Prasugrel in Severe COVID-19 Pneumonia

COVID19 Clinical Trial

— PARTISAN  

Official title:

Prasugrel in the Prevention of Severe SARS-CoV2 Pneumonia in Hospitalised Patients

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04445623
• Other study ID #: MGI-COVID-19-prasugrel
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: July 2020
• Est. completion date: January 2021

Study information

• Verified date: May 2020
• Source: Azienda Ospedaliera Universitaria Integrata Verona
• Contact: Pietro Minuz, Professor
• Phone: 045-8124414
• Email: pietro.minuz[@]univr.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Inflammatory diseases favour the onset of venous thromboembolic events in hospitalized patients. Thromboprophylaxis with a fixed dose of heparin/low molecular weight heparin (LMWH) is recommended if concomitant inflammatory disease. In severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) pneumonia an inflammation-dependent thrombotic process occurs and platelet activation may promote thrombosis and amplify inflammation, as indicated by previous experimental evidence , and the similarities with atherothrombosis and thrombotic microangiopathies. Antiplatelet agents represent the cornerstone in the prevention and treatment of atherosclerotic arterial thromboembolism, with limited efficacy in the context of venous thromboembolism. The use of 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 128
• Est. completion date: January 2021
• Est. primary completion date: October 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

Inclusion Criteria:

• Covid-19 pneumonia

• Age over 18 years

• Willingness to express consent

Exclusion Criteria:

• 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

• 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).

Related Conditions & MeSH terms

• COVID19
• Pneumonia
• Thrombosis

Intervention

Drug:
• Prasugrel Hydrochloride 10 MG Oral Tablet
administration of prasugrel daily for 15 days
• Placebo
administration of placebo daily for 15 days

Locations

Country	Name	City	State
Italy	Azienda Ospedaliera Universitaria Integrata Verona	Verona

Sponsors (2)

Lead Sponsor	Collaborator
Azienda Ospedaliera Universitaria Integrata Verona	University of Milan

Country where clinical trial is conducted

Italy, 

References & Publications (19)

Ancrenaz V, Déglon 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. — View Citation

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. — View Citation

Bikdeli 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, Quéré 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. Review. — View Citation

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 Apr 29. doi: 10.1055/s-0040-1712097. [Epub ahead of print] — View Citation

Eck 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). pii: E2039. doi: 10.3390/jcm8122039. Review. — View Citation

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. Review. — View Citation

Johnston 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. — View Citation

Margraf A, Zarbock A. Platelets in Inflammation and Resolution. J Immunol. 2019 Nov 1;203(9):2357-2367. doi: 10.4049/jimmunol.1900899. Review. — View Citation

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, in press.

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. Erratum in: J Vasc Surg Venous Lymphat Disord. 2019 Jul;7(4):621. — View Citation

Rudolph 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. — View Citation

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. — View Citation

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. — View Citation

Själander A, Jansson JH, Bergqvist D, Eriksson H, Carlberg B, Svensson P. Efficacy and safety of anticoagulant prophylaxis to prevent venous thromboembolism in acutely ill medical inpatients: a meta-analysis. J Intern Med. 2008 Jan;263(1):52-60. Review. — View Citation

Smeeth 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. — View Citation

Tang 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. — View Citation

Totani 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. — View Citation

Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, Jüni 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. — View Citation

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. 2020 Apr 3. doi: 10.1007/s11239-020-02105-8. [Epub ahead of print] — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	day 7
Secondary	Daily P/F ratio	PaO2/FiO2 ratio (arterial oxygen tension divided by the fraction of inspired oxygen) detected daily for 15 days	15 days
Secondary	Daily need for oxygen supply	daily need for oxygen supply for 15 days	15 days
Secondary	Need for ICU	Number of patients requiring transfer to the intensive care unit (ICU) by treatment arm	day 15 and day 30
Secondary	Death	death by day 15 and day 30 by treatment arm	15 day and day 30
Secondary	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	day 15 and day 30
Secondary	Discharge	Number of patients discharged after improvement by day 15 and day 30 by treatment arm	day 15 and day 30
Secondary	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	day 15 and day 30
Secondary	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	day 15 and day 30
Secondary	Venous thrombosis/ pulmonary embolism/thrombosis	Number of patients with venous thrombosis/ pulmonary embolism/thrombosis by day 15 and day 30	day 15 and day 30
Secondary	Need for CT imaging	Number of patients requiring computerized tomography (CT) imaging due to worsening of respiratory function by treatment arm	day 15
Secondary	Daily Temperature	Body temperature measured twice daily for 15 days, C°	15 days
Secondary	Daily blood pressure	Blood pressure measured twice daily for 15 days, mmHg	15 days
Secondary	Daily total blood count Hemoglobin	Total blood count measured in venous blood for 15 days, Hemoglobin, g/L (cell/mcL	15 days
Secondary	Daily total blood count Red Blood Cells	Total blood count measured in venous blood for 15 days, Red Blood cells (cell/mcL)	15 days
Secondary	Daily total blood count Leukocytes	Total blood count measured in venous blood for 15 days, Leukocytes (cell/mcL)	15 days
Secondary	Daily total blood count Platelets	Total blood count measured in venous blood for 15 days, platelets (cell/mcL)	15 days
Secondary	Daily indices of organ damage Liver	ALT U/L in venous blood	15 days
Secondary	Indices of inflammation C-reactive protein	C-reactive protein microg/L in venous blood	day 1, 2, 7, 15
Secondary	Indices of haemostasis PT	PT ratio in venous blood by treatment arm	day 1, 2, 7,15
Secondary	Daily progression at imaging (chest-X-ray)	progression of lung infiltrates as detected by chest-X-ray by treatment arm	15 days
Secondary	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.	day 1, 2, 7, 15, 30
Secondary	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.	day 1, 2, 7, 15, 30
Secondary	Unexpected clinical or laboratory findings	Number of unexpected changes in clinical or laboratory findings not included in the predefined list of outcomes during treatment. .	day 1, 2, 7, 15
Secondary	Indices of inflammation D-dimer	D-dimer microg/L in venous blood	day 1, 2, 7, 15
Secondary	Indices of inflammation Fibrinogen	Fibrinogen g/L in venous blood	day 1, 2, 7, 15
Secondary	Indices of inflammation IL-6	Interleukin (IL)-6 pg/mL in venous blood by treatment arm	day 1, 2, 7, 15
Secondary	Indices of inflammation IL-1	Interleukin (IL)-1 pg/mL in venous blood by treatment arm	day 1, 2, 7, 15
Secondary	Daily indices of organ damage kidney	serum creatinine micromol/L by treatment arm	15 days
Secondary	Daily indices of organ damage heart	troponin t ng/L by treatment arm	15 days
Secondary	Haemostasis aPTT	aPTT ratio by treatment arm	day 1, 2, 7,15
Secondary	Haemostasis VASP PRI	Vasodilator stimulated phosphoprotein (VASP) phosphorylation (PRI) % by treatment arm	day 1, 2, 7,15
Secondary	Haemostasis platelet-leukocytes aggregates	Platelet-leukocytes aggregates % in peripheral by treatment arm	day 1, 2, 7,15