The Role of the P2Y12 Receptor in Tissue Factor Induced Coagulation

NCT01099566 | Completed Phase 4

• 2 other identifiers: LPSP2Y122008-001320-32
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

Severe sepsis still carries a high mortality rate despite advantages in intensive care medicine and antimicrobial therapy. The inflammatory and procoagulant host response to infection are intricately linked and interactions between platelets, leukocytes and the endothelium play a central role in the pathogenesis of septic shock and disseminated intravascular coagulation (DIC). Interestingly, one key player cell in coagulation, i.e. the platelet, has been somewhat neglected as to its position in the pathogenesis of coagulation abnormalities in sepsis. However, thienopyridines, irreversible platelet P2Y12 ADP-receptor antagonists, e.g. prasugrel, could potentially provide beneficial anticoagulatory and antiinflammatory effects: P2Y12 ADP-receptor antagonists reduce TF-induced coagulation activation in various ex vivo and in vitro models. Moreover, various lines of evidence indicate that thienopyridines may block platelet leukocyte interactions and thereby reduce the propagation of the coagulation and inflammation process. LPS-infusion in healthy volunteers provides a standardized model to safely study non overt DIC and to document possible effects of therapeutic and prophylactic interventions. The investigators hypothesize that thienopyridines, irreversible platelet P2Y12 ADP-receptor antagonists, may blunt TF-triggered coagulation activation in humans, which will be studied in a TF-dependent coagulation model in humans.

Conditions

Healthy Volunteers; Sepsis

Keywords

human endotoxemia; tissue factor induced coagulation; platelet activation; thienopyridines

Outcome Measures

Primary Outcomes (1)

• prothrombin fragments (F1+2)

  To explore whether P2Y12 ADP-receptor antagonism can block activation of the coagulation cascade induced by endotoxemia, in particular decrease LPS mediated thrombin formation as measured by prothrombin fragment (F1+2).

  -2 to 24 hours after LPS infusion

Secondary Outcomes (3)

• platelet-leukocyte co-aggregation

  -2 to 24 hours after LPS infusion

• tissue factor expression

  -2 to 24 hours after LPS infusion

• anti-platelet effects of prasugrel

  -2 to 24 hours after LPS infusion

Study Arms (2)

Prasugrel

EXPERIMENTAL

Drug: Prasugrel

pills consisting of lactose-starch

PLACEBO COMPARATOR

Drug: Placebo

Interventions

Prasugrel DRUG

Prasugrel will be given as loading dose (60mg) on the first trial day two hours prior to endotoxin infusion. Prasugrel is an orally administered prodrug that is converted in the liver by CYP to its active metabolite.

Also known as: Generic name: Prasugrel, Brand name: Efient, Manufacturer: Eli Lilly, Dose: 60mg loading dose (6 tablets a 10mg) on trial day 1

Prasugrel

Placebo DRUG

A pharmacist not otherwise involved in the trial will encapsulate pills consisting of lactose-starch. Six pills will be administered as placebo 2 hours before LPS administration on trial day 1.

Also known as: Content: Pills consisting of lactose-starch, Manufacturer: AKH Anstaltsapotheke, Dose: Same number of pills as in the prasugrel period (6 tablets on trial day 1); identically encapsulated by a pharmacist not otherwise involved in the trial

pills consisting of lactose-starch

Eligibility Criteria

• Age: 19 Years - 40 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Signed informed consent obtained before any trial-related activities.
• Men aged \>18 and \<41 years
• Normal findings in medical history and physical examination unless the investigator considers an abnormality to be clinically irrelevant
• Normal laboratory values unless the investigator considers an abnormality to be clinically irrelevant

You may not qualify if:

• Known or suspected allergy to trial product or related products (Prasugrel, Clopidogrel, Ticlopidine)
• Known or suspected hereditary problems of galactose intolerance, Lapp lactase deficiency or glucosegalactose malabsorption
• Treatment with an investigational drug within three weeks prior to this trial
• Treatment with a drug (e.g. ketoconazole, omeprazole) that interferes with cytochrome P450, the enzyme responsible for the conversion of prasugrel to its active form, three weeks prior to this trial
• Participation in an LPS trial within the last 6 weeks
• Smoking of more than 5 cigarettes per day
• Hereditary deficiency of protein C or S, or a mutation of FV (Leiden), or any other known abnormality affecting coagulation, fibrinolysis or platelet function
• History of gastro-duodenal ulcera, cardiovascular disease, vasculitis, diabetes mellitus, or hypertension
• History of brain tumor or history of neurosurgery
• Hemorrhagic diathesis, trauma or surgery within last 3 months
• History of hemorrhagic retinopathy
• Hematuria or detection of occult blood in stool sample
• Liver or kidney dysfunction
• Regular use of medication or abuse of alcohol
• Use of any medication within one week prior to the first trial day

Sponsors & Collaborators

• Medical University of Vienna: lead

Study Sites (1)

Medical University of Vienna, Department of Clinical Pharmacology

Vienna, Vienna, A-1090, Austria

Location

Related Publications (6)

• Jilma B, Blann A, Pernerstorfer T, Stohlawetz P, Eichler HG, Vondrovec B, Amiral J, Richter V, Wagner OF. Regulation of adhesion molecules during human endotoxemia. No acute effects of aspirin. Am J Respir Crit Care Med. 1999 Mar;159(3):857-63. doi: 10.1164/ajrccm.159.3.9805087.

  PMID: 10051263 BACKGROUND

• Pernerstorfer T, Hollenstein U, Hansen JB, Stohlawetz P, Eichler HG, Handler S, Speiser W, Jilma B. Lepirudin blunts endotoxin-induced coagulation activation. Blood. 2000 Mar 1;95(5):1729-34.

  PMID: 10688831 BACKGROUND

• Mavrommatis AC, Theodoridis T, Orfanidou A, Roussos C, Christopoulou-Kokkinou V, Zakynthinos S. Coagulation system and platelets are fully activated in uncomplicated sepsis. Crit Care Med. 2000 Feb;28(2):451-7. doi: 10.1097/00003246-200002000-00027.

  PMID: 10708182 BACKGROUND

• Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007 Nov 15;357(20):2001-15. doi: 10.1056/NEJMoa0706482. Epub 2007 Nov 4.

  PMID: 17982182 BACKGROUND

• Kirschenbaum LA, Aziz M, Astiz ME, Saha DC, Rackow EC. Influence of rheologic changes and platelet-neutrophil interactions on cell filtration in sepsis. Am J Respir Crit Care Med. 2000 May;161(5):1602-7. doi: 10.1164/ajrccm.161.5.9902105.

  PMID: 10806162 BACKGROUND

• Spiel AO, Derhaschnig U, Schwameis M, Bartko J, Siller-Matula JM, Jilma B. Effects of prasugrel on platelet inhibition during systemic endotoxaemia: a randomized controlled trial. Clin Sci (Lond). 2012 Nov;123(10):591-600. doi: 10.1042/CS20120194.

  PMID: 22646240 DERIVED

MeSH Terms

Conditions

Sepsis

Interventions

Prasugrel Hydrochloride

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Thiophenes; Sulfur Compounds; Organic Chemicals; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Bernd Jilma, MD

  Medical University of Vienna

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: April 6, 2010
• First Posted: April 7, 2010
• Study Start: November 1, 2009
• Primary Completion: October 1, 2010
• Study Completion: November 1, 2010
• Last Updated: July 11, 2011

Record last verified: 2011-07

Locations

AU (1)