COVID-19 Pneumonitis Low Dose Lung Radiotherapy (COLOR-19) (COLOR-19)
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT04377477|
Recruitment Status : Recruiting
First Posted : May 6, 2020
Last Update Posted : July 22, 2020
|First Submitted Date ICMJE||May 4, 2020|
|First Posted Date ICMJE||May 6, 2020|
|Last Update Posted Date||July 22, 2020|
|Actual Study Start Date ICMJE||May 10, 2020|
|Estimated Primary Completion Date||August 10, 2021 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
|Original Primary Outcome Measures ICMJE
||Lenght of hospital stay and number of Intensive Care Unit admissions [ Time Frame: Six months ]
Evaluation of the feasibility of low-dose radiotherapy treatment of SARS-Cov2 pneumonia, for the purpose of the subsequent implementation of a phase II study; lenght of hospital stay and number of Intensive Care Unit admissions will be recorded
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||COVID-19 Pneumonitis Low Dose Lung Radiotherapy (COLOR-19)|
|Official Title ICMJE||Pilot Study on the Feasibility of Low Dose Radiotherapy for SARS-Cov-2 Pneumonitis (COVID-19 Low Dose Radiotherapy - COLOR 19)|
|Brief Summary||Low-dose radiotherapy treatment delivered to both lungs in patients with immune-related pneumonia following COVID-19 infection is backed up by biological and clinical bases that justify its use as a possible therapeutic option in these patients. This is a preliminary exploratory study (non-pharmacological interventional) to evaluate the feasibility and tolerability of low-dose radiotherapy treatment of SARS-Cov-2 immune-mediated pneumonia, for the subsequent implementation of a phase II study.This is a preliminary, monocentric, single-arm, interventional, non-pharmacological exploratory study. All enrolled patients will be treated with low-dose radiotherapy. Participants will undergo irradiation of the lungs, administered in a single fraction at the average prescription dose of 0.7 Gy (further details in the dedicated section).|
Since the first case of Severe Acute Respiratory Syndrome - Coronavirus - 2 (SARS-CoV-2) infection and its subsequent clinical manifestation (COronaVIrus Disease 19, COVID-19) in the city of Wuhan (Hubei, China) in December 2019, contagion abruptly spread to different regions of China and, subsequently, to all continents. To date, 1 521 252 cases have been confirmed worldwide. With the first case ascertained in Lombardy at the end of February 2020, Italy soon became the first European country to face the exponential growth in the number of infected people (to date -May 3, 2020-210,717 total cases, currently positive 100,179).The disease turned into an actual health emergency due to the rapid spread and the need of hospitalization and respiratory function support in Intensive Care Unit (ICU) for a significant fraction of the patients. However, the clinical presentation of COVID-19 is non-specific and extremely heterogeneous. Many patients are asymptomatic or exhibit mild symptoms, which include cough, fever, general malaise with myalgias, anosmia and ageusia. The most common changes in blood tests include lymphopenia, thrombocytopenia and increased C-reactive protein and ferritin.
As emerged by clinical data, the viral infection could be divided into three different phases: stage I, asymptomatic incubation period with little or undetectable viral load; stage II, mild symptomatic period with considerable and detectable viral load; stage III, severe symptomatic period with high viral load.
The definitive diagnosis requires a positive molecular test with Real Time PCR (RT-PCR) method for SARS-CoV-2 on nasopharyngeal swab. However, this technique suffers from sub-optimal sensitivity, which may require repetition on bronchoalveolar lavage. The execution of chest CT is therefore essential, as it is characterized by high sensitivity and can detect highly suggestive findings even in patients with negative RT-PCR.
Although the majority of infections resolve spontaneously without the need for specific therapy, up to 20% of patients can develop severe clinical pictures with pneumonia characterized by dyspnea, tachypnea and hypoxemia that requires treatment in a hospital setting. Pulmonary involvement is typically bilateral, peripheral and basal in most cases, presenting on CT scan with multifocal ground glass opacities and interstitial infiltrations; complete resolution usually takes several weeks. Despite active treatment, about 5-10% of cases can precipitate, often suddenly, into critical conditions including respiratory failure, ARDS and multi-organ dysfunction that require ICU admission and are burdened with high mortality.
Even though the understanding of the pathogenesis of COVID-19 is still incomplete, the central role of the immune response in determining the development of severe clinical pictures is increasingly being defined. Organ damage could therefore not be induced by the direct effect of the infection, but mediated by an uncontrolled immune response resulting in the development of a "cytokine storm", as suggested by the high levels of inflammatory cytokines (among which interleukin 6 (IL-6), tumor necrosis factor (TNF) and interferon γ (IFNγ) play a major role) in patients who exhibit severe or fatal disease. To date, no drug has been approved with a specific indication for the treatment of COVID-19. The current treatment encompasses antiviral agents approved for other viral infections, including protease inhibitors (lopinavir and ritonavir), anti-influenza drugs (oseltamivir and arbidol) and compassionate use of nucleotide analogues. Several studies are evaluating the possible effectiveness of the inhibition of pro-inflammatory cytokines activity in preventing or treating severe COVID-19, through the use of immunomodulators (chloroquine and hydroxychloroquine) or monoclonal antibodies such as tocilizumab, which targets the IL-6 receptor. Despite promising preliminary results, a multitude of patients need an immediate treatment while the results of ongoing clinical trials are awaited.
Although most COVID-19 infections resolve spontaneously without the need for specific therapy, up to 20% of patients can develop severe clinical pictures with interstitial-alveolar pneumonia characterized by dyspnoea, tachypnea and hypoxemia up to an acute respiratory distress syndrome (ARDS), severe respiratory failure and multi-organ dysfunction requiring ICU hospitalization and burdened with high mortality.
To date, the pathogenesis of SARS-CoV-2 pneumonia is poorly understood, but the immune-inflammatory response to infection is progressively emerging as pivotal in the development of severe clinical manifestations. An adequate viral load might stimulate the immune cells to synthesize pro-inflammatory cytokines as interleukin 1 and 6 (IL-1, IL-6), tumor necrosis factor α (TNF α) and attract macrophages, responsible for the secretion of several chemokines that could trigger an unregulated "cytokine storm". A few reports of histological analysis of lung tissue specimens from COVID-19 patients highlighted nonspecific inflammatory changes with the appearance of edema, hyaline membranes and an inflammatory infiltrate dominated mainly by lymphocytes. Peripheral blood tests often reveal lymphocytopenia and a high neutrophil count are found, especially in case of severe disease, with a high value of neutrophil to lymphocyte ratio (NLR), and a relevant increase in circulating pro-inflammatory cytokines levels.
While vaccines and drugs directly targeting the virus are currently being developed and are not yet available, preventing the excessive and uncontrolled cytokine release and inflammatory response could be the key to avoid the occurrence of severe disease.
Different clinical trials are exploring this path, evaluating immunomodulators and monoclonal antibodies targeting mediators such as interleukin 6(IL-6).
Although conventionally fractionated (1.8-2 Gy/fraction) and hypofractionated (> 3 Gy fraction) radiotherapy, used in the field of neoplastic diseases, provides its therapeutic effect also inducing pro-inflammatory molecules, it has widely been documented in the first decades of the last century that low-dose radiotherapy (LD-RT) is potentially effective and relatively safe in the control of acute and/or chronic inflammatory diseases (e.g. skin diseases such as psoriasis, necrotizing abscesses, tendonitis, impingement syndrome).
Many studies reported the effectiveness of radiation treatment after a single application, with a prompt improvement of symptoms, usually occurring within 24 ours and often definitive or long-lasting. Low dose radiotherapy exerts its effect on several cells involved in the immune response: endothelial cells, polymorphonuclear leukocytes, lymphocytes and macrophages. This is true also for pneumonia.
Endothelial cells play a crucial role in the inflammation process, both for the "homing" process of leukocytes, and for the expression of a wide variety of cytokines and growth factors. Different studies have shown that a dose of 0.5 Gy induces an over-expression of tumor growth factor β (TGF-β), which has immunosuppressive activity and leads to a reduction in leukocyte adhesion on endothelial cells.
The leukocyte "rolling" on the endothelium in the sites where inflammation is present represents the initial step of the inflammatory cascade. The effects of LD-RT were analyzed in vitro; after radiation doses of 0.3 - 0.6 Gy, there was a 25-40% reduction in adhesion compared to control after 24 hours from irradiation.
Ionizing radiation at doses below 1 Gy are also capable to polarize macrophages towards the M2 anti-inflammatory phenotype. Conversely, doses greater than 1 Gy tend to induce polarization towards the M1 pro-inflammatory subtype. The use of low doses of radiation seems to act on macrophages also reducing their cytotoxic action, reducing the production of nitric oxide (NO) through to the inhibitory action on the enzyme cytokine inducible nitric oxide synthetase (iNOS) .
Neutrophils play a central role in lung damage induced by Middle East Respiratory Syndrome (MERS) and SARS-CoV, and likewise in COVID-19, as they migrate into the alveoli where they release proteinases and trigger the innate response, with consequent development of cell damage and clinical presentations like ARDs (30,31). Low-dose radiation therapy is able to initiate the apoptotic process of polymorphonuclear granulocytes (neutrophils), thus reducing their cytotoxic activity (32). This treatment can therefore exert an anti-inflammatory activity through several mechanisms of action, with an optimal and long lasting effect demonstrated for a dose of 0.5 Gy (32).
In the absence of a specific treatment, while ongoing trial are evaluating pharmacological approaches and vaccines, innovative approaches could be undertaken to face the emergency and allow a satisfactory management of the disease.
A single fraction radiation treatment delivering low doses to the entire bilateral lung parenchyma (whole lung treatment) is a reasonable and conceptually valid option to inhibit inflammation and obtain a prompt improve of the symptoms in the short term.
Unlike most of the drugs analyzed so far in the framework of COVID-19 infection, low dose radiotherapy is characterized by a minor risk of side effect (negligible, considering the acute phase) and could therefore represent an optimal complementary therapeutic approach due to its safety and absence of interaction with pharmacological treatments. Moreover, this treatment requires less than one hour including treatment planning and administration.
The patient will undergo radiation treatment on both lungs in a single session. From the physical-dosimetric point of view, the treatment plan will be calculated in an isocentric manner. The isocenter will be positioned at a depth of 10 cm with respect to an anterior skin landmark specifically defined during CT-scan acquisition. The treatment plan will be elaborated using a field in field irradiation technique, with 2 beams each one composed by 3 beamlets: one conformed to the volume resulting by the union of the lungs with a 2 cm margin, the other two will be obtained by shielding the spine and alternately one lung each. This set up allows to obtain a dose distribution in which the vertebral bodies receive a dose lower than 55 cGy with an average lung dose of 70 cGy and maximum lungs dose lower than than 90 centigray (cGy). The Pinnacle ® treatment planning system (TPS) with Collapsed Convolution calculation algorithm will be used. Prescription doses were determined according to data and indications currently published and optimized to minimize the dose to the vertebrae.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Not Applicable|
|Study Design ICMJE||Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Intervention ICMJE||Radiation: Single fraction whole lung radiotherapy
Participants will undergo irradiation of the lungs, administered in a single fraction at the average prescription dose of 0.7 Gy
|Study Arms ICMJE||Experimental: Lung low dose radiotherapy
Irradiation of the lungs, administered in a single fraction at the average prescription dose of 0.7 Gy
Intervention: Radiation: Single fraction whole lung radiotherapy
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE
|Original Estimated Enrollment ICMJE||Same as current|
|Estimated Study Completion Date ICMJE||August 30, 2022|
|Estimated Primary Completion Date||August 10, 2021 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||50 Years and older (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Listed Location Countries ICMJE||Italy|
|Removed Location Countries|
|NCT Number ICMJE||NCT04377477|
|Other Study ID Numbers ICMJE||NP 4097|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||
|Responsible Party||Stefano Maria Magrini, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia|
|Study Sponsor ICMJE||Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia|
|Collaborators ICMJE||Not Provided|
|PRS Account||Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia|
|Verification Date||July 2020|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP