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

Pneumonia, Viral Clinical Trial

— ULTRA-COVID  

Official title:

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

Clinical Trial Details — Status: Suspended

Administrative data

• NCT number: NCT04394182
• Other study ID #: 20.4.1597-GHM
• Status: Suspended
• Phase: N/A
• Start date: April 21, 2020
• Est. completion date: March 21, 2022

Study information

• Verified date: March 2022
• Source: Fundacion GenesisCare
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Suspended
• Enrollment: 15
• Est. completion date: March 21, 2022
• Est. primary completion date: December 31, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 120 Years

Eligibility

Inclusion Criteria:

1. Age > 18 years-old.

2. Diagnosis of pneumonia due to COVID-19 serologically proven by polymerase chain reaction (PCR) or highly suspected to be COVID-related.

3. Charlson Comorbidity Index (CCI) less than 6 score.

4. 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.

5. Eastern Cooperative Oncology Group (ECOG) Status < or = 3

6. Life expectancy (LE)> 1 month at hospital admission for COVID-19

7. No previous thoracic RT (relative-individualization criteria) or chemotherapy (chemoinduced pulmonary toxicity, eg Bleomycin).

8. 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.

Related Conditions & MeSH terms

• COVID-19
• Cytokine Release Syndrome
• Cytokine Storm
• Pneumonia
• Pneumonia, Viral

Intervention

Radiation:
• Ultra-Low-dose radiotherapy
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.

Device:
• ventilatory support with oxygen therapy
Oxygen Therapy: Nasal Cannula (NC); Ventimask (VMK) or VMK with reservoir

Drug:
• Lopinavir/ritonavir
100/400 mg/12h; 7-10 days
• Hydroxychloroquine
200 mg/12h
• Azithromycin
500 mg/24h, 3 days
• Piperacillin/tazobactam
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
• Low molecular weight heparin
prophylactic doses
• Corticosteroid injection
250mg x 3 boluses
• Tocilizumab
600mg single dose

Locations

Country	Name	City	State
Spain	Hospital La Milagrosa, GenesisCare	Madrid
Spain	Hospital Vithas Valencia Consuelo	Valencia

Sponsors (3)

Lead Sponsor	Collaborator
Fundacion GenesisCare	Hospital La Milagrosa, Hospital Vithas Valencia Consuelo

Country where clinical trial is conducted

Spain, 

References & Publications (10)

Arenas M, Sabater S, Hernández V, Rovirosa A, Lara PC, Biete A, Panés J. Anti-inflammatory effects of low-dose radiotherapy. Indications, dose, and radiobiological mechanisms involved. Strahlenther Onkol. 2012 Nov;188(11):975-81. doi: 10.1007/s00066-012-0 — View Citation

Berk LB, Hodes PJ. Roentgen therapy for infections: an historical review. Yale J Biol Med. 1991 Mar-Apr;64(2):155-65. — View Citation

Calabrese EJ, Dhawan G, Kapoor R, Kozumbo WJ. Radiotherapy treatment of human inflammatory diseases and conditions: Optimal dose. Hum Exp Toxicol. 2019 Aug;38(8):888-898. doi: 10.1177/0960327119846925. Epub 2019 May 6. Review. — View Citation

Calabrese EJ, Dhawan G. How radiotherapy was historically used to treat pneumonia: could it be useful today? Yale J Biol Med. 2013 Dec 13;86(4):555-70. — View Citation

Cuttler JM. Application of Low Doses of Ionizing Radiation in Medical Therapies. Dose Response. 2020 Jan 6;18(1):1559325819895739. doi: 10.1177/1559325819895739. eCollection 2020 Jan-Mar. — View Citation

Kirkby C, Mackenzie M. Is low dose radiation therapy a potential treatment for COVID-19 pneumonia? Radiother Oncol. 2020 Jun;147:221. doi: 10.1016/j.radonc.2020.04.004. Epub 2020 Apr 6. — View Citation

Lara PC, Burgos J, Macias D. Low dose lung radiotherapy for COVID-19 pneumonia. The rationale for a cost-effective anti-inflammatory treatment. Clin Transl Radiat Oncol. 2020 Apr 25;23:27-29. doi: 10.1016/j.ctro.2020.04.006. eCollection 2020 Jul. — View Citation

Rödel F, Keilholz L, Herrmann M, Sauer R, Hildebrandt G. Radiobiological mechanisms in inflammatory diseases of low-dose radiation therapy. Int J Radiat Biol. 2007 Jun;83(6):357-66. Review. — View Citation

Schaue D, Jahns J, Hildebrandt G, Trott KR. Radiation treatment of acute inflammation in mice. Int J Radiat Biol. 2005 Sep;81(9):657-67. — View Citation

Torres Royo L, Antelo Redondo G, Árquez Pianetta M, Arenas Prat M. Low-Dose radiation therapy for benign pathologies. Rep Pract Oncol Radiother. 2020 Mar-Apr;25(2):250-254. doi: 10.1016/j.rpor.2020.02.004. Epub 2020 Feb 22. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	Blood Gas Analysis at Day 2	Pa02 / Fi02 > 300 mmHg	At 2 days after RT
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	COVID-19 status	COVID-19 negativization test	At 7 days after RT
Secondary	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
Secondary	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

External Links

•   Li, K., Fang, Y., Li, W. et al. CT image visual quantitative evaluation and clinical classification of coronavirus disease (COVID-19). Eur Radiol (2020). https://doi.org/10.1007/s00330-020-06817-6