Prasugrel in Severe COVID-19 Pneumonia

NCT04445623 | Unknown Phase 3 DMC

• 1 other identifier: MGI-COVID-19-prasugrel
• Study Type: interventional
• Target: 128
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

COVID19; Thrombosis

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (32)

• Daily P/F ratio

  15 days

• Daily need for oxygen supply

  15 days

• Need for ICU

  day 15 and day 30

• Death

  15 day and day 30

• MOF

  day 15 and day 30

Study Arms (2)

prasugrel hydrochloride

ACTIVE COMPARATOR

film-coated tablets of prasugrel hydrochloride (10 mg daily dose after loading dose of 60 mg)

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)

Drug: Placebo

Interventions

Prasugrel Hydrochloride 10 MG Oral Tablet DRUG

administration of prasugrel daily for 15 days

prasugrel hydrochloride

Placebo DRUG

administration of placebo daily for 15 days

placebo

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Covid-19 pneumonia
• Age over 18 years
• Willingness to express consent

You may not qualify if:

• 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).

Sponsors & Collaborators

• Azienda Ospedaliera Universitaria Integrata Verona: lead
• University of Milan: collaborator

Study Sites (1)

Azienda Ospedaliera Universitaria Integrata Verona

Verona, 37126, Italy

Location

Related Publications (20)

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  PMID: 22621626 BACKGROUND

• 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.

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  PMID: 30175268 BACKGROUND

• 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.

  PMID: 28709700 BACKGROUND

• 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.

  PMID: 25635327 BACKGROUND

• 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.

  PMID: 22436970 BACKGROUND

• Ancrenaz 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.

  PMID: 22900583 BACKGROUND

• 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, 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.

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• 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.

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• Yin S, Huang M, Li D, Tang N. Difference of coagulation features between severe pneumonia induced by SARS-CoV2 and non-SARS-CoV2. J Thromb Thrombolysis. 2021 May;51(4):1107-1110. doi: 10.1007/s11239-020-02105-8.

  PMID: 32246317 BACKGROUND

• Minuz P, Mansueto G, Mazzaferri F, Fava C, Dalbeni A, Ambrosetti MC, Sibani M, Tacconelli E. High rate of pulmonary thromboembolism in patients with SARS-CoV-2 pneumonia. Clin Microbiol Infect. 2020 Nov;26(11):1572-1573. doi: 10.1016/j.cmi.2020.06.011. Epub 2020 Jun 18. No abstract available.

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• Cattaneo M, Bertinato EM, Birocchi S, Brizio C, Malavolta D, Manzoni M, Muscarella G, Orlandi M. Pulmonary Embolism or Pulmonary Thrombosis in COVID-19? Is the Recommendation to Use High-Dose Heparin for Thromboprophylaxis Justified? Thromb Haemost. 2020 Aug;120(8):1230-1232. doi: 10.1055/s-0040-1712097. Epub 2020 Apr 29. No abstract available.

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• Sjalander 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. doi: 10.1111/j.1365-2796.2007.01878.x.

  PMID: 18088252 BACKGROUND

• Fischer AL, Messer S, Riera R, Martimbianco ALC, Stegemann M, Estcourt LJ, Weibel S, Monsef I, Andreas M, Pacheco RL, Skoetz N. Antiplatelet agents for the treatment of adults with COVID-19. Cochrane Database Syst Rev. 2023 Jul 25;7(7):CD015078. doi: 10.1002/14651858.CD015078.

  PMID: 37489818 DERIVED

MeSH Terms

Conditions

COVID-19; Thrombosis

Interventions

Prasugrel Hydrochloride; Tablets

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Thiophenes; Sulfur Compounds; Organic Chemicals; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Dosage Forms; Pharmaceutical Preparations

Central Study Contacts

Pietro Minuz, Professor

CONTACT

045-8124414; pietro.minuz@univr.it

Marco Cattaneo, Professor

CONTACT

02-50323095; marco.cattaneo@unimi.it

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Masking Details: use of placebo tablets of the same shape, colour of the investigational drug. Identical time and route of administration.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Experimental phase 3 drug trial, randomized 1:1, double-blind, multicentre in patients treated with prasugrel vs placebo.

Study Record Dates

• First Submitted: June 4, 2020
• First Posted: June 24, 2020
• Study Start: July 1, 2020
• Primary Completion: October 1, 2020
• Study Completion: January 1, 2021
• Last Updated: June 26, 2020

Record last verified: 2020-05

Locations

IT (1)