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Prasugrel in Severe COVID-19 Pneumonia (PARTISAN)

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ClinicalTrials.gov Identifier: NCT04445623
Recruitment Status : Not yet recruiting
First Posted : June 24, 2020
Last Update Posted : June 26, 2020
Sponsor:
Collaborator:
University of Milan
Information provided by (Responsible Party):
Azienda Ospedaliera Universitaria Integrata Verona

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.

Condition or disease Intervention/treatment Phase
COVID19 Thrombosis Drug: Prasugrel Hydrochloride 10 MG Oral Tablet Drug: Placebo Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 128 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Experimental phase 3 drug trial, randomized 1:1, double-blind, multicentre in patients treated with prasugrel vs placebo.
Masking: Double (Participant, Care Provider)
Masking Description: use of placebo tablets of the same shape, colour of the investigational drug. Identical time and route of administration.
Primary Purpose: Treatment
Official Title: Prasugrel in the Prevention of Severe SARS-CoV2 Pneumonia in Hospitalised Patients
Estimated Study Start Date : July 2020
Estimated Primary Completion Date : October 2020
Estimated Study Completion Date : January 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: prasugrel hydrochloride
film-coated tablets of prasugrel hydrochloride (10 mg daily dose after loading dose of 60 mg)
Drug: Prasugrel Hydrochloride 10 MG Oral Tablet
administration of prasugrel daily for 15 days

Placebo Comparator: placebo
film-coated tablets of placebo (10 mg daily dose after loading dose of 60 mg)
Drug: Placebo
administration of placebo daily for 15 days




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. Daily P/F ratio [ Time Frame: 15 days ]
    PaO2/FiO2 ratio (arterial oxygen tension divided by the fraction of inspired oxygen) detected daily for 15 days

  2. Daily need for oxygen supply [ Time Frame: 15 days ]
    daily need for oxygen supply for 15 days

  3. Need for ICU [ Time Frame: day 15 and day 30 ]
    Number of patients requiring transfer to the intensive care unit (ICU) by treatment arm

  4. Death [ Time Frame: 15 day and day 30 ]
    death by day 15 and day 30 by treatment arm

  5. MOF [ Time Frame: day 15 and day 30 ]
    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

  6. Discharge [ Time Frame: day 15 and day 30 ]
    Number of patients discharged after improvement by day 15 and day 30 by treatment arm

  7. Clinical progression of the disease SOFA score [ Time Frame: day 15 and day 30 ]
    Clinical progression of the disease evaluated by SOFA score (Units 0-6 better outcome, 15-24 worse outcome) by day 15 and day 30

  8. Clinical progression of the disease APACHE II [ Time Frame: day 15 and day 30 ]
    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

  9. Venous thrombosis/ pulmonary embolism/thrombosis [ Time Frame: day 15 and day 30 ]
    Number of patients with venous thrombosis/ pulmonary embolism/thrombosis by day 15 and day 30

  10. Need for CT imaging [ Time Frame: day 15 ]
    Number of patients requiring computerized tomography (CT) imaging due to worsening of respiratory function by treatment arm

  11. Daily Temperature [ Time Frame: 15 days ]
    Body temperature measured twice daily for 15 days, C°

  12. Daily blood pressure [ Time Frame: 15 days ]
    Blood pressure measured twice daily for 15 days, mmHg

  13. Daily total blood count Hemoglobin [ Time Frame: 15 days ]
    Total blood count measured in venous blood for 15 days, Hemoglobin, g/L (cell/mcL

  14. Daily total blood count Red Blood Cells [ Time Frame: 15 days ]
    Total blood count measured in venous blood for 15 days, Red Blood cells (cell/mcL)

  15. Daily total blood count Leukocytes [ Time Frame: 15 days ]
    Total blood count measured in venous blood for 15 days, Leukocytes (cell/mcL)

  16. Daily total blood count Platelets [ Time Frame: 15 days ]
    Total blood count measured in venous blood for 15 days, platelets (cell/mcL)

  17. Daily indices of organ damage Liver [ Time Frame: 15 days ]
    ALT U/L in venous blood

  18. Indices of inflammation C-reactive protein [ Time Frame: day 1, 2, 7, 15 ]
    C-reactive protein microg/L in venous blood

  19. Indices of haemostasis PT [ Time Frame: day 1, 2, 7,15 ]
    PT ratio in venous blood by treatment arm

  20. Daily progression at imaging (chest-X-ray) [ Time Frame: 15 days ]
    progression of lung infiltrates as detected by chest-X-ray by treatment arm

  21. Major bleeding [ Time Frame: day 1, 2, 7, 15, 30 ]
    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.

  22. Total bleeding [ Time Frame: day 1, 2, 7, 15, 30 ]
    Total bleeding according to International Society of Thrombosis and Haemostasis (ISTH bleeding) scale (Unit 0 better outcome, 4 worse outcome, 11 items) during treatment.

  23. Unexpected clinical or laboratory findings [ Time Frame: day 1, 2, 7, 15 ]
    Number of unexpected changes in clinical or laboratory findings not included in the predefined list of outcomes during treatment. .

  24. Indices of inflammation D-dimer [ Time Frame: day 1, 2, 7, 15 ]
    D-dimer microg/L in venous blood

  25. Indices of inflammation Fibrinogen [ Time Frame: day 1, 2, 7, 15 ]
    Fibrinogen g/L in venous blood

  26. Indices of inflammation IL-6 [ Time Frame: day 1, 2, 7, 15 ]
    Interleukin (IL)-6 pg/mL in venous blood by treatment arm

  27. Indices of inflammation IL-1 [ Time Frame: day 1, 2, 7, 15 ]
    Interleukin (IL)-1 pg/mL in venous blood by treatment arm

  28. Daily indices of organ damage kidney [ Time Frame: 15 days ]
    serum creatinine micromol/L by treatment arm

  29. Daily indices of organ damage heart [ Time Frame: 15 days ]
    troponin t ng/L by treatment arm

  30. Haemostasis aPTT [ Time Frame: day 1, 2, 7,15 ]
    aPTT ratio by treatment arm

  31. Haemostasis VASP PRI [ Time Frame: day 1, 2, 7,15 ]
    Vasodilator stimulated phosphoprotein (VASP) phosphorylation (PRI) % by treatment arm

  32. Haemostasis platelet-leukocytes aggregates [ Time Frame: day 1, 2, 7,15 ]
    Platelet-leukocytes aggregates % in peripheral by treatment arm



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04445623


Contacts
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Contact: Pietro Minuz, Professor 045-8124414 ext +39 pietro.minuz@univr.it
Contact: Marco Cattaneo, Professor 02-50323095 ext +39 marco.cattaneo@unimi.it

Locations
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Italy
Azienda Ospedaliera Universitaria Integrata Verona
Verona, Italy, 37126
Sponsors and Collaborators
Azienda Ospedaliera Universitaria Integrata Verona
University of Milan
Publications:
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.
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.

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Responsible Party: Azienda Ospedaliera Universitaria Integrata Verona
ClinicalTrials.gov Identifier: NCT04445623    
Other Study ID Numbers: MGI-COVID-19-prasugrel
First Posted: June 24, 2020    Key Record Dates
Last Update Posted: June 26, 2020
Last Verified: May 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Pneumonia
Thrombosis
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Prasugrel Hydrochloride
Platelet Aggregation Inhibitors