Targeting Platelet-Leukocyte Aggregates in Pneumonia With Ticagrelor (XANTHIPPE)

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by University of Kentucky
Sponsor:
Information provided by (Responsible Party):
Susan Smyth, University of Kentucky
ClinicalTrials.gov Identifier:
NCT01883869
First received: May 1, 2013
Last updated: May 21, 2014
Last verified: May 2014
  Purpose

The hypothesis to be tested is that ticagrelor (Brilinta™) will reduce platelet activation and markers of inflammation in patients with pneumonia.


Condition Intervention Phase
Pneumonia
Community Acquired Pneumonia
Hospital Acquired Pneumonia
Acute Lung Injury
Drug: ticagrelor
Drug: placebo
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: XANTHIPPE: Examining the Effect of Ticagrelor on Platelet Activation, Platelet-Leukocyte Aggregates, and Acute Lung Injury in Pneumonia

Resource links provided by NLM:


Further study details as provided by University of Kentucky:

Primary Outcome Measures:
  • Platelet-Leukocyte Aggregates [ Time Frame: 30 day ] [ Designated as safety issue: No ]
    Platelet-leukocyte aggregates will be measured by flow cytometry.


Secondary Outcome Measures:
  • Platelet function tests [ Time Frame: 30 day ] [ Designated as safety issue: No ]
    Platelet function will be monitored by aggregation and by measuring markers of platelet secretion

  • Systemic inflammation [ Time Frame: 30 day ] [ Designated as safety issue: No ]
    Markers of inflammation will be measured in plasma or serum

  • Lung function [ Time Frame: During hospital stay up to 30 days. ] [ Designated as safety issue: No ]

    In non-ventilated patients, spirometry, maximal voluntary ventilation, maximal inspiratory and expiratory pressure generation, and P/F ratio (PaO2/FiO2)

    In ventilated patients, respiratory system static compliance, airway resistance, oxygenation index (PaO2/FiO2), and maximal inspiratory and expiratory pressure generation.



Other Outcome Measures:
  • Significant Bleeding Event [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]

    The PLATO definition of bleeding will be used to classify events. Life-threatening bleeding is defined as fatal or intracranial or intrapericardial with cardiac tamponade or hypovolemic shock, or severe hypotension requiring pressors or surgery, decrease in hemoglobin of >50mg/ml or transfusion of ≥ 4units of packed red blood cells(pRBCs).

    Major bleeding is defined as significantly disabling (intraocular with permanent vision loss), 30 - 50 mg/ml decrease in hemoglobin, or transfusion of 2 - 3 U pRBCs.

    Minor bleeding will be captured using PLATO bleeding definition of bleeding that requires medication intervention to stop or treat.


  • Mechanical Ventilation [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    mechanical ventilation or ventilator free days at day 30

  • Sepsis [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    Diagnosis of Sepsis

  • Mortality [ Time Frame: 30 days ] [ Designated as safety issue: No ]
  • Major Cardiovascular Event [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    Major cardiovascular event can by myocardial infarction, stroke, or life threatening arrhythmia.


Estimated Enrollment: 100
Study Start Date: June 2013
Estimated Study Completion Date: June 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ticagrelor
180 mg orally once and then 90 mg orally daily for 7 days or until hospital discharge if sooner
Drug: ticagrelor
Other Name: Brilinta
Placebo Comparator: placebo
One loading dose and then daily for 7 days or until hospital discharge if sooner
Drug: placebo
placebo
Other Name: placebo

Detailed Description:

While it is well established that platelets are integral to hemostasis, more recent evidence points to an important role for platelets in inflammation and immunity. Platelet activation and sequestration in pulmonary tissue is a key feature in inflammatory or infectious states such as sepsis and acute respiratory distress syndrome (ARDS). Platelets may mediate acute lung injury (ALI) by recruiting neutrophils, triggering neutrophil extracellular DNA nets, and releasing granule contents and microparticles. Anti-platelet therapy in this setting may prevent platelet activation, platelet - leukocyte aggregate formation, and inflammation.

The objective of this pilot study is to determine if ticagrelor therapy in individuals with pneumonia reduces markers of platelet activation, platelet-leukocyte aggregates, inflammation, acute lung injury, and lung mechanics. Because the benefit of anti-platelet therapy may the greatest in patients with more significant lung injury, the investigators will enroll patients with community-acquired pneumonia (CAP) requiring hospitalization or patients with hospital acquired pneumonia (HAP) within 48 hours of diagnosis. On study day 1, subjects will be randomized to receive ticagrelor (180 mg load and 90 mg BID) or placebo. Study medication (ticagrelor or placebo) will be administered twice daily on days 2 - 7 or until hospital discharge, if sooner than 7 days. Blood will be collected and assays performed on day 1 prior to study medication administration (baseline), day 2, 3, 7, day of discharge (if before 7 days), and 30 days for analysis of platelet count, markers of platelet activation, platelet - leukocyte interactions, biomarkers of inflammation, and measurements of lung mechanics.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects must be 18 years of age or older
  • Subjects must diagnosed with Community acquired pneumonia (CAP) or hospital acquired pneumonia (HAP) within 48 hours of diagnosis or presentation to hospital.
  • Pneumonia will be defined as patients with a new radiographic finding(s) consistent with pneumonia and at least two of the following signs.

    1. Cough
    2. Fever: axillary temperature >37.5ºC or tympanic temperature >38.5ºC
    3. Hypothermia: axillary temperature <34ºC or tympanic temperature <35ºC.
    4. Purulent sputum production or respiratory secretion.
    5. Total peripheral white blood cell (WBC) count >10,000/mm3; or >15% band forms, regardless of total peripheral white count; or leucopenia with total WBC < 4500/mm
    6. Auscultatory findings on pulmonary examination of rales and/or evidence of pulmonary consolidation (dullness on percussion, bronchial breath sounds, or egophony)
    7. Hypoxemia - defined as partial O2 pressure <60mmHg while the patient was breathing normal air or a decrease in the partial O2 pressure of >= 25% from an initial range.

Exclusion Criteria:

  1. Contraindication to ticagrelor (hypersensitivity or reaction to ticagrelor or another P2Y12 antagonist)
  2. Active bleeding or major bleeding history (e.g. intracranial bleeding)
  3. Clinically important anemia or thrombocytopenia (platelet count <30)
  4. Surgery within 30 days or anticipated major surgery (Thoracic, Abdominal, Brain; placement of lines, tracheostomy, and chest tubes are not considered major).
  5. Oral anticoagulant therapy that cannot be stopped.
  6. Inability or unwillingness of treating physician to reduce dose of aspirin to 81mg.
  7. Fibrinolytic therapy in the last 24 hours.
  8. Increased risk of bradycardic events - 2nd or 3rd degree heart block, bradycardia induced syncope - unless pacemaker in place.
  9. Underlying immunodeficiency (HIV, neutropenia, receiving immunomodulating agents, active hematologic malignancy, functional or anatomical asplenia and hypogammaglobulinemia).
  10. Moderate or severe liver disease defined by Child Pugh score >7 using data from outpatient setting or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 fold upper limits of normal.
  11. Renal dialysis
  12. Concomitant therapy with strong CYP3A inhibitors; ketoconazole, itraconazole, voriconazole, saquinavir, nelfinavir, indinavir, or atazanavir.
  13. Concomitant therapy with CYP3A substate with narrow therapeutic window: cyclosporin, quinidine.
  14. Concomitant therapy with CYP3A inducer; rifampin/rifampicin, phenytoin, carbamazepine.
  15. Pregnancy or lactation
  16. Active treatment for cancer.
  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: NCT01883869

Contacts
Contact: Susan S Smyth, MD PhD 859-323-2274 susansmyth@uky.edu

Locations
United States, Kentucky
University of Kentucky Hospitals Recruiting
Lexington, Kentucky, United States, 40536
Contact: Travis Sexton    859-323-5484    trsext2@uky.edu   
Principal Investigator: Susan S Smyth, MD PhD         
Sub-Investigator: Leighann Callahan, MD         
Sub-Investigator: Tracy Macaulay, PharmD         
Sub-Investigator: Travis R Sexton, PhD         
University of Kentucky Hospital Not yet recruiting
Lexington, Kentucky, United States, 40536
Contact: Travis Sexton    859-323-5484    trsext2@uky.edu   
Sponsors and Collaborators
University of Kentucky
Investigators
Principal Investigator: Susan S Smyth, MD PhD University of Kentucky
  More Information

No publications provided

Responsible Party: Susan Smyth, Principle Investigator, University of Kentucky
ClinicalTrials.gov Identifier: NCT01883869     History of Changes
Other Study ID Numbers: 13-0374-F6A
Study First Received: May 1, 2013
Last Updated: May 21, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by University of Kentucky:
Platelet inhibition
Platelet-leukocyte aggregates
Platelet-neutrophil aggregates
CAP
HAP
ALI
Blood Platelets

Additional relevant MeSH terms:
Pneumonia
Lung Injury
Acute Lung Injury
Respiratory Distress Syndrome, Adult
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Thoracic Injuries
Wounds and Injuries
Respiration Disorders
Ticagrelor
Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 19, 2014