocol of Low-Dose Whole Thorax Megavoltage Radiotherapy for Patients With SARS-COV-2 Pneumonia
• Actual Study Start Date: August 28, 2020
• Estimated Primary Completion Date: December 31, 2021
• Estimated Study Completion Date: December 31, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Low radiation arm; A single dose of 35 cGY delivered to the whole thorax	Radiation: Low dose radiation 35 cGy; A dose of 35 cGy of whole thorax irradiation will be delivered at a single timepoint
Experimental: High radiation arm; A single dose of 100 cGY delivered to the whole thorax	Radiation: High dose radiation 100 cGy; A dose of 100 cGy of whole thorax irradiation will be delivered at a single timepoint
No Intervention: Control arm; Patients will receive no radiation therapy but will have research samples collected and best supportive care

Outcome Measures

Primary Outcome Measures :

1. Step 1 Dose selection [ Time Frame: At least 2 weeks after the 60th patient enrolled has been evaluated for adverse events. It is estimated that the time frame will be about 1 year to complete enrollment. ]
   The rate of grade 4 toxicity, the rate of mechanical ventilation, the rate of hospital stay greater than 10 days, and the crude all-cause mortality rate will be used to calculate the clinically meaningful event rate (CMER). The rates range would be from 0 to 100% with a lower rate indicating a more favorable dose.
2. Clinical benefit of Step 2 Radiation dose [ Time Frame: up to 30 days from the last patient enrollment in Step 2 which is estimated to be about 2 years. ]
   Clinical benefit will have the composite endpoint with the following 3 elements: the rate of mechanical ventilation, the rate of hospital stays of greater than 10 days and the rate of all-cause mortality at 30 from enrollment. A lower rate would indicate a positive clinical benefit and would range from 0 to 100%

Secondary Outcome Measures :

1. Changes of the cost of care for the control arm versus the radiation arms [ Time Frame: The discharge of the last patient enrolled is estimated to be about 2 years. ]
   Billing codes will be collected to determine the total cost of hospitalization for each patient at discharge. The cost of hospitalization for the control arm versus experimental radiation arms will be compared.

Other Outcome Measures:

1. Changes in lymphocyte count between control and experimental arms [ Time Frame: Samples are collected pre-dose, 48-72 hours post radiation dose, and 7 days after radiation dose. Control subjects have blood samples collected post randomization, 48-72 hours post randomization, and 7 days post randomization. ]
   Compare differences within and between arms lymphocyte count in K/ul.
2. Changes in neutrophil count between control and experimental arms [ Time Frame: Samples are collected pre-dose, 48-72 hours post radiation dose, and 7 days after radiation dose. Control subjects have blood samples collected post randomization, 48-72 hours post randomization, and 7 days post randomization ]
   Compare differences within and between arms neutrophil count in K/ul .
3. Changes in neutrophil to lymphocyte ratio between control and experimental arms [ Time Frame: Samples are collected pre-dose, 48-72 hours post radiation dose, and 7 days after radiation dose. Control subjects have blood samples collected post randomization, 48-72 hours post randomization, and 7 days post randomization ]
   Compare differences within and between arms for the neutrophil to lymphocyte ratio. A decrease in the ratio of neutrophil to lymphocyte count would indicate a more favorable treatment outcome.
4. Changes in blood C-reactive protein between control and experimental arms [ Time Frame: Samples are collected pre-dose, 48-72 hours post radiation dose, and 7 days after radiation dose. Control subjects have blood samples collected post randomization, 48-72 hours post randomization, and 7 days post randomization ]
   Compare differences within and between arms for the C-reactive protein in mg/L. A decrease in C-reactive protein value would indicate a more favorable treatment outcome.
5. Changes in blood IL-6 levels between control and experimental arms [ Time Frame: Samples are collected pre-dose, 48-72 hours post radiation dose, and 7 days after radiation dose. Control subjects have blood samples collected post randomization, 48-72 hours post randomization, and 7 days post randomization ]
   Compare differences within and between arms for the IL-6 in pg/ml. A decrease in IL-6 value would indicate a more favorable treatment outcome.
6. Changes in blood D-Dimer levels between control and experimental arms [ Time Frame: Samples are collected pre-dose, 48-72 hours post radiation dose, and 7 days after radiation dose. Control subjects have blood samples collected post randomization, 48-72 hours post randomization, and 7 days post randomization ]
   Compare differences within and between arms for the D-Dimer in mcg/ml. A decrease in D-Dimer value would indicate a more favorable treatment outcome.
7. Changes in blood Lactate dehydrogenase (LDH) levels between control and experimental arms [ Time Frame: Samples are collected pre-dose, 48-72 hours post radiation dose, and 7 days after radiation dose. Control subjects have blood samples collected post randomization, 48-72 hours post randomization, and 7 days post randomization ]
   Compare differences within and between arms for the LDH in U/L. A decrease in LDH value would indicate a more favorable treatment outcome.
8. Changes in blood ferritin levels between control and experimental arms [ Time Frame: Samples are collected pre-dose, 48-72 hours post radiation dose, and 7 days after radiation dose. Control subjects have blood samples collected post randomization, 48-72 hours post randomization, and 7 days post randomization ]
   Compare differences within and between arms for ferritin in ng/ml. A decrease in Ferritin value would indicate a more favorable treatment outcome.

Eligibility Criteria

• Ages Eligible for Study: 50 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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:

  1. Fever > 102 degrees Fahrenheit during index admission
  2. Respiratory rate of ≥ 26 / minute within 24 hours of screening
  3. SpO2 ≤ 95% on room air within 24 hours of screening
  4. Any patient requiring 4 L/min oxygen therapy to maintain SpO2 >93% within 24 hours of screening
  5. 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:

  1. Breast or post-mastectomy chest wall radiation (without regional nodal irradiation) may be included at the discretion of the site primary investigator, and
  2. 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.

Contacts and Locations

Contacts

Contact: Arnab Chakravarti, MD; 614-293-0672; Arnab.Chakravarti@osumc.edu

Contact: Kimberly Mahler; 614-685-4247; kimberly.mahler@osumc.edu

Locations

United States, Florida

Boca Raton Regional Hospital Lynn Cancer Institute; Recruiting

Boca Raton, Florida, United States, 33486

Contact: Viviana Boronat 561-955-4145 Vbornat@baptisthealth.net

Miami Cancer Institute; Recruiting

Miami, Florida, United States, 33176

Contact: Alex Kudryashev AlexKu@baptisthealth.net

Sub-Investigator: Minesh Mehta, MD

United States, Illinois

Loyola University Chicago; Recruiting

Maywood, Illinois, United States, 60153

Contact: Susan Fargo 708-216-8046 sfargo@luc.edu

Sub-Investigator: William Small, MD

United States, Indiana

Indiana University School of Medicine; Recruiting

Indianapolis, Indiana, United States, 46202

Contact: Amy Miller 317-944-1242 amym@iu.edu

Sub-Investigator: Paul Anthony, MD

United States, Massachusetts

Lowell General Hospital Cancer Center; Recruiting

Lowell, Massachusetts, United States, 01854

Contact: Gayle Hincks 978-788-7084 gayle.hincks@lowellgeneral.org

Sub-Investigator: Matthew Katz, MD

United States, Michigan

Beaumont Hospital; Recruiting

Royal Oak, Michigan, United States, 48073

Contact: Grace San Agustin 248-551-7835 grace.sanagustin@beaumont.org

Sub-Investigator: James Fontanesi, MD

United States, Ohio

Ohio State University James Cancer Hospital; Recruiting

Columbus, Ohio, United States, 43210

Contact: Kimberly Mahler 614-685-4247 kimberly.mahler@osumc.edu

Contact: Isabel Manring 6143663760 isabel.manring@osumc.edu

Principal Investigator: Arnab Chakravarti, MD

Colombia

Hospital Universitario San Ignacio; Recruiting

Bogotá, Colombia

Contact: Angelica Maria Arango Gutierrez amarangog@husi.org.co

Contact: Juan Carlos Galvis Serrano, MD jcgalvis@husi.org.co

Sub-Investigator: Juan Carlos Galvis Serrano

Sponsors and Collaborators

Ohio State University Comprehensive Cancer Center

Varian Medical Systems

Investigators

• Principal Investigator: Arnab Chakravarti, MD; James Cancer Hospital, Department of Radiation Oncology

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

McClelland S 3rd, Miller AC, Williams MD, Anthony BP, Chakravarti A, Anthony PA. Low-dose whole thorax radiation therapy for COVID-19 pneumonia: inpatient onboarding process for a randomized controlled trial. Rep Pract Oncol Radiother. 2021 Dec 30;26(6):1057-1059. doi: 10.5603/RPOR.a2021.0112. eCollection 2021.

• Responsible Party: Arnab Chakravarti, Principal Investigator, Ohio State University Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT04466683
• Other Study ID Numbers: PREVENT
• First Posted: July 10, 2020
• Last Update Posted: March 15, 2021
• Last Verified: March 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Arnab Chakravarti, Ohio State University Comprehensive Cancer Center:

radiation; radiotherapy; Linac

Additional relevant MeSH terms:

COVID-19; Pneumonia; Respiratory Tract Infections; Infections; Pneumonia, Viral; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases