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

Multicenter Randomized, Double-blind, Placebo-controlled, Clinical Trial of Acetylsalicylic Acid in the Prevention of Severe SARS-CoV2 Pneumonia in Hospitalised Patients (Asperum)

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.

Study Overview

• Status: Unknown
• Conditions: COVID-19; Thrombosis Pulmonary
• Intervention / Treatment: Drug: Acetylsalicylic acid; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Anticipated): 204
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Verona, Italy, 37126
    • Azienda Ospedaliera Universitaria Integrata Verona

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Acetylsalicylic acid; Tablets of 100 mg acetylsalicylic acid (one 100 mg daily dose. On the first day a loading dose of 300 mg will be administered)	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 Comparator: Placebo; Tablets of placebo, identical to active comparator (one tablet daily dose. On the first day 3 tablets will be administered)	Drug: Placebo; administration of one tablet daily for 15 days. On the first day 3 tablets will be administered

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevention of clinical worsening	Transfer to ICU	day 15
Prevention of lung function worsening	PaO2/FiO2 lower than 150 mm Hg	day 15
Prevention of death	Death for any cause	day 15

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Azienda Ospedaliera Universitaria Integrata Verona
• Investigators: Study Director: Pietro Minuz, Professor, University of Verona, AOUI Verona; Study Director: Marco Cattaneo, Professor, University of Milan; Study Director: Roberto Leone, Professor, Universita di Verona

Publications and helpful links

General Publications

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• Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, Wang T, Zhang X, Chen H, Yu H, Zhang X, Zhang M, Wu S, Song J, Chen T, Han M, Li S, Luo X, Zhao J, Ning Q. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020 May 1;130(5):2620-2629. doi: 10.1172/JCI137244.
• Jackson SP, Darbousset R, Schoenwaelder SM. Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms. Blood. 2019 Feb 28;133(9):906-918. doi: 10.1182/blood-2018-11-882993. Epub 2019 Jan 14.
• Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, Mehra MR, Schuepbach RA, Ruschitzka F, Moch H. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020 May 2;395(10234):1417-1418. doi: 10.1016/S0140-6736(20)30937-5. Epub 2020 Apr 21. No abstract available.
• Margraf A, Zarbock A. Platelets in Inflammation and Resolution. J Immunol. 2019 Nov 1;203(9):2357-2367. doi: 10.4049/jimmunol.1900899.
• Becattini C, Agnelli G, Schenone A, Eichinger S, Bucherini E, Silingardi M, Bianchi M, Moia M, Ageno W, Vandelli MR, Grandone E, Prandoni P; WARFASA Investigators. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012 May 24;366(21):1959-67. doi: 10.1056/NEJMoa1114238. Erratum In: N Engl J Med. 2012 Oct 18;367(16):1573.
• Simes J, Becattini C, Agnelli G, Eikelboom JW, Kirby AC, Mister R, Prandoni P, Brighton TA; INSPIRE Study Investigators (International Collaboration of Aspirin Trials for Recurrent Venous Thromboembolism). Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE collaboration. Circulation. 2014 Sep 23;130(13):1062-71. doi: 10.1161/CIRCULATIONAHA.114.008828. Epub 2014 Aug 25.
• Sexton TR, Zhang G, Macaulay TE, Callahan LA, Charnigo R, Vsevolozhskaya OA, Li Z, Smyth S. Ticagrelor Reduces Thromboinflammatory Markers in Patients With Pneumonia. JACC Basic Transl Sci. 2018 Aug 28;3(4):435-449. doi: 10.1016/j.jacbts.2018.05.005. eCollection 2018 Aug.
• Yin S, Huang M, Li D, Tang N. Difference of coagulation features between severe pneumonia induced by SARS-CoV2 and non-SARS-CoV2. J Thromb Thrombolysis. 2021 May;51(4):1107-1110. doi: 10.1007/s11239-020-02105-8.
• Minuz P, Mansueto G, Mazzaferri F, Fava C, Dalbeni A, Ambrosetti MC, Sibani M, Tacconelli E. High rate of pulmonary thromboembolism in patients with SARS-CoV-2 pneumonia. Clin Microbiol Infect. 2020 Nov;26(11):1572-1573. doi: 10.1016/j.cmi.2020.06.011. Epub 2020 Jun 18. No abstract available.
• Cattaneo M, Bertinato EM, Birocchi S, Brizio C, Malavolta D, Manzoni M, Muscarella G, Orlandi M. Pulmonary Embolism or Pulmonary Thrombosis in COVID-19? Is the Recommendation to Use High-Dose Heparin for Thromboprophylaxis Justified? Thromb Haemost. 2020 Aug;120(8):1230-1232. doi: 10.1055/s-0040-1712097. Epub 2020 Apr 29. No abstract available.
• Bianconi V, Violi F, Fallarino F, Pignatelli P, Sahebkar A, Pirro M. Is Acetylsalicylic Acid a Safe and Potentially Useful Choice for Adult Patients with COVID-19 ? Drugs. 2020 Sep;80(14):1383-1396. doi: 10.1007/s40265-020-01365-1.
• Carestia A, Davis RP, Grosjean H, Lau MW, Jenne CN. Acetylsalicylic acid inhibits intravascular coagulation during Staphylococcus aureus-induced sepsis in mice. Blood. 2020 Apr 9;135(15):1281-1286. doi: 10.1182/blood.2019002783.
• Chow JH, Khanna AK, Kethireddy S, Yamane D, Levine A, Jackson AM, McCurdy MT, Tabatabai A, Kumar G, Park P, Benjenk I, Menaker J, Ahmed N, Glidewell E, Presutto E, Cain S, Haridasa N, Field W, Fowler JG, Trinh D, Johnson KN, Kaur A, Lee A, Sebastian K, Ulrich A, Pena S, Carpenter R, Sudhakar S, Uppal P, Fedeles BT, Sachs A, Dahbour L, Teeter W, Tanaka K, Galvagno SM, Herr DL, Scalea TM, Mazzeffi MA. Aspirin Use Is Associated With Decreased Mechanical Ventilation, Intensive Care Unit Admission, and In-Hospital Mortality in Hospitalized Patients With Coronavirus Disease 2019. Anesth Analg. 2021 Apr 1;132(4):930-941. doi: 10.1213/ANE.0000000000005292.
• Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020 Jun 4;135(23):2033-2040. doi: 10.1182/blood.2020006000.
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• Hottz ED, Azevedo-Quintanilha IG, Palhinha L, Teixeira L, Barreto EA, Pao CRR, Righy C, Franco S, Souza TML, Kurtz P, Bozza FA, Bozza PT. Platelet activation and platelet-monocyte aggregate formation trigger tissue factor expression in patients with severe COVID-19. Blood. 2020 Sep 10;136(11):1330-1341. doi: 10.1182/blood.2020007252.
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• Scavone M, Rizzo J, Femia EA, Podda GM, Bossi E, Caberlon S, Paroni R, Cattaneo M. Patients with Essential Thrombocythemia may be Poor Responders to Enteric-Coated Aspirin, but not to Plain Aspirin. Thromb Haemost. 2020 Oct;120(10):1442-1453. doi: 10.1055/s-0040-1714351. Epub 2020 Jul 27.
• Taus F, Salvagno G, Cane S, Fava C, Mazzaferri F, Carrara E, Petrova V, Barouni RM, Dima F, Dalbeni A, Romano S, Poli G, Benati M, De Nitto S, Mansueto G, Iezzi M, Tacconelli E, Lippi G, Bronte V, Minuz P. Platelets Promote Thromboinflammation in SARS-CoV-2 Pneumonia. Arterioscler Thromb Vasc Biol. 2020 Dec;40(12):2975-2989. doi: 10.1161/ATVBAHA.120.315175. Epub 2020 Oct 14.

Study record dates

Study Major Dates

• Study Start (Anticipated): April 1, 2021
• Primary Completion (Anticipated): July 1, 2021
• Study Completion (Anticipated): August 31, 2021

Study Registration Dates

• First Submitted: March 15, 2021
• First Submitted That Met QC Criteria: March 19, 2021
• First Posted (Actual): March 22, 2021

Study Record Updates

• Last Update Posted (Actual): March 22, 2021
• Last Update Submitted That Met QC Criteria: March 19, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Inflammation; COVID-19; Platelets; Heparin; Acetylsalicylic acid; Pulmonary thrombosis; Respiratoty failure
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Lung Diseases; Embolism and Thrombosis; COVID-19; Pneumonia; Thrombosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Aspirin
• Other Study ID Numbers: EudraCT 2020-006130-12

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No