The Role of the P2Y12 Receptor in Tissue Factor Induced Coagulation

This study has been completed.
Sponsor:
Information provided by:
Medical University of Vienna
ClinicalTrials.gov Identifier:
NCT01099566
First received: April 6, 2010
Last updated: July 8, 2011
Last verified: July 2011
  Purpose

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.


Condition Intervention Phase
Healthy Volunteers
Sepsis
Drug: Prasugrel
Drug: Placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: The Role of the P2Y12 Receptor in Tissue Factor Induced Coagulation

Resource links provided by NLM:


Further study details as provided by Medical University of Vienna:

Primary Outcome Measures:
  • prothrombin fragments (F1+2) [ Time Frame: -2 to 24 hours after LPS infusion ] [ Designated as safety issue: No ]
    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).


Secondary Outcome Measures:
  • platelet-leukocyte co-aggregation [ Time Frame: -2 to 24 hours after LPS infusion ] [ Designated as safety issue: No ]
    to explore whether P2Y12 ADP-receptor antagonism decreases platelet -leukocyte co-aggregation

  • tissue factor expression [ Time Frame: -2 to 24 hours after LPS infusion ] [ Designated as safety issue: No ]
    to investigate the influence of P2Y12 ADP-receptor antagonism on tissue factor expression

  • anti-platelet effects of prasugrel [ Time Frame: -2 to 24 hours after LPS infusion ] [ Designated as safety issue: No ]
    to explore if low dose endotoxemia interferes with the anti-platelet effects of prasugrel


Enrollment: 20
Study Start Date: November 2009
Study Completion Date: November 2010
Primary Completion Date: October 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Prasugrel Drug: Prasugrel
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.
Other Names:
  • Prasugrel
  • Generic name: Prasugrel
  • Brand name: Efient
  • Manufacturer: Eli Lilly
  • Dose: 60mg loading dose (6 tablets a 10mg) on trial day 1
Placebo Comparator: pills consisting of lactose-starch Drug: Placebo
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.
Other Names:
  • Placebo
  • 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

  Eligibility

Ages Eligible for Study:   19 Years to 40 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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
  • Symptoms of a clinically relevant illness in the 3 weeks before the first trial day
  • Excessive sporting activities
  • Weight >95kg and <60kg
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01099566

Locations
Austria
Medical University of Vienna, Department of Clinical Pharmacology
Vienna, Austria, A-1090
Sponsors and Collaborators
Medical University of Vienna
Investigators
Principal Investigator: Bernd Jilma, MD Medical University of Vienna
  More Information

Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Bernd Jilma, MD, Medical University of Vienna, Department of Clinical Pharmacology
ClinicalTrials.gov Identifier: NCT01099566     History of Changes
Other Study ID Numbers: LPSP2Y12, 2008-001320-32
Study First Received: April 6, 2010
Last Updated: July 8, 2011
Health Authority: Austria: Agency for Health and Food Safety

Keywords provided by Medical University of Vienna:
human endotoxemia
tissue factor induced coagulation
platelet activation
thienopyridines

Additional relevant MeSH terms:
Sepsis
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Thromboplastin
Prasugrel
Hemostatics
Coagulants
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions
Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 22, 2014