Back to resultsTargeting Platelet-Leukocyte Aggregates in Pneumonia With Ticagrelor (XANTHIPPE)
Primary Purpose
Pneumonia, Community Acquired Pneumonia, Hospital Acquired Pneumonia
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
ticagrelor
placebo
Sponsored by
About this trial
This is an interventional treatment trial for Pneumonia focused on measuring Platelet inhibition, Platelet-leukocyte aggregates, Platelet-neutrophil aggregates, CAP, HAP, ALI, Blood Platelets
Eligibility 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.
- Cough
- Fever: axillary temperature >37.5ºC or tympanic temperature >38.5ºC
- Hypothermia: axillary temperature <34ºC or tympanic temperature <35ºC.
- Purulent sputum production or respiratory secretion.
- 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
- Auscultatory findings on pulmonary examination of rales and/or evidence of pulmonary consolidation (dullness on percussion, bronchial breath sounds, or egophony)
- 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:
- Contraindication to ticagrelor (hypersensitivity or reaction to ticagrelor or another P2Y12 antagonist)
- Active bleeding or major bleeding history (e.g. intracranial bleeding)
- Clinically important anemia or thrombocytopenia (platelet count <30)
- Surgery within 30 days or anticipated major surgery (Thoracic, Abdominal, Brain; placement of lines, tracheostomy, and chest tubes are not considered major).
- Oral anticoagulant therapy that cannot be stopped.
- Inability or unwillingness of treating physician to reduce dose of aspirin to 81mg.
- Fibrinolytic therapy in the last 24 hours.
- Increased risk of bradycardic events - 2nd or 3rd degree heart block, bradycardia induced syncope - unless pacemaker in place.
- Underlying immunodeficiency (HIV, neutropenia, receiving immunomodulating agents, active hematologic malignancy, functional or anatomical asplenia and hypogammaglobulinemia).
- 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.
- Renal dialysis
- Concomitant therapy with strong CYP3A inhibitors; ketoconazole, itraconazole, voriconazole, saquinavir, nelfinavir, indinavir, or atazanavir.
- Concomitant therapy with CYP3A substate with narrow therapeutic window: cyclosporin, quinidine.
- Concomitant therapy with CYP3A inducer; rifampin/rifampicin, phenytoin, carbamazepine.
- Pregnancy or lactation
- Active treatment for cancer.
Sites / Locations
- University of Kentucky Hospitals
- University of Kentucky Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
ticagrelor
placebo
Arm Description
180 mg orally once and then 90 mg orally daily for 7 days or until hospital discharge if sooner
One loading dose and then daily for 7 days or until hospital discharge if sooner
Outcomes
Primary Outcome Measures
Platelet-Leukocyte Aggregates
Platelet-leukocyte aggregates will be measured by flow cytometry.
Secondary Outcome Measures
Platelet function tests
Platelet function will be monitored by aggregation and by measuring markers of platelet secretion
Systemic inflammation
Markers of inflammation will be measured in plasma or serum
Lung function
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01883869
Brief Title
Targeting Platelet-Leukocyte Aggregates in Pneumonia With Ticagrelor
Acronym
XANTHIPPE
Official Title
XANTHIPPE: Examining the Effect of Ticagrelor on Platelet Activation, Platelet-Leukocyte Aggregates, and Acute Lung Injury in Pneumonia
Study Type
Interventional
2. Study Status
Record Verification Date
September 2018
Overall Recruitment Status
Completed
Study Start Date
June 2013 (undefined)
Primary Completion Date
June 2016 (Actual)
Study Completion Date
June 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Kentucky
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The hypothesis to be tested is that ticagrelor (Brilinta™) will reduce platelet activation and markers of inflammation in patients with pneumonia.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pneumonia, Community Acquired Pneumonia, Hospital Acquired Pneumonia, Acute Lung Injury
Keywords
Platelet inhibition, Platelet-leukocyte aggregates, Platelet-neutrophil aggregates, CAP, HAP, ALI, Blood Platelets
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
60 (Actual)
8. Arms, Groups, and Interventions
Arm Title
ticagrelor
Arm Type
Experimental
Arm Description
180 mg orally once and then 90 mg orally daily for 7 days or until hospital discharge if sooner
Arm Title
placebo
Arm Type
Placebo Comparator
Arm Description
One loading dose and then daily for 7 days or until hospital discharge if sooner
Intervention Type
Drug
Intervention Name(s)
ticagrelor
Other Intervention Name(s)
Brilinta
Intervention Type
Drug
Intervention Name(s)
placebo
Intervention Description
placebo
Primary Outcome Measure Information:
Title
Platelet-Leukocyte Aggregates
Description
Platelet-leukocyte aggregates will be measured by flow cytometry.
Time Frame
30 day
Secondary Outcome Measure Information:
Title
Platelet function tests
Description
Platelet function will be monitored by aggregation and by measuring markers of platelet secretion
Time Frame
30 day
Title
Systemic inflammation
Description
Markers of inflammation will be measured in plasma or serum
Time Frame
30 day
Title
Lung function
Description
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.
Time Frame
During hospital stay up to 30 days.
Other Pre-specified Outcome Measures:
Title
Significant Bleeding Event
Description
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.
Time Frame
30 days
Title
Mechanical Ventilation
Description
mechanical ventilation or ventilator free days at day 30
Time Frame
30 days
Title
Sepsis
Description
Diagnosis of Sepsis
Time Frame
30 days
Title
Mortality
Time Frame
30 days
Title
Major Cardiovascular Event
Description
Major cardiovascular event can by myocardial infarction, stroke, or life threatening arrhythmia.
Time Frame
30 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Cough
Fever: axillary temperature >37.5ºC or tympanic temperature >38.5ºC
Hypothermia: axillary temperature <34ºC or tympanic temperature <35ºC.
Purulent sputum production or respiratory secretion.
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
Auscultatory findings on pulmonary examination of rales and/or evidence of pulmonary consolidation (dullness on percussion, bronchial breath sounds, or egophony)
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:
Contraindication to ticagrelor (hypersensitivity or reaction to ticagrelor or another P2Y12 antagonist)
Active bleeding or major bleeding history (e.g. intracranial bleeding)
Clinically important anemia or thrombocytopenia (platelet count <30)
Surgery within 30 days or anticipated major surgery (Thoracic, Abdominal, Brain; placement of lines, tracheostomy, and chest tubes are not considered major).
Oral anticoagulant therapy that cannot be stopped.
Inability or unwillingness of treating physician to reduce dose of aspirin to 81mg.
Fibrinolytic therapy in the last 24 hours.
Increased risk of bradycardic events - 2nd or 3rd degree heart block, bradycardia induced syncope - unless pacemaker in place.
Underlying immunodeficiency (HIV, neutropenia, receiving immunomodulating agents, active hematologic malignancy, functional or anatomical asplenia and hypogammaglobulinemia).
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.
Renal dialysis
Concomitant therapy with strong CYP3A inhibitors; ketoconazole, itraconazole, voriconazole, saquinavir, nelfinavir, indinavir, or atazanavir.
Concomitant therapy with CYP3A substate with narrow therapeutic window: cyclosporin, quinidine.
Concomitant therapy with CYP3A inducer; rifampin/rifampicin, phenytoin, carbamazepine.
Pregnancy or lactation
Active treatment for cancer.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Susan S Smyth, MD PhD
Organizational Affiliation
University of Kentucky
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Kentucky Hospitals
City
Lexington
State/Province
Kentucky
ZIP/Postal Code
40536
Country
United States
Facility Name
University of Kentucky Hospital
City
Lexington
State/Province
Kentucky
ZIP/Postal Code
40536
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
30175268
Citation
Sexton TR, Zhang G, Macaulay TE, Callahan LA, Charnigo R, Vsevolozhskaya OA, Li Z, Smyth S. Ticagrelor Reduces Thromboinflammatory Markers in Patients With Pneumonia. JACC Basic Transl Sci. 2018 Aug 28;3(4):435-449. doi: 10.1016/j.jacbts.2018.05.005. eCollection 2018 Aug.
Results Reference
derived
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Targeting Platelet-Leukocyte Aggregates in Pneumonia With Ticagrelor
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