Acetylsalicylic Acid in the Prevention of Severe SARS-CoV2 Pneumonia in Hospitalised Patients With COVID-19

COVID-19 Clinical Trial

— Asperum  

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)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04808895
• Other study ID #: EudraCT 2020-006130-12
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: April 1, 2021
• Est. completion date: August 31, 2021

Study information

• Verified date: March 2021
• Source: Azienda Ospedaliera Universitaria Integrata Verona
• Contact: Pietro Minuz, Professor
• Phone: +39 045-8124414
• Email: pietro.minuz[@]univr.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 204
• Est. completion date: August 31, 2021
• Est. primary completion date: July 1, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

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

Related Conditions & MeSH terms

• COVID-19
• Pneumonia
• Thrombosis
• Thrombosis Pulmonary

Intervention

Drug:
• Acetylsalicylic acid
administration of one tablet daily for 15 days. On the first day a loading dose of 300 mg will be administered
• Placebo
administration of one tablet daily for 15 days. On the first day 3 tablets will be administered

Locations

Country	Name	City	State
Italy	Azienda Ospedaliera Universitaria Integrata Verona	Verona

Sponsors (1)

Lead Sponsor	Collaborator
Azienda Ospedaliera Universitaria Integrata Verona

Country where clinical trial is conducted

Italy, 

References & Publications (26)

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* Note: There are 26 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Prevention of clinical worsening	Transfer to ICU	day 15
Primary	Prevention of lung function worsening	PaO2/FiO2 lower than 150 mm Hg	day 15
Primary	Prevention of death	Death for any cause	day 15
Secondary	Change in body temperature	Body temperature	Daily for 15 days
Secondary	Change in oxygen saturation	Oxygen saturation	Daily for 15 days
Secondary	Change in blood gases	blood gas analysis	Daily for 15 days
Secondary	Change in blood cell count	blood cell count	Daily for 15 days
Secondary	Change in blood oxygen	Oxygen administration when O2 saturation <92%	Daily for 15 days
Secondary	Change in clinical markers of lung function	PaO2/FiO2; progression of disease at Rx	Daily for 15 days
Secondary	Change in clinical markers of liver damage	markers of organ damage (ALT)	Daily for 15 days
Secondary	Change in clinical markers of hearth damage	markers of organ damage (troponin)	Daily for 15 days
Secondary	Change in clinical markers of renal damage	markers of organ damage (creatinine)	Daily for 15 days
Secondary	Effects on blood cell count	Inflammatory markers (blood cell count)	Baseline, day 1, 2, 7 and 15.
Secondary	Effects on CRP	Inflammatory markers (CRP)	Baseline, day 1, 2, 7 and 15.
Secondary	Effects on D-dimer	Inflammatory markers (D-dimer)	Baseline, day 1, 2, 7 and 15.
Secondary	Effects on interleukin-1	Inflammatory markers ( IL-1)	Baseline, day 1, 2, 7 and 15.
Secondary	Effects on interleukin-6	Inflammatory markers (IL-6)	Baseline, day 1, 2, 7 and 15.
Secondary	Effects on fibrinogen	Inflammatory markers (fibrinogen)	Baseline, day 1, 2, 7 and 15.
Secondary	Effects on plasma albumin	Inflammatory markers (albumin)	Baseline, day 1, 2, 7 and 15.
Secondary	Effects on protrombin time	platelet and hemostatic markets (prothrombin time)	Baseline, day 1, 2, 7 and 15.
Secondary	Effects on activated partial thromboplastin time	platelet and hemostatic markets (activated partial thromboplastin time)	Baseline, day 1, 2, 7 and 15.
Secondary	Effects on serum thromboxane	platelet and hemostatic markets ( serum TxB2)	Baseline, day 1, 2, 7 and 15.
Secondary	Effects on thromboxane metabolite	platelet and hemostatic markets (urinary 11-dehydro TXB2)	Baseline, day 1, 2, 7 and 15.
Secondary	Effects on platelet count	platelet and hemostatic markets (platelet count)	Baseline, day 1, 2, 7 and 15.
Secondary	Effects on reticulated platelets	platelet and hemostatic markets (reticulated platelets)	Baseline, day 1, 2, 7 and 15.
Secondary	Effects on platelet/leukocyte conjugates	platelet and hemostatic markets (platelets/leukocytes conjugates)	Baseline, day 1, 2, 7 and 15.
Secondary	Effects on plasma P-selectin	platelet and hemostatic markets (plasma P-selectin)	Baseline, day 1, 2, 7 and 15.
Secondary	Effects on P-selectin expression	platelet and hemostatic markets (platelet expression of P-selectin)	Baseline, day 1, 2, 7 and 15.
Secondary	Clincal mixed outcome of lung function, ROX score	ROX score	Days 7 and 15
Secondary	Clincal mixed outcome of lung function, SOfa score	SOfa score	Days 7 and 15
Secondary	Clincal mixed outcome of lung function, Apache index	Apache index	Days 7 and 15
Secondary	Clincal mixed outcome of lung function, need to perform CT scan due to worsening of blood gases	need to perform CT scan due to worsening of blood gases	Days 7 and 15
Secondary	Clincal mixed outcome of lung function, need to transfer the patient to ICU	need to transfer the patient to ICU	Days 7 and 15
Secondary	Clincal mixed outcome of lung function, need for mechanical ventilation	need for mechanical ventilation	Days 7 and 15
Secondary	Clincal mixed outcome of lung function, days without need of mechanical ventilation	days without need of mechanical ventilation	Days 7 and 15
Secondary	Clincal mixed outcome of lung function, venous thromboembolism	venous thromboembolism	Days 7 and 15
Secondary	Clincal mixed outcome of lung function, pulmonary thrombosis	pulmonary thrombosis	Days 7 and 15
Secondary	Clincal mixed outcome of lung function, cardiovascular event	cardiovascular event	Days 7 and 15
Secondary	Clincal mixed outcome of lung function, death	death	Days 7 and 15
Secondary	Clincal mixed outcome of lung function, multiorgan failure	multiorgan failure	Days 7 and 15
Secondary	Clincal mixed outcome of lung function, discharge due to resolution of signs and symptoms	discharge due to resolution of signs and symptoms	Days 7 and 15
Secondary	Safety outcomes, Major or clinically relevant bleeding	Major or clinically relevant bleeding	days 1,2,7 and 15
Secondary	Safety outcomes, total bleeding based on ISTH bleeding score	total bleeding based on ISTH bleeding score	days 1,2,7 and 15
Secondary	Safety outcomes, minor bleeding according to ISTH BS	minor bleeding according to ISTH BS	days 1,2,7 and 15
Secondary	Safety outcomes, decrease in platelet count below 100x109/L	decrease in platelet count below 100x109/L	days 1,2,7 and 15
Secondary	Safety outcomes, decrease of al least 2 g/dl Hb levels	decrease of al least 2 g/dl Hb levels	days 1,2,7 and 15
Secondary	Safety outcomes, need for blood transfusion	need for blood transfusion	days 1,2,7 and 15
Secondary	Safety outcomes, alterations of clinical or laboratory parameters	alterations of clinical or laboratory parameters	days 1,2,7 and 15