Ultra Low Doses of Therapy With Radiation Applicated to COVID-19

Study Overview
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Brief Summary
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The host response against the coronavirus 2 (SARS-CoV-2) appears to be mediated by a 'cytoquine storm' developing a systemic inflammatory mechanism and an acute respiratory distress syndrome (ARDS), in the form of a bilateral pneumonitis, requiring invasive mechanical ventilation (IMV) in an important group of patients. In terms of preventing progression to the critical phase with the consequent need of admission to the intensive care units (ICU), it has been recently proposed that this inflammatory cytoquine-mediated process can be safely treated by a single course of ultra-low radiotherapy (RT) dose < 1 Gy. The main purpose of the study was to analyze the efficacy of ultra low-dose pulmonary RT, as an anti-inflammatory intention in patients with SARS-Cov-2 pneumonia with a poor or no response to standard medical treatment and without IMV.

Detailed Description
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The exceedingly high mortality rates of severe and critical COVID-19 warrant the evaluation of novel therapies that could potentially mitigate the advanced disease manifestations. In this context, is proposes a prospective multicenter study. It will include 15 patients, to assess the feasibility and efficacy of low-dose lung irradiation in COVID-19 pneumonia.

Official Title
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Low Doses of Lung Radiation Therapy in Cases of COVID-19 Pneumonia: Prospective Multicentric Study in Radiation Oncology Centers

Conditions
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Pneumonia, Viral, Cytokine Storm

Intervention / Treatment
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* Radiation: Ultra-Low-dose radiotherapy
* Device: ventilatory support with oxygen therapy
* Drug: Lopinavir/ritonavir
* Drug: Hydroxychloroquine
* Drug: Azithromycin
* Drug: Piperacillin/tazobactam
* Drug: Low molecular weight heparin
* Drug: Corticosteroid injection
* Drug: Tocilizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years-old. Diagnosis of pneumonia due to COVID-19 serologically proven by polymerase chain reaction (PCR) or highly suspected to be COVID-related. Charlson Comorbidity Index (CCI) less than 6 score. Poor or no response to standard medical treatment, based on: *% Sat02 <93% Oxygen therapy escalation (Understanding from less to more need for support: Nasal Cannula-NC-; Ventimask -VMK- and VMK with reservoir) Pa02 / Fi02 (blood gas analysis) <300 mmHg 1 or more inflammatory and immunological analytical parameters such as lymphocytes, IL-6, D-dimer, ferritin, LDH, C Reactive Protein (CRP) and fibrinogen with values above the normal range, except lymphocytes. Radiological impairment defined as worsening of TSS throughout admission or score at admission: TSS> 5 by a diagnostic baseline CT scan. Eastern Cooperative Oncology Group (ECOG) Status < or = 3 Life expectancy (LE)> 1 month at hospital admission for COVID-19 No previous thoracic RT (relative-individualization criteria) or chemotherapy (chemoinduced pulmonary toxicity, eg Bleomycin). Verbal information on the procedure, objective and secondary effects, acceptance and signing of informed consent by the patient or legal guardian. Exclusion Criteria: Failure to meet the inclusion criteria. Any uncontrolled intercurrent illness that would put the patient at greater risk or limit compliance with study requirements in the opinion of the investigator. Patients admitted in ICU. Refusal of treatment after verbal information.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Intervention Model: Single Group Assignment
Interventional Model Description: an experimental group will receive ultra low-dose lung radiotherapy
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: An experimental group receiving radiotherapy<br>an experimental group with a poor or no response to standard medical treatment and without invasive mechanical ventilation (IMV) will receive ultra low-dose lung radiotherapy (0.8 Gy single dose) | Radiation: Ultra-Low-dose radiotherapy<br>* The total dose to be administered was 0.8 Gy in an only single session including both whole-lungs extended 1cm isometric in all directions.<br>Device: ventilatory support with oxygen therapy<br>* Oxygen Therapy: Nasal Cannula (NC); Ventimask (VMK) or VMK with reservoir<br>Drug: Lopinavir/ritonavir<br>* 100/400 mg/12h; 7-10 days<br>* Other names: Kaletra;Drug: Hydroxychloroquine<br>* 200 mg/12h<br>* Other names: Dolquine;Drug: Azithromycin<br>* 500 mg/24h, 3 days<br>Drug: Piperacillin/tazobactam<br>* 4 g / 0.5 g administered every 6-8 hours through a vein (directly into the bloodstream), for 5-14 days. Adjustment to kidney function<br>Drug: Low molecular weight heparin<br>* prophylactic doses<br>Drug: Corticosteroid injection<br>* 250mg x 3 boluses<br>* Other names: Urbason;Drug: Tocilizumab<br>* 600mg single dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxygen Therapy Status at Day 2 | To evaluate the efficacy of ultra low-dose pulmonary RT through clinical evaluation.It was performed by oxygen therapy status assessment after RT treatment. Improvement criteria is considered as an oxygen therapy de-escalation (more to less need for support: Ventimask (VMK) with reservoir >VMK >Nasal Cannula-(NC).) | At 2 after RT | 
| Oxygen Saturation (Sat02; Pulse oximeter measurement) at Day 2 | To evaluate the efficacy of ultra low-dose pulmonary RT through clinical evaluation. .It was performed by oxygen saturation (Sat02 %) status assessment after RT treatment. Improvement criteria is considered as a Sat02 with/without oxygen therapy >93% (Pulse oximeter measurement) | At 2 days after RT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Gas Analysis at Day 2 | Pa02 / Fi02 > 300 mmHg | At 2 days after RT | 
| Blood Test at Day 2 | Achievement of normal range value in 1 or more of the inflammatory and immunological parameters (lymphocytes, IL-6, D-dimer, ferritin, LDH, C Reactive Protein (CRP) and fibrinogen) | At 2 days after RT | 
| Oxygen Therapy Status at Day 5 | To evaluate the efficacy of ultra low-dose pulmonary RT through clinical evaluation.It was performed by oxygen therapy status assessment after RT treatment. Improvement criteria is considered as an oxygen therapy de-escalation (more to less need for support: Ventimask (VMK) with reservoir >VMK >Nasal Cannula-(NC).) | At 5 after RT | 
| Oxygen Saturation (Sat02; Pulse oximeter measurement) at Day 5 | To evaluate the efficacy of ultra low-dose pulmonary RT through clinical evaluation. .It was performed by oxygen saturation (Sat02 %) status assessment after RT treatment. Improvement criteria is considered as a Sat02 with/without oxygen therapy >93% (Pulse oximeter measurement) | At 5 days after RT | 
| Blood Test at Day 5 | Achievement of normal range value in 1 or more of the inflammatory and immunological parameters (lymphocytes, IL-6, D-dimer, ferritin, LDH, C Reactive Protein (CRP) and fibrinogen) | At 5 days after RT | 
| Oxygen Therapy Status at Day 7 | To evaluate the efficacy of ultra low-dose pulmonary RT through clinical evaluation.It was performed by oxygen therapy status assessment after RT treatment. Improvement criteria is considered as an oxygen therapy de-escalation (more to less need for support: Ventimask (VMK) with reservoir >VMK >Nasal Cannula-(NC).) | At 7 after RT | 
| Oxygen Saturation (Sat02; Pulse oximeter measurement) at Day 7 | To evaluate the efficacy of ultra low-dose pulmonary RT through clinical evaluation. .It was performed by oxygen saturation (Sat02 %) status assessment after RT treatment. Improvement criteria is considered as a Sat02 with/without oxygen therapy >93% (Pulse oximeter measurement) | At 7 days after RT | 
| Blood Test at Day 7 | Achievement of normal range value in 1 or more of the inflammatory and immunological parameters (lymphocytes, IL-6, D-dimer, ferritin, LDH, C Reactive Protein (CRP) and fibrinogen) | At 7 days after RT | 
| Change from baseline Total Severity Score (TSS) analyzed in a thoracic CT scan at Day 7 | To evaluate the efficacy of ultra low-dose pulmonary RT through radiological evaluation.It was performed by thoracic CT scan after RT treatment . It is considered a radiological improvement the decrease of the Total Severity Score (TSS) from the baseline in > or = 1 point. NOTE: The score values ranged from 0 to 4 according to the sum of the percentage involvement of each of the 5 lung lobes. The total severity score (TSS), was reached by summing the overall involvement in the lung (0-20 points) | At 7 days after RT | 
| Recovery time | Recovery time after RT administration until hospital discharge or death (<48h; 2-7 days; >7 days; clinical worsening or death) | From RT administration until hospital discharge or death | 
| COVID-19 status | COVID-19 negativization test | At 7 days after RT | 
| Change from baseline Total Severity Score (TSS) analyzed in a thoracic CT scan al Month 1 | To evaluate the efficacy of ultra low-dose pulmonary RT through radiological evaluation.It was performed by thoracic CT scan after RT treatment . It is considered a radiological improvement the decrease of the Total Severity Score (TSS) from the baseline in > or = 1 point. NOTE: The score values ranged from 0 to 4 according to the sum of the percentage involvement of each of the 5 lung lobes. The total severity score (TSS), was reached by summing the overall involvement in the lung (0-20 points) | At 1 month after RT | 
| Acute Toxicity | Toxicity was assessed and rated according to the NIH Common Terminology Criteria for Adverse Events (CTCAE version 5.0) and RTOG scales. | 1-3 months after RT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Low Dose Radiotherapy, COVID19 pneumonia, Anti-inflammatory effects, Acute Respiratory Distress Syndrome (ARDS)