COVID19Phase 3PARTISANNCT04445623
Prasugrel in Severe COVID-19 Pneumonia
A Phase 3 study testing Prasugrel Hydrochloride 10 MG Oral Tablet in people with COVID19 and Thrombosis, 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
- COVID19, Thrombosis
- What is being tested?
- Prasugrel Hydrochloride 10 MG Oral Tablet
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 128 participants
- Where
- 1 siteItaly
- Study dates
- Jul 2020to Jan 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
- Covid-19 pneumonia
- Age over 18 years
- Willingness to express consent
Who cannot join
- Active neoplasia or in maintenance therapy
- Pregnancy and breastfeeding
- Any absolute contraindication to the use of antiplatelet drugs
- Pathological bleeding in progress.
- Recent major bleeding at any location
- Need to use therapeutic doses of oral anticoagulants or heparins
Show all 10Show fewer
- Need to use antiplatelet in combination for clinical indication
- Hypersensitivity to the active substance prasugrel or any of the excipients
- Clinical history of stroke or transient ischemic attack (TIA).
- Severe liver failure (Child-Pugh class C).
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Prasugrel in the Prevention of Severe SARS-CoV2 Pneumonia in Hospitalised Patients
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 purinergic receptor P2Y12 inhibitors in pneumococcal pneumonia may improve inflammation and respiratory function in humans. There are no validated protocols for thrombosis prevention in Covid-19. There is scientific rationale to consider a P2Y12 inhibitor 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 P2Y12 inhibitors and the evidence of improvement in respiratory function both in human and experimental pathology. Prasugrel could be considered as an ideal candidate drug for Covid-19 patients because of higher efficacy and limited Interactions with drugs used in the treatment of Sars-CoV2. 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 a P2Y12 inhibitor 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, antibiotics), except for specific contraindications.
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. Preliminary observations indicate that the use of purinergic receptor P2Y12 inhibitors during pneumococcal pneumonia may improve the inflammatory process and respiratory function in humans. There are currently no validated protocols for thrombosis prevention in the field of pulmonary viral diseases, in particular COVID-19. There is adequate scientific rationale to consider the use of a P2Y12 inhibitor antiplatelet drug for the prevention of thrombosis in the pulmonary circulation and the attenuation of pulmonary inflammation. The use of a P2Y12 inhibitor is motivated by numerous experimental demonstrations of the anti-inflammatory activity of P2Y12 inhibitors and by the evidence of improvement of respiratory function parameters both in humans and experimental models. Prasugrel could be considered as an ideal candidate drug for administration in Covid-19 patients because of its higher efficacy in acute coronary syndrome compared to clopidogrel. Interactions of prasugrel with drugs used for the treatment of SARS-CoV2 are limited. 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 clinical features described, according to a note of the "Italian Medicines Agency" (AIFA), together with the prevention of thrombogenic activity of platelets by means of a P2Y12 inhibitor 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 COVID-19 patients, regardless of the treatment regimen used for their condition (antivirals, anti-inflammatory drugs, antibiotics), except for specific contraindications to the use of prasugrel, or placebo if patients are treated with antiplatelet drugs.
- Conditions
- COVID19, Thrombosis
- Being tested
- Prasugrel Hydrochloride 10 MG Oral Tablet, Placebo
- Medical subject headings
- COVID-19, Thrombosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Prasugrel Hydrochloride 10 MG Oral TabletDrug
administration of prasugrel daily for 15 days
PlaceboDrug
administration of placebo daily for 15 days
| Study group | Role | What they receive |
|---|---|---|
| prasugrel hydrochloride | Active comparator | film-coated tablets of prasugrel hydrochloride (10 mg daily dose after loading dose of 60 mg) Receives: Drug: Prasugrel Hydrochloride 10 MG Oral Tablet |
| placebo | Placebo comparator | film-coated tablets of placebo (10 mg daily dose after loading dose of 60 mg) Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
P/F ratio at day 7
PaO2/FiO2 ratio (arterial oxygen tension divided by the fraction of inspired oxygen) detected after 7 days of treatment
Measured: day 7
Secondary outcomes (32)
Daily P/F ratio
PaO2/FiO2 ratio (arterial oxygen tension divided by the fraction of inspired oxygen) detected daily for 15 days
Measured: 15 days
Daily need for oxygen supply
daily need for oxygen supply for 15 days
Measured: 15 days
Need for ICU
Number of patients requiring transfer to the intensive care unit (ICU) by treatment arm
Measured: day 15 and day 30
Death
death by day 15 and day 30 by treatment arm
Measured: 15 day and day 30
MOF
Multi-organ failure (MOF) by day 15 and day 30 assessed using sequential organ failure assessment score (SOFA) score (Units 0-4 better outcome, over 30 worse outcome) by treatment arm
Measured: day 15 and day 30
Discharge
Number of patients discharged after improvement by day 15 and day 30 by treatment arm
Measured: day 15 and day 30
Clinical progression of the disease SOFA score
Clinical progression of the disease evaluated by SOFA score (Units 0-6 better outcome, 15-24 worse outcome) by day 15 and day 30
Measured: day 15 and day 30
Clinical progression of the disease APACHE II
Clinical progression of the disease evaluated by Acute Physiology And Chronic Health Evaluation (APACHE II) score (Units 1-5 better outcome, over 30 worse outcome) by day 15 and day 30
Measured: day 15 and day 30
Venous thrombosis/ pulmonary embolism/thrombosis
Number of patients with venous thrombosis/ pulmonary embolism/thrombosis by day 15 and day 30
Measured: day 15 and day 30
Need for CT imaging
Number of patients requiring computerized tomography (CT) imaging due to worsening of respiratory function by treatment arm
Measured: day 15
Daily Temperature
Body temperature measured twice daily for 15 days, C°
Measured: 15 days
Daily blood pressure
Blood pressure measured twice daily for 15 days, mmHg
Measured: 15 days
Daily total blood count Hemoglobin
Total blood count measured in venous blood for 15 days, Hemoglobin, g/L (cell/mcL
Measured: 15 days
Daily total blood count Red Blood Cells
Total blood count measured in venous blood for 15 days, Red Blood cells (cell/mcL)
Measured: 15 days
Daily total blood count Leukocytes
Total blood count measured in venous blood for 15 days, Leukocytes (cell/mcL)
Measured: 15 days
Daily total blood count Platelets
Total blood count measured in venous blood for 15 days, platelets (cell/mcL)
Measured: 15 days
Daily indices of organ damage Liver
ALT U/L in venous blood
Measured: 15 days
Indices of inflammation C-reactive protein
C-reactive protein microg/L in venous blood
Measured: day 1, 2, 7, 15
Indices of haemostasis PT
PT ratio in venous blood by treatment arm
Measured: day 1, 2, 7,15
Daily progression at imaging (chest-X-ray)
progression of lung infiltrates as detected by chest-X-ray by treatment arm
Measured: 15 days
Major bleeding
Major and/or clinically relevant bleeding according to International Society of Thrombosis and Haemostasis (ISTH) bleeding scale (Unit 0 better outcome, 4 worse outcome, 11 items) during treatment.
Measured: day 1, 2, 7, 15, 30
Total bleeding
Total bleeding according to International Society of Thrombosis and Haemostasis (ISTH bleeding) scale (Unit 0 better outcome, 4 worse outcome, 11 items) during treatment.
Measured: day 1, 2, 7, 15, 30
Unexpected clinical or laboratory findings
Number of unexpected changes in clinical or laboratory findings not included in the predefined list of outcomes during treatment. .
Measured: day 1, 2, 7, 15
Indices of inflammation D-dimer
D-dimer microg/L in venous blood
Measured: day 1, 2, 7, 15
Indices of inflammation Fibrinogen
Fibrinogen g/L in venous blood
Measured: day 1, 2, 7, 15
Indices of inflammation IL-6
Interleukin (IL)-6 pg/mL in venous blood by treatment arm
Measured: day 1, 2, 7, 15
Indices of inflammation IL-1
Interleukin (IL)-1 pg/mL in venous blood by treatment arm
Measured: day 1, 2, 7, 15
Daily indices of organ damage kidney
serum creatinine micromol/L by treatment arm
Measured: 15 days
Daily indices of organ damage heart
troponin t ng/L by treatment arm
Measured: 15 days
Haemostasis aPTT
aPTT ratio by treatment arm
Measured: day 1, 2, 7,15
Haemostasis VASP PRI
Vasodilator stimulated phosphoprotein (VASP) phosphorylation (PRI) % by treatment arm
Measured: day 1, 2, 7,15
Haemostasis platelet-leukocytes aggregates
Platelet-leukocytes aggregates % in peripheral by treatment arm
Measured: day 1, 2, 7,15
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Jun 2020
- Study startJul 2020 (estimated)
- Primary completionOct 2020 (estimated)
- Study completionJan 2021 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (20)Papers the sponsor has linked to this study.
- Other trials for COVID19Studies 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 prasugrel vs placebo.
- Masking
- Double blind
- Who is masked
- Participant, Care provider
- Enrolment
- 128 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Azienda Ospedaliera Universitaria Integrata Verona
- Sponsor type
- University, hospital or other
- Collaborators
- University of Milan
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04445623
- Sponsor's protocol ID
- MGI-COVID-19-prasugrel
- Acronym
- PARTISAN
- Status last verified
- May 2020
- First submitted
- 4 Jun 2020
- Last updated
- 26 Jun 2020
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Obi AT, Tignanelli CJ, Jacobs BN, Arya S, Park PK, Wakefield TW, Henke PK, Napolitano LM. Empirical systemic anticoagulation is associated with decreased venous thromboembolism in critically ill influenza A H1N1 acute respiratory distress syndrome patients. J Vasc Surg Venous Lymphat Disord. 2019 May;7(3):317-324. doi: 10.1016/j.jvsv.2018.08.010. Epub 2018 Nov 23.
PubMed 30477976Smeeth L, Cook C, Thomas S, Hall AJ, Hubbard R, Vallance P. Risk of deep vein thrombosis and pulmonary embolism after acute infection in a community setting. Lancet. 2006 Apr 1;367(9516):1075-1079. doi: 10.1016/S0140-6736(06)68474-2.
PubMed 16581406Margraf A, Zarbock A. Platelets in Inflammation and Resolution. J Immunol. 2019 Nov 1;203(9):2357-2367. doi: 10.4049/jimmunol.1900899.
PubMed 31636134Eck RJ, Bult W, Wetterslev J, Gans ROB, Meijer K, van der Horst ICC, Keus F. Low Dose Low-Molecular-Weight Heparin for Thrombosis Prophylaxis: Systematic Review with Meta-Analysis and Trial Sequential Analysis. J Clin Med. 2019 Nov 21;8(12):2039. doi: 10.3390/jcm8122039.
PubMed 31766453Jackson 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 30642917Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, Juni P, Kastrati A, Kolh P, Mauri L, Montalescot G, Neumann FJ, Petricevic M, Roffi M, Steg PG, Windecker S, Zamorano JL, Levine GN; ESC Scientific Document Group; ESC Committee for Practice Guidelines (CPG); ESC National Cardiac Societies. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2018 Jan 14;39(3):213-260. doi: 10.1093/eurheartj/ehx419. No abstract available.
PubMed 28886622Becattini 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 22621626Simes 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.
PubMed 25156992Sexton 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.
PubMed 30175268Rudolph TK, Fuchs A, Klinke A, Schlichting A, Friedrichs K, Hellmich M, Mollenhauer M, Schwedhelm E, Baldus S, Rudolph V. Prasugrel as opposed to clopidogrel improves endothelial nitric oxide bioavailability and reduces platelet-leukocyte interaction in patients with unstable angina pectoris: A randomized controlled trial. Int J Cardiol. 2017 Dec 1;248:7-13. doi: 10.1016/j.ijcard.2017.06.099. Epub 2017 Jul 1.
PubMed 28709700Johnston LR, La Flamme AC, Larsen PD, Harding SA. Prasugrel inhibits platelet-enhanced pro-inflammatory CD4+ T cell responses in humans. Atherosclerosis. 2015 Mar;239(1):283-6. doi: 10.1016/j.atherosclerosis.2015.01.006. Epub 2015 Jan 14.
PubMed 25635327Totani L, Dell'Elba G, Martelli N, Di Santo A, Piccoli A, Amore C, Evangelista V. Prasugrel inhibits platelet-leukocyte interaction and reduces inflammatory markers in a model of endotoxic shock in the mouse. Thromb Haemost. 2012 Jun;107(6):1130-40. doi: 10.1160/TH11-12-0867. Epub 2012 Mar 22.
PubMed 22436970Ancrenaz V, Deglon J, Samer C, Staub C, Dayer P, Daali Y, Desmeules J. Pharmacokinetic interaction between prasugrel and ritonavir in healthy volunteers. Basic Clin Pharmacol Toxicol. 2013 Feb;112(2):132-7. doi: 10.1111/j.1742-7843.2012.00932.x. Epub 2012 Oct 5.
PubMed 22900583Bikdeli B, Madhavan MV, Jimenez D, Chuich T, Dreyfus I, Driggin E, Nigoghossian C, Ageno W, Madjid M, Guo Y, Tang LV, Hu Y, Giri J, Cushman M, Quere I, Dimakakos EP, Gibson CM, Lippi G, Favaloro EJ, Fareed J, Caprini JA, Tafur AJ, Burton JR, Francese DP, Wang EY, Falanga A, McLintock C, Hunt BJ, Spyropoulos AC, Barnes GD, Eikelboom JW, Weinberg I, Schulman S, Carrier M, Piazza G, Beckman JA, Steg PG, Stone GW, Rosenkranz S, Goldhaber SZ, Parikh SA, Monreal M, Krumholz HM, Konstantinides SV, Weitz JI, Lip GYH; Global COVID-19 Thrombosis Collaborative Group, Endorsed by the ISTH, NATF, ESVM, and the IUA, Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020 Jun 16;75(23):2950-2973. doi: 10.1016/j.jacc.2020.04.031. Epub 2020 Apr 17.
PubMed 32311448Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020 Apr;18(4):844-847. doi: 10.1111/jth.14768. Epub 2020 Mar 13.
PubMed 32073213
Study at a glance
From the registry record, last updated by the sponsor on 26 Jun 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prasugrel in the Prevention of Severe SARS-CoV2 Pneumonia in Hospitalised Patients
- ClinicalTrials.gov ID
- NCT04445623
- Acronym / sponsor ID
- PARTISAN / MGI-COVID-19-prasugrel
- Conditions
- COVID19, Thrombosis
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 128 participants (estimated)
- Lead sponsor
- Azienda Ospedaliera Universitaria Integrata VeronaUniversity, hospital or other
- Collaborators
- University of Milan
- Study start
- Jul 2020 (estimated)
- Primary completion
- Oct 2020 (estimated)
- Study completion
- Jan 2021 (estimated)
- First posted
- 24 Jun 2020 (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 purinergic receptor P2Y12 inhibitors in pneumococcal pneumonia may improve inflammation and respiratory function in humans. There are no validated protocols for thrombosis prevention in Covid-19. There is scientific rationale to consider a P2Y12 inhibitor 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 P2Y12 inhibitors and the evidence of improvement in respiratory function both in human and experimental pathology. Prasugrel could be considered as an ideal candidate drug for Covid-19 patients because of higher efficacy and limited Interactions with drugs used in the treatment of Sars-CoV2. 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 a P2Y12 inhibitor 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, antibiotics), except for specific contraindications.
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. Preliminary observations indicate that the use of purinergic receptor P2Y12 inhibitors during pneumococcal pneumonia may improve the inflammatory process and respiratory function in humans. There are currently no validated protocols for thrombosis prevention in the field of pulmonary viral diseases, in particular COVID-19. There is adequate scientific rationale to consider the use of a P2Y12 inhibitor antiplatelet drug for the prevention of thrombosis in the pulmonary circulation and the attenuation of pulmonary inflammation. The use of a P2Y12 inhibitor is motivated by numerous experimental demonstrations of the anti-inflammatory activity of P2Y12 inhibitors and by the evidence of improvement of respiratory function parameters both in humans and experimental models. Prasugrel could be considered as an ideal candidate drug for administration in Covid-19 patients because of its higher efficacy in acute coronary syndrome compared to clopidogrel. Interactions of prasugrel with drugs used for the treatment of SARS-CoV2 are limited. 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 clinical features described, according to a note of the "Italian Medicines Agency" (AIFA), together with the prevention of thrombogenic activity of platelets by means of a P2Y12 inhibitor 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 COVID-19 patients, regardless of the treatment regimen used for their condition (antivirals, anti-inflammatory drugs, antibiotics), except for specific contraindications to the use of prasugrel, or placebo if patients are treated with antiplatelet drugs.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, care provider)
- Number of arms
- 2
- Model description
- Experimental phase 3 drug trial, randomized 1:1, double-blind, multicentre in patients treated with prasugrel vs placebo.
| Arm | Type | Receives |
|---|---|---|
| prasugrel hydrochloride | Active comparator | Drug: Prasugrel Hydrochloride 10 MG Oral Tabletfilm-coated tablets of prasugrel hydrochloride (10 mg daily dose after loading dose of 60 mg) |
| placebo | Placebo comparator | Drug: Placebofilm-coated tablets of placebo (10 mg daily dose after loading dose of 60 mg) |
Who may qualify
- Ages
- 18 to 99 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Covid-19 pneumonia
- Age over 18 years
- Willingness to express consent
Key exclusion criteria (10 listed)
- Active neoplasia or in maintenance therapy
- Pregnancy and breastfeeding
- Any absolute contraindication to the use of antiplatelet drugs
- Pathological bleeding in progress.
- Recent major bleeding at any location
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 |
|---|---|---|
| Prasugrel Hydrochloride 10 MG Oral Tabletadministration of prasugrel daily for 15 days | Drug | prasugrel hydrochloride |
| Placeboadministration of placebo daily for 15 days | Drug | placebo |
Primary outcome
P/F ratio at day 7
Time frame: day 7
PaO2/FiO2 ratio (arterial oxygen tension divided by the fraction of inspired oxygen) detected after 7 days of treatment
32 secondary outcomes
Daily P/F ratio
Time frame: 15 days
Daily need for oxygen supply
Time frame: 15 days
Need for ICU
Time frame: day 15 and day 30
Death
Time frame: 15 day and day 30
MOF
Time frame: day 15 and day 30
Discharge
Time frame: day 15 and day 30
Clinical progression of the disease SOFA score
Time frame: day 15 and day 30
Clinical progression of the disease APACHE II
Time frame: day 15 and day 30
Venous thrombosis/ pulmonary embolism/thrombosis
Time frame: day 15 and day 30
Need for CT imaging
Time frame: day 15
Daily Temperature
Time frame: 15 days
Daily blood pressure
Time frame: 15 days
Daily total blood count Hemoglobin
Time frame: 15 days
Daily total blood count Red Blood Cells
Time frame: 15 days
Daily total blood count Leukocytes
Time frame: 15 days
Daily total blood count Platelets
Time frame: 15 days
Daily indices of organ damage Liver
Time frame: 15 days
Indices of inflammation C-reactive protein
Time frame: day 1, 2, 7, 15
Indices of haemostasis PT
Time frame: day 1, 2, 7,15
Daily progression at imaging (chest-X-ray)
Time frame: 15 days
Major bleeding
Time frame: day 1, 2, 7, 15, 30
Total bleeding
Time frame: day 1, 2, 7, 15, 30
Unexpected clinical or laboratory findings
Time frame: day 1, 2, 7, 15
Indices of inflammation D-dimer
Time frame: day 1, 2, 7, 15
Indices of inflammation Fibrinogen
Time frame: day 1, 2, 7, 15
Indices of inflammation IL-6
Time frame: day 1, 2, 7, 15
Indices of inflammation IL-1
Time frame: day 1, 2, 7, 15
Daily indices of organ damage kidney
Time frame: 15 days
Daily indices of organ damage heart
Time frame: 15 days
Haemostasis aPTT
Time frame: day 1, 2, 7,15
Haemostasis VASP PRI
Time frame: day 1, 2, 7,15
Haemostasis platelet-leukocytes aggregates
Time frame: day 1, 2, 7,15
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Jun 2020.
- Background: PubMed 30477976Obi AT, Tignanelli CJ, Jacobs BN, Arya S, Park PK, Wakefield TW, Henke PK, Napolitano LM. Empirical systemic anticoagulation is associated with decreased venous thromboembolism in critically ill influenza A H1N1 acute respiratory distress syndrome patients. J Vasc Surg Venous Lymphat Disord. 2019 May;7(3):317-324. doi: 10.1016/j.jvsv.2018.08.010. Epub 2018 Nov 23.
- Background: PubMed 16581406Smeeth L, Cook C, Thomas S, Hall AJ, Hubbard R, Vallance P. Risk of deep vein thrombosis and pulmonary embolism after acute infection in a community setting. Lancet. 2006 Apr 1;367(9516):1075-1079. doi: 10.1016/S0140-6736(06)68474-2.
- Background: PubMed 31636134Margraf A, Zarbock A. Platelets in Inflammation and Resolution. J Immunol. 2019 Nov 1;203(9):2357-2367. doi: 10.4049/jimmunol.1900899.
- Background: PubMed 31766453Eck RJ, Bult W, Wetterslev J, Gans ROB, Meijer K, van der Horst ICC, Keus F. Low Dose Low-Molecular-Weight Heparin for Thrombosis Prophylaxis: Systematic Review with Meta-Analysis and Trial Sequential Analysis. J Clin Med. 2019 Nov 21;8(12):2039. doi: 10.3390/jcm8122039.
- 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 28886622Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, Juni P, Kastrati A, Kolh P, Mauri L, Montalescot G, Neumann FJ, Petricevic M, Roffi M, Steg PG, Windecker S, Zamorano JL, Levine GN; ESC Scientific Document Group; ESC Committee for Practice Guidelines (CPG); ESC National Cardiac Societies. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2018 Jan 14;39(3):213-260. doi: 10.1093/eurheartj/ehx419. No abstract available.
- 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 25156992Simes 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.
- Background: PubMed 30175268Sexton 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.
- Background: PubMed 28709700Rudolph TK, Fuchs A, Klinke A, Schlichting A, Friedrichs K, Hellmich M, Mollenhauer M, Schwedhelm E, Baldus S, Rudolph V. Prasugrel as opposed to clopidogrel improves endothelial nitric oxide bioavailability and reduces platelet-leukocyte interaction in patients with unstable angina pectoris: A randomized controlled trial. Int J Cardiol. 2017 Dec 1;248:7-13. doi: 10.1016/j.ijcard.2017.06.099. Epub 2017 Jul 1.
- Background: PubMed 25635327Johnston LR, La Flamme AC, Larsen PD, Harding SA. Prasugrel inhibits platelet-enhanced pro-inflammatory CD4+ T cell responses in humans. Atherosclerosis. 2015 Mar;239(1):283-6. doi: 10.1016/j.atherosclerosis.2015.01.006. Epub 2015 Jan 14.
- Background: PubMed 22436970Totani L, Dell'Elba G, Martelli N, Di Santo A, Piccoli A, Amore C, Evangelista V. Prasugrel inhibits platelet-leukocyte interaction and reduces inflammatory markers in a model of endotoxic shock in the mouse. Thromb Haemost. 2012 Jun;107(6):1130-40. doi: 10.1160/TH11-12-0867. Epub 2012 Mar 22.
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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.
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 Prasugrel Hydrochloride 10 MG Oral Tablet in people with COVID19 and Thrombosis, 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 3 inclusion and 10 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 26 Jun 2020. 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 (045-8124414 ext. +39, pietro.minuz@univr.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
P/F ratio at day 7 (time frame: day 7). 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 NCT04445623, which also lists 20 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 26 Jun 2020.