COVID-19Phase 3AsperumNCT04808895
Acetylsalicylic Acid in the Prevention of Severe SARS-CoV2 Pneumonia in Hospitalised Patients With COVID-19
A Phase 3 study testing Acetylsalicylic acid in people with COVID-19 and Thrombosis Pulmonary, run by Azienda Ospedaliera Universitaria Integrata Verona at 1 site in Italy.
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. Read more about this study
- Who is it for?
- Ages 18 to 99 years
- Conditions the study is for
- COVID-19, Thrombosis Pulmonary
- What is being tested?
- Acetylsalicylic acid
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 204 participants
- Where
- 1 siteItaly
- Study dates
- 1 Apr 2021to 31 Aug 2021
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 99 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 21Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
About this study
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)
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.
Read the 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.
- Conditions
- COVID-19, Thrombosis Pulmonary
- Being tested
- Acetylsalicylic acid, Placebo
- Keywords
- Acetylsalicylic acid, Heparin, Pulmonary thrombosis, COVID-19, Platelets, Inflammation, Respiratoty failure
- Medical subject headings
- COVID-19, Inflammation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Acetylsalicylic acidDrug
administration of one tablet daily for 15 days. On the first day a loading dose of 300 mg will be administered
PlaceboDrug
administration of one tablet daily for 15 days. On the first day 3 tablets will be administered
| Study group | Role | What they receive |
|---|---|---|
| Acetylsalicylic acid | Active comparator | Tablets of 100 mg acetylsalicylic acid (one 100 mg daily dose. On the first day a loading dose of 300 mg will be administered) Receives: Drug: Acetylsalicylic acid |
| Placebo | Placebo comparator | Tablets of placebo, identical to active comparator (one tablet daily dose. On the first day 3 tablets will be administered) Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Prevention of clinical worsening
Transfer to ICU
Measured: day 15
Prevention of lung function worsening
PaO2/FiO2 lower than 150 mm Hg
Measured: day 15
Prevention of death
Death for any cause
Measured: day 15
Secondary outcomes (45)
Change in body temperature
Body temperature
Measured: Daily for 15 days
Change in oxygen saturation
Oxygen saturation
Measured: Daily for 15 days
Change in blood gases
blood gas analysis
Measured: Daily for 15 days
Change in blood cell count
blood cell count
Measured: Daily for 15 days
Change in blood oxygen
Oxygen administration when O2 saturation <92%
Measured: Daily for 15 days
Change in clinical markers of lung function
PaO2/FiO2; progression of disease at Rx
Measured: Daily for 15 days
Change in clinical markers of liver damage
markers of organ damage (ALT)
Measured: Daily for 15 days
Change in clinical markers of hearth damage
markers of organ damage (troponin)
Measured: Daily for 15 days
Change in clinical markers of renal damage
markers of organ damage (creatinine)
Measured: Daily for 15 days
Effects on blood cell count
Inflammatory markers (blood cell count)
Measured: Baseline, day 1, 2, 7 and 15.
Effects on CRP
Inflammatory markers (CRP)
Measured: Baseline, day 1, 2, 7 and 15.
Effects on D-dimer
Inflammatory markers (D-dimer)
Measured: Baseline, day 1, 2, 7 and 15.
Effects on interleukin-1
Inflammatory markers ( IL-1)
Measured: Baseline, day 1, 2, 7 and 15.
Effects on interleukin-6
Inflammatory markers (IL-6)
Measured: Baseline, day 1, 2, 7 and 15.
Effects on fibrinogen
Inflammatory markers (fibrinogen)
Measured: Baseline, day 1, 2, 7 and 15.
Effects on plasma albumin
Inflammatory markers (albumin)
Measured: Baseline, day 1, 2, 7 and 15.
Effects on protrombin time
platelet and hemostatic markets (prothrombin time)
Measured: Baseline, day 1, 2, 7 and 15.
Effects on activated partial thromboplastin time
platelet and hemostatic markets (activated partial thromboplastin time)
Measured: Baseline, day 1, 2, 7 and 15.
Effects on serum thromboxane
platelet and hemostatic markets ( serum TxB2)
Measured: Baseline, day 1, 2, 7 and 15.
Effects on thromboxane metabolite
platelet and hemostatic markets (urinary 11-dehydro TXB2)
Measured: Baseline, day 1, 2, 7 and 15.
Effects on platelet count
platelet and hemostatic markets (platelet count)
Measured: Baseline, day 1, 2, 7 and 15.
Effects on reticulated platelets
platelet and hemostatic markets (reticulated platelets)
Measured: Baseline, day 1, 2, 7 and 15.
Effects on platelet/leukocyte conjugates
platelet and hemostatic markets (platelets/leukocytes conjugates)
Measured: Baseline, day 1, 2, 7 and 15.
Effects on plasma P-selectin
platelet and hemostatic markets (plasma P-selectin)
Measured: Baseline, day 1, 2, 7 and 15.
Effects on P-selectin expression
platelet and hemostatic markets (platelet expression of P-selectin)
Measured: Baseline, day 1, 2, 7 and 15.
Clincal mixed outcome of lung function, ROX score
ROX score
Measured: Days 7 and 15
Clincal mixed outcome of lung function, SOfa score
SOfa score
Measured: Days 7 and 15
Clincal mixed outcome of lung function, Apache index
Apache index
Measured: 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
Measured: Days 7 and 15
Clincal mixed outcome of lung function, need to transfer the patient to ICU
need to transfer the patient to ICU
Measured: Days 7 and 15
Clincal mixed outcome of lung function, need for mechanical ventilation
need for mechanical ventilation
Measured: Days 7 and 15
Clincal mixed outcome of lung function, days without need of mechanical ventilation
days without need of mechanical ventilation
Measured: Days 7 and 15
Clincal mixed outcome of lung function, venous thromboembolism
venous thromboembolism
Measured: Days 7 and 15
Clincal mixed outcome of lung function, pulmonary thrombosis
pulmonary thrombosis
Measured: Days 7 and 15
Clincal mixed outcome of lung function, cardiovascular event
cardiovascular event
Measured: Days 7 and 15
Clincal mixed outcome of lung function, death
death
Measured: Days 7 and 15
Clincal mixed outcome of lung function, multiorgan failure
multiorgan failure
Measured: 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
Measured: Days 7 and 15
Safety outcomes, Major or clinically relevant bleeding
Major or clinically relevant bleeding
Measured: days 1,2,7 and 15
Safety outcomes, total bleeding based on ISTH bleeding score
total bleeding based on ISTH bleeding score
Measured: days 1,2,7 and 15
Safety outcomes, minor bleeding according to ISTH BS
minor bleeding according to ISTH BS
Measured: days 1,2,7 and 15
Safety outcomes, decrease in platelet count below 100x109/L
decrease in platelet count below 100x109/L
Measured: 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
Measured: days 1,2,7 and 15
Safety outcomes, need for blood transfusion
need for blood transfusion
Measured: days 1,2,7 and 15
Safety outcomes, alterations of clinical or laboratory parameters
alterations of clinical or laboratory parameters
Measured: days 1,2,7 and 15
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Mar 2021
- Study start1 Apr 2021 (estimated)
- Primary completion1 Jul 2021 (estimated)
- Study completion31 Aug 2021 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (27)Papers the sponsor has linked to this study.
- Other trials for COVID-19Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Experimental phase 3 drug trial, randomized 1:1, double-blind, multicentre in patients treated with acetylsalicylic acid vs placebo.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 204 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Azienda Ospedaliera Universitaria Integrata Verona
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Pietro Minuz, Professor, Study director, University of Verona, AOUI VeronaMarco Cattaneo, Professor, Study director, University of MilanRoberto Leone, Professor, Study director, Universita di Verona
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04808895
- Sponsor's protocol ID
- EudraCT 2020-006130-12
- Acronym
- Asperum
- Status last verified
- Mar 2021
- First submitted
- 15 Mar 2021
- Last updated
- 22 Mar 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, Vanstapel A, Werlein C, Stark H, Tzankov A, Li WW, Li VW, Mentzer SJ, Jonigk D. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med. 2020 Jul 9;383(2):120-128. doi: 10.1056/NEJMoa2015432. Epub 2020 May 21.
PubMed 32437596Becattini 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.
PubMed 22621626Bianconi 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.
PubMed 32705604Carestia 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.
PubMed 31951648Cattaneo 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.
PubMed 32349132Chen 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.
PubMed 32217835Chow 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.
PubMed 33093359Connors 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.
PubMed 32339221Gu SX, Tyagi T, Jain K, Gu VW, Lee SH, Hwa JM, Kwan JM, Krause DS, Lee AI, Halene S, Martin KA, Chun HJ, Hwa J. Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation. Nat Rev Cardiol. 2021 Mar;18(3):194-209. doi: 10.1038/s41569-020-00469-1. Epub 2020 Nov 19.
PubMed 33214651Jackson 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.
PubMed 30642917Hottz 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.
PubMed 32678428Koupenova M, Corkrey HA, Vitseva O, Manni G, Pang CJ, Clancy L, Yao C, Rade J, Levy D, Wang JP, Finberg RW, Kurt-Jones EA, Freedman JE. The role of platelets in mediating a response to human influenza infection. Nat Commun. 2019 Apr 16;10(1):1780. doi: 10.1038/s41467-019-09607-x.
PubMed 30992428Margraf A, Zarbock A. Platelets in Inflammation and Resolution. J Immunol. 2019 Nov 1;203(9):2357-2367. doi: 10.4049/jimmunol.1900899.
PubMed 31636134Marongiu F, Mameli A, Grandone E, Barcellona D. Pulmonary Thrombosis: A Clinical Pathological Entity Distinct from Pulmonary Embolism? Semin Thromb Hemost. 2019 Nov;45(8):778-783. doi: 10.1055/s-0039-1696942. Epub 2019 Sep 19.
PubMed 31537029Middleton EA, He XY, Denorme F, Campbell RA, Ng D, Salvatore SP, Mostyka M, Baxter-Stoltzfus A, Borczuk AC, Loda M, Cody MJ, Manne BK, Portier I, Harris ES, Petrey AC, Beswick EJ, Caulin AF, Iovino A, Abegglen LM, Weyrich AS, Rondina MT, Egeblad M, Schiffman JD, Yost CC. Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome. Blood. 2020 Sep 3;136(10):1169-1179. doi: 10.1182/blood.2020007008.
PubMed 32597954
Study at a glance
From the registry record, last updated by the sponsor on 22 Mar 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT04808895
- Acronym / sponsor ID
- Asperum / EudraCT 2020-006130-12
- Conditions
- COVID-19, Thrombosis Pulmonary
- Keywords
- Acetylsalicylic acid, Heparin, Pulmonary thrombosis, COVID-19, Platelets, Inflammation, Respiratoty failure
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 204 participants (estimated)
- Lead sponsor
- Azienda Ospedaliera Universitaria Integrata VeronaUniversity, hospital or other
- Study start
- 1 Apr 2021 (estimated)
- Primary completion
- 1 Jul 2021 (estimated)
- Study completion
- 31 Aug 2021 (estimated)
- First posted
- 22 Mar 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Experimental phase 3 drug trial, randomized 1:1, double-blind, multicentre in patients treated with acetylsalicylic acid vs placebo.
| Arm | Type | Receives |
|---|---|---|
| Acetylsalicylic acid | Active comparator | Drug: Acetylsalicylic acidTablets of 100 mg acetylsalicylic acid (one 100 mg daily dose. On the first day a loading dose of 300 mg will be administered) |
| Placebo | Placebo comparator | Drug: PlaceboTablets of placebo, identical to active comparator (one tablet daily dose. On the first day 3 tablets will be administered) |
Who may qualify
- Ages
- 18 to 99 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (21 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Acetylsalicylic acidadministration of one tablet daily for 15 days. On the first day a loading dose of 300 mg will be administered | Drug | Acetylsalicylic acid |
| Placeboadministration of one tablet daily for 15 days. On the first day 3 tablets will be administered | Drug | Placebo |
Primary outcome
Prevention of clinical worsening
Time frame: day 15
Transfer to ICU
Prevention of lung function worsening
Time frame: day 15
PaO2/FiO2 lower than 150 mm Hg
Prevention of death
Time frame: day 15
Death for any cause
45 secondary outcomes
Change in body temperature
Time frame: Daily for 15 days
Change in oxygen saturation
Time frame: Daily for 15 days
Change in blood gases
Time frame: Daily for 15 days
Change in blood cell count
Time frame: Daily for 15 days
Change in blood oxygen
Time frame: Daily for 15 days
Change in clinical markers of lung function
Time frame: Daily for 15 days
Change in clinical markers of liver damage
Time frame: Daily for 15 days
Change in clinical markers of hearth damage
Time frame: Daily for 15 days
Change in clinical markers of renal damage
Time frame: Daily for 15 days
Effects on blood cell count
Time frame: Baseline, day 1, 2, 7 and 15.
Effects on CRP
Time frame: Baseline, day 1, 2, 7 and 15.
Effects on D-dimer
Time frame: Baseline, day 1, 2, 7 and 15.
Effects on interleukin-1
Time frame: Baseline, day 1, 2, 7 and 15.
Effects on interleukin-6
Time frame: Baseline, day 1, 2, 7 and 15.
Effects on fibrinogen
Time frame: Baseline, day 1, 2, 7 and 15.
Effects on plasma albumin
Time frame: Baseline, day 1, 2, 7 and 15.
Effects on protrombin time
Time frame: Baseline, day 1, 2, 7 and 15.
Effects on activated partial thromboplastin time
Time frame: Baseline, day 1, 2, 7 and 15.
Effects on serum thromboxane
Time frame: Baseline, day 1, 2, 7 and 15.
Effects on thromboxane metabolite
Time frame: Baseline, day 1, 2, 7 and 15.
Effects on platelet count
Time frame: Baseline, day 1, 2, 7 and 15.
Effects on reticulated platelets
Time frame: Baseline, day 1, 2, 7 and 15.
Effects on platelet/leukocyte conjugates
Time frame: Baseline, day 1, 2, 7 and 15.
Effects on plasma P-selectin
Time frame: Baseline, day 1, 2, 7 and 15.
Effects on P-selectin expression
Time frame: Baseline, day 1, 2, 7 and 15.
Clincal mixed outcome of lung function, ROX score
Time frame: Days 7 and 15
Clincal mixed outcome of lung function, SOfa score
Time frame: Days 7 and 15
Clincal mixed outcome of lung function, Apache index
Time frame: Days 7 and 15
Clincal mixed outcome of lung function, need to perform CT scan due to worsening of blood gases
Time frame: Days 7 and 15
Clincal mixed outcome of lung function, need to transfer the patient to ICU
Time frame: Days 7 and 15
Clincal mixed outcome of lung function, need for mechanical ventilation
Time frame: Days 7 and 15
Clincal mixed outcome of lung function, days without need of mechanical ventilation
Time frame: Days 7 and 15
Clincal mixed outcome of lung function, venous thromboembolism
Time frame: Days 7 and 15
Clincal mixed outcome of lung function, pulmonary thrombosis
Time frame: Days 7 and 15
Clincal mixed outcome of lung function, cardiovascular event
Time frame: Days 7 and 15
Clincal mixed outcome of lung function, death
Time frame: Days 7 and 15
Clincal mixed outcome of lung function, multiorgan failure
Time frame: Days 7 and 15
Clincal mixed outcome of lung function, discharge due to resolution of signs and symptoms
Time frame: Days 7 and 15
Safety outcomes, Major or clinically relevant bleeding
Time frame: days 1,2,7 and 15
Safety outcomes, total bleeding based on ISTH bleeding score
Time frame: days 1,2,7 and 15
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Mar 2021.
- Background: PubMed 32437596Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, Vanstapel A, Werlein C, Stark H, Tzankov A, Li WW, Li VW, Mentzer SJ, Jonigk D. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med. 2020 Jul 9;383(2):120-128. doi: 10.1056/NEJMoa2015432. Epub 2020 May 21.
- Background: PubMed 22621626Becattini 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.
- Background: PubMed 32705604Bianconi 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.
- Background: PubMed 31951648Carestia 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.
- Background: PubMed 32349132Cattaneo 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.
- Background: PubMed 32217835Chen 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.
- Background: PubMed 33093359Chow 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.
- Background: PubMed 32339221Connors 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.
- Background: PubMed 33214651Gu SX, Tyagi T, Jain K, Gu VW, Lee SH, Hwa JM, Kwan JM, Krause DS, Lee AI, Halene S, Martin KA, Chun HJ, Hwa J. Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation. Nat Rev Cardiol. 2021 Mar;18(3):194-209. doi: 10.1038/s41569-020-00469-1. Epub 2020 Nov 19.
- Background: PubMed 30642917Jackson 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.
- Background: PubMed 32678428Hottz 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.
- Background: PubMed 30992428Koupenova M, Corkrey HA, Vitseva O, Manni G, Pang CJ, Clancy L, Yao C, Rade J, Levy D, Wang JP, Finberg RW, Kurt-Jones EA, Freedman JE. The role of platelets in mediating a response to human influenza infection. Nat Commun. 2019 Apr 16;10(1):1780. doi: 10.1038/s41467-019-09607-x.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Pietro Minuz, Professor study director
University of Verona, AOUI Verona
Marco Cattaneo, Professor study director
University of Milan
Roberto Leone, Professor study director
Universita di Verona
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Acetylsalicylic acid in people with COVID-19 and Thrombosis Pulmonary, run by Azienda Ospedaliera Universitaria Integrata Verona at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 22 Mar 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Pietro Minuz, Professor (+39 045-8124414, pietro.minuz@univr.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Prevention of clinical worsening (time frame: day 15). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04808895, which also lists 27 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Mar 2021; AzTrials last refreshed its copy on 8 Nov 2026.