Clinical trial NCT04808895: Acetylsalicylic Acid in the Prevention of Severe SARS-CoV2 Pneumonia in Hospitalised Patients With COVID-19
Official title: Multicenter Randomized, Double-blind, Placebo-controlled, Clinical Trial of Acetylsalicylic Acid in the Prevention of Severe SARS-CoV2 Pneumonia in Hospitalised Patients (Asperum)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: COVID-19
Thrombosis Pulmonary
Keywords: Acetylsalicylic acid
Heparin
Pulmonary thrombosis
COVID-19
Platelets
Inflammation
Respiratoty failure
Lead sponsor: Azienda Ospedaliera Universitaria Integrata Verona
Sponsor class: OTHER
First posted: 2021-03-22
Enrollment: 204
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Experimental phase 3 drug trial, randomized 1:1, double-blind, multicentre in patients treated with acetylsalicylic acid vs placebo.
Primary purpose: TREATMENT

Brief summary: Inflammatory diseases favour the onset of venous thromboembolic events in hospitalized patients. Thromboprophylaxis with a fixed dose of heparin/low molecular weight heparin (LMWH) is recommended if concomitant inflammatory disease. In severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) pneumonia an inflammation-dependent thrombotic process occurs and platelet activation may promote thrombosis and amplify inflammation, as indicated by previous experimental evidence, and the similarities with atherothrombosis and thrombotic microangiopathies. Antiplatelet agents represent the cornerstone in the prevention and treatment of atherosclerotic arterial thromboembolism, with limited efficacy in the context of venous thromboembolism. The use of acetylsalicylic acid may improve inflammation and respiratory function in humans as indicated by the results of observational studies. There are no validated protocols for thrombosis prevention in Covid-19. There is scientific rationale to consider acetylsalicylic acid for the prevention of thrombosis in the pulmonary circulation and attenuation of inflammation. This is supported by numerous demonstrations of the anti-inflammatory activity of antiplatelet agents and the evidence of improvement in respiratory function both in human and experimental pathology. The hypothesis underlying the present study project is that in Covid-19 platelet activation occurs through an inflammation-dependent mechanism and that early antithrombotic prophylaxis in non-critical patients could reduce the incidence of pulmonary thrombosis and respiratory and multi-organ failure improving clinical outcome in patients with SARS-CoV2 pneumonia. The prevention of thrombogenic platelet activity with acetylsalicylic acid could be superior to fixed dose enoxaparin alone. The proposed treatment is feasible in all coronavirus disease 2019 (COVID-19) patients, regardless of the treatment regimen (antivirals, anti-inflammatory drugs), except for specific contraindications. To this aim, the investigators a randomised, placebo-controlled, double blind, parallel arms study to investigate the potential protection of acetylsalicylic acid towards the progression of lung failure in patients admitted to a medical ward for SARS-CoV-2 pneumonia. A 15-day treatment period is considered. Primary endpoint is the occurrence of one of the following events: admission to an intensive care unit, requirement of mechanical ventilation, PaO2/FiO2 less than 150 mm Hg.

Detailed description: Severe respiratory failure and multi-organ damage in coronavirus disease 2019 (COVID-19) patients have not a unitary pathophysiological interpretation. There is evidence of an association between the clinical entity of the disease and its severity with the plasma levels of D-dimer and inflammatory indexes. On the basis of retrospective investigations there is accumulating evidence of alterations in the haemostatic parameters that with increased D-dimer values, increased coagulation time and platelets may be predictors of worse prognosis. A systematic survey conducted in the coronavirus disease 2019 (COVID-19) Centre of the AOUI Verona, as part of the Database and Study on the role of platelets in the clinical manifestations of COVID-19 (Ethics Committee CESC Verona and Rovigo approved) revealed by means of computerized tomography (CT) angiograph in patients with a persistent respiratory deficit and very high D-dimer values mainly multiple, bilateral vascular occlusions involving the segmental and subsegmental branches of the pulmonary arteries. This finding is suggestive of a frequent and clinically relevant thrombotic process in a appreciable number (approximately 20%) of patients with COVID-19 pneumonia hospitalized in medical wards. It is a well-established clinical notion that acute and chronic inflammatory diseases may favour the onset of venous thromboembolic events in hospitalized patients. Thromboprophylaxis with a fixed dose of heparin/low molecular weight heparin (LMWH) is recommended for medical patient with concomitant neoplasia or inflammatory disease. It is conceivable that under conditions, such as SARS-CoV2 pneumonia, an inflammation-dependent thrombotic process takes place and that platelet activation may play a pathogenic role both in the thrombotic process and in the amplification of the inflammatory process. In fact, there is experimental evidence that platelet activation in inflammation would lead to accelerated coagulation and a thrombotic vascular occlusion, with similarities to what is widely documented in atherothrombosis and thrombotic microangiopathies. The administration of antiplatelet drugs represents the cornerstone for the prevention and treatment of arterial thromboembolism in atherosclerotic disease and has also shown some limited efficacy also in the context of venous and arterial thromboembolism associated with atrial fibrillation. The use of acetylsalicylic acid may improve inflammation and respiratory function in humans as indicated by the results of observational studies. There are currently no validated protocols for thrombosis prevention in the field of pulmonary viral diseases, in particular COVID-19. There is scientific rationale to consider acetylsalicylic acid for the prevention of thrombosis in the pulmonary circulation and attenuation of inflammation. This is supported by numerous demonstrations of the anti-inflammatory activity of antiplatelet agents and the evidence of improvement in respiratory function both in human and experimental pathology. A retrospective observational study showed that patients with COVID-19 pneumonia treated with acetyl salicylic acid had a lower incidence of progression to respiratory failure requiring mechanical ventilation, without evidence of increased incidence of bleeding complications. The hypothesis underlying the present study project is that in Covid-19 platelet activation occurs via an inflammation-dependent mechanism and that early antithrombotic prophylaxis in non-critical patients, like those admitted to medical wards, could reduce the incidence of pulmonary thrombosis as well as respiratory and multi-organ failure, contributing to improve clinical outcome of the patients with pneumonia caused by SARS-CoV2 viruses. The anticoagulant activity exerted by a fixed dose of enoxaparin (4000U/day), recommended in patients with the described clinical features, according to a note of the "Italian Medicines Agency" (AIFA), together with the prevention of thrombogenic activity of platelets by acetylsalicylic acid could prevent aggravation of COVID-19 patients to a greater extent than enoxaparin alone given at the same dose. Early initiation of treatment should mitigate the presentation of pneumonia. The proposed treatment is feasible in all coronavirus disease 2019 (COVID-19) patients, regardless of the treatment regimen (antivirals, anti-inflammatory drugs), except for specific contraindications. To this aim, it was designed a randomised, placebo-controlled, double blind, parallel arms study to investigate the potential protection of acetylsalicylic acid towards the progression of lung failure in patients admitted to a medical ward for SARS-CoV-2 pneumonia. A 15-day treatment period is considered. Primary endpoint is the occurrence of one of the following events: admission to an intensive care unit, requirement of mechanical ventilation, PaO2/FiO2 less than 150 mm Hg.

Eligibility criteria: Inclusion Criteria:

* in a medical area ward dedicated to Covid-19 patients
* Positivity by RT_PCR of the search for genetic material of SARS-CoV2
* Covid-19 pneumonia with moderate clinical picture based on clinical parameters
* O2 saturation\> 94% with maximum FiO2 32%
* Respiratory acts \<30 / minute
* age \>18 years
* Consent to participate in the study

Exclusion Criteria:

* Any Antithrombotic treatment including acetylsalicylic acid
* Active Bacterial infection
* Active or in maintenance therapy neoplasm
* Inability to provide consent
* Any contraindication to the acetylsalicylic acid use
* Active peptic disease
* Active Major pathological bleeding
* Recent (\<30 days) major bleeding
* Recent intracranial bleeding
* Need to use therapeutic doses of oral anticoagulants or heparins
* Need to use combination antiplatelet drugs for clinical indication
* Hypersensitivity to acetylsalicylic acid or to any of the excipients
* Hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs)
* Severe hepatic insufficiency (Child-Pugh class C).
* Severe heart failure (NYHA class 3-4)
* Platelet count less than 150000 / mmc
* Haemostasis alteration (INR\> 1.5, APTT\> 1.5)
* Plasma fibrinogen \<100 mg / dL
* Blood pressure \>160/100 mmHg
* Concomitant treatment with serotonin reuptake inhibitors
* Participation in another pharmacological clinical trial

Primary outcomes:
measure: Prevention of clinical worsening
timeFrame: day 15
measure: Prevention of lung function worsening
timeFrame: day 15
measure: Prevention of death
timeFrame: day 15
Secondary outcomes:
measure: Change in body temperature
timeFrame: Daily for 15 days
measure: Change in oxygen saturation
timeFrame: Daily for 15 days
measure: Change in blood gases
timeFrame: Daily for 15 days
measure: Change in blood cell count
timeFrame: Daily for 15 days
measure: Change in blood oxygen
timeFrame: Daily for 15 days
measure: Change in clinical markers of lung function
timeFrame: Daily for 15 days
measure: Change in clinical markers of liver damage
timeFrame: Daily for 15 days
measure: Change in clinical markers of hearth damage
timeFrame: Daily for 15 days
measure: Change in clinical markers of renal damage
timeFrame: Daily for 15 days
measure: Effects on blood cell count
timeFrame: Baseline, day 1, 2, 7 and 15.
measure: Effects on CRP
timeFrame: Baseline, day 1, 2, 7 and 15.
measure: Effects on D-dimer
timeFrame: Baseline, day 1, 2, 7 and 15.
measure: Effects on interleukin-1
timeFrame: Baseline, day 1, 2, 7 and 15.
measure: Effects on interleukin-6
timeFrame: Baseline, day 1, 2, 7 and 15.
measure: Effects on fibrinogen
timeFrame: Baseline, day 1, 2, 7 and 15.
measure: Effects on plasma albumin
timeFrame: Baseline, day 1, 2, 7 and 15.
measure: Effects on protrombin time
timeFrame: Baseline, day 1, 2, 7 and 15.
measure: Effects on activated partial thromboplastin time
timeFrame: Baseline, day 1, 2, 7 and 15.
measure: Effects on serum thromboxane
timeFrame: Baseline, day 1, 2, 7 and 15.
measure: Effects on thromboxane metabolite
timeFrame: Baseline, day 1, 2, 7 and 15.
measure: Effects on platelet count
timeFrame: Baseline, day 1, 2, 7 and 15.
measure: Effects on reticulated platelets
timeFrame: Baseline, day 1, 2, 7 and 15.
measure: Effects on platelet/leukocyte conjugates
timeFrame: Baseline, day 1, 2, 7 and 15.
measure: Effects on plasma P-selectin
timeFrame: Baseline, day 1, 2, 7 and 15.
measure: Effects on P-selectin expression
timeFrame: Baseline, day 1, 2, 7 and 15.
measure: Clincal mixed outcome of lung function, ROX score
timeFrame: Days 7 and 15
measure: Clincal mixed outcome of lung function, SOfa score
timeFrame: Days 7 and 15
measure: Clincal mixed outcome of lung function, Apache index
timeFrame: Days 7 and 15
measure: Clincal mixed outcome of lung function, need to perform CT scan due to worsening of blood gases
timeFrame: Days 7 and 15
measure: Clincal mixed outcome of lung function, need to transfer the patient to ICU
timeFrame: Days 7 and 15
measure: Clincal mixed outcome of lung function, need for mechanical ventilation
timeFrame: Days 7 and 15
measure: Clincal mixed outcome of lung function, days without need of mechanical ventilation
timeFrame: Days 7 and 15
measure: Clincal mixed outcome of lung function, venous thromboembolism
timeFrame: Days 7 and 15
measure: Clincal mixed outcome of lung function, pulmonary thrombosis
timeFrame: Days 7 and 15
measure: Clincal mixed outcome of lung function, cardiovascular event
timeFrame: Days 7 and 15
measure: Clincal mixed outcome of lung function, death
timeFrame: Days 7 and 15
measure: Clincal mixed outcome of lung function, multiorgan failure
timeFrame: Days 7 and 15
measure: Clincal mixed outcome of lung function, discharge due to resolution of signs and symptoms
timeFrame: Days 7 and 15
measure: Safety outcomes, Major or clinically relevant bleeding
timeFrame: days 1,2,7 and 15
measure: Safety outcomes, total bleeding based on ISTH bleeding score
timeFrame: days 1,2,7 and 15
measure: Safety outcomes, minor bleeding according to ISTH BS
timeFrame: days 1,2,7 and 15
measure: Safety outcomes, decrease in platelet count below 100x109/L
timeFrame: days 1,2,7 and 15
measure: Safety outcomes, decrease of al least 2 g/dl Hb levels
timeFrame: days 1,2,7 and 15
measure: Safety outcomes, need for blood transfusion
timeFrame: days 1,2,7 and 15
measure: Safety outcomes, alterations of clinical or laboratory parameters
timeFrame: days 1,2,7 and 15
Other outcomes:
Locations:
city: Verona
country: Italy
facility: Azienda Ospedaliera Universitaria Integrata Verona
Study officials:
affiliation: University of Verona, AOUI Verona
name: Pietro Minuz, Professor
role: STUDY_DIRECTOR
affiliation: University of Milan
name: Marco Cattaneo, Professor
role: STUDY_DIRECTOR
affiliation: Universita di Verona
name: Roberto Leone, Professor
role: STUDY_DIRECTOR
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