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

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

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.

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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

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Pneumonia

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



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.



Information from the National Library of Medicine

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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04466683


Contacts
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Contact: Arnab Chakravarti, MD 614-293-0672 Arnab.Chakravarti@osumc.edu
Contact: Kimberly Mahler 614-685-4247 kimberly.mahler@osumc.edu

Locations
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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
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Principal Investigator: Arnab Chakravarti, MD James Cancer Hospital, Department of Radiation Oncology
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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    Key Record Dates
Last Update Posted: March 15, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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Pneumonia
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections