Community Acquired Pneumonia, Severe
Conditions
Keywords
CAP, Pneumonia, Intensive Care Unit, Mechanical Ventilation
Brief summary
The purpose of this study is to determine if the drug ticagrelor will be an effective treatment for patients with severe community acquired pneumonia. The primary objective is to reduce all-cause mortality in the ticagrelor group compared to the placebo group.
Interventions
DRUGTicagrelor
Ticagrelor 180 mg loading dose followed by 90 mg BID for 90 days
DRUGPlacebo
Placebo 180 mg loading dose followed by 90 mg BID for 90 days.
Sponsors
AstraZeneca
Gordon Bernard
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1\. Patients will have new severe CAP as defined by a. New (within 72 hours of hospital admission) radiographic finding consistent with pneumonia and admission or planned admission to an ICU for: i. Mechanical Ventilation (invasive or non-invasive) OR ii. Vasopressors (dobutamine and phosphodiesterase are not considered vasopressors for this criteria) OR iii. ICU admission due to severe respiratory distress or arterial desaturation. b. At least two of the following; i. recent increase in dyspnea ii. increased sputum production iii. change of character of sputum iv. White Blood Cells \> 12,000 or \< 4,000 cells/mm3 or \>10% bands v. Body temperature \>38ºC or \<36ºC (any route)
Exclusion criteria
1. More than 72 hours have passed since meeting required inclusion criteria. 2. Development of pneumonia after 72 hours of current hospitalization. 3. Underlying disease likely to cause mortality within 90 days of randomization. 4. A resident in a hospital, not nursing home, within 30 days prior to development of pneumonia. 5. Patients who are moribund (not expected to live for more than 48 hours). 6. No consent/inability to obtain consent from patient or surrogate. 7. Patient's physician is unwilling to have patient enter the study. 8. Age less than 50 years. 9. Pregnancy. 10. Breast feeding. 11. Underlying immunodeficiency (e.g. HIV, neutropenia, active hematologic malignancy, functional or anatomical asplenia and hypogammaglobulinemia). 12. Patient, surrogate, or physician not committed to full support (exception: a patient will not be excluded if he/she will receive all supportive care except for attempts at resuscitation from cardiac arrest). 13. Unable to receive or unlikely to absorb enteral study drug (e.g., patients with partial or complete mechanical bowel obstruction, intestinal ischemia, infarction, and short bowel syndrome). 14. Hepatic impairment a. Child Pugh score \> 7 using data from outpatient setting 15. Conditions that increase the risk of bleeding, e.g.: 1. Surgery or the likely need for surgery during study, or evidence of active bleeding postoperatively (ICU procedures such as line placement, tracheostomy and chest tubes are not to be considered for this exclusion); 2. A history of severe head trauma requiring hospitalization or intra-cranial surgery within 3 months; 3. Any history of intracerebral arteriovenous malformation, cerebral aneurysm, or mass lesions of the central nervous system, hemorrhagic stroke or intracranial hemorrhage, or congenital bleeding diathesis; 4. Gastrointestinal bleeding within 6 weeks before the study unless a corrective procedure has been performed; 5. Recent trauma considered to increase the risk of bleeding. 16. Chronic renal disease requiring renal replacement therapy. 17. Creatinine \> 3 mg/dL. 18. Platelet count \< 50,000 /mm3. 19. Use of a P2Y12 inhibitor within the 3 months prior to randomization or physician intent to initiate one of the CYP3A inhibitors, e.g. ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, atazanovir, saquinavir, nelfinavir, indinavir, or telithromycin. 20. Use of CYP3A inducers, e.g. rifampin, phenytoin, carbamazepine and phenobarbital. 21. Simvastatin or Lovastatin doses \> 40 mg per day. 22. Digoxin use. 23. Receiving aspirin and physician and/or patient unwilling to reduce aspirin dose to \<100 mg per day. 24. Daily Non-steroidal anti-inflammatory drugs (NSAID) use as an outpatient (other than Aspirin (ASA) as above). 25. Sick Sinus Syndrome, 2nd or 3rd degree heart block, bradycardia induced syncope - unless pacemaker in place. 26. Otherwise unsuitable for participation in the opinion of the investigator (i.e., homeless, non-compliant, etc.).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| All-cause Mortality | 90 days | death during 90 day study period |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ventilator Free Days | 29 days | — |
| Shock Free Days | 15 days | Not requiring pressor support for hypotension |
| In-hospital Mortality | Throughout hospitalization (About 2 weeks) | Did the patient die during the hospitalization? |
| Hospital Free Days | 29 days | Number of days the patient is not in the hospital |
| Stroke | 90 days | Did the patient develop a stroke during the 90 day study? |
| Stroke, Myocardial Infarct, Mortality | 90 days | number of participants that suffered stroke, myocardial infarct, mortality |
| Myocardial Infarction | 90 days | Did the patient have a myocardial infarction during the 90 day study? |
Other
| Measure | Time frame | Description |
|---|---|---|
| Need for Dialysis | 28 days | — |
| ICU Length of Stay | 29 days | Includes ICU readmission if during same hospital stay |
| Hospital Length of Stay | 29 days | In days |
| Discharge Disposition | 90 days | (Home, other facility, with or without assisted ventilation) |
| Need for Re-instituting Assisted or Mechanical Ventilation After Achieving 48 Consecutive Hours of Unassisted Breathing or Comfort Care Chosen (Withdrawal of Support) | 90 days | — |
| Time to Initiation of Unassisted Breathing | 29 days | Only in patients on mechanical ventilation and assuming patient achieves 48 consecutive hours of unassisted breathing |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ticagrelor Ticagrelor 180 mg loading dose followed by 90 mg BID for 90 days
Ticagrelor: Ticagrelor 180 mg loading dose followed by 90 mg BID for 90 days | 12 |
| Placebo Placebo 180 mg loading dose followed by 90 mg BID for 90 days.
Placebo: Placebo 180 mg loading dose followed by 90 mg BID for 90 days. | 13 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 4 | 2 |
| Overall Study | Lost to Follow-up | 1 | 3 |
| Overall Study | Study stopped before dosing completed | 3 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Ticagrelor | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 4 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 9 Participants | 17 Participants |
| Region of Enrollment United States | 12 participants | 13 participants | 25 participants |
| Sex: Female, Male Female | 5 Participants | 7 Participants | 12 Participants |
| Sex: Female, Male Male | 7 Participants | 6 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 12 | 1 / 13 |
| serious Total, serious adverse events | 5 / 12 | 1 / 13 |
Outcome results
Primary
All-cause Mortality
death during 90 day study period
Time frame: 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ticagrelor | All-cause Mortality | 4 participants |
| Placebo | All-cause Mortality | 2 participants |
Comparison: Total enrollment only 25 patients and the study was terminated early due to low enrollment. No further statistical analysis was done.p-value: 0.41Chi-squared
Secondary
Hospital Free Days
Number of days the patient is not in the hospital
Time frame: 29 days
Population: 2 participants from each group died during this time period
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ticagrelor | Hospital Free Days | 14.16 days |
| Placebo | Hospital Free Days | 16.53 days |
Secondary
In-hospital Mortality
Did the patient die during the hospitalization?
Time frame: Throughout hospitalization (About 2 weeks)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ticagrelor | In-hospital Mortality | 2 Participants |
| Placebo | In-hospital Mortality | 2 Participants |
Secondary
Myocardial Infarction
Did the patient have a myocardial infarction during the 90 day study?
Time frame: 90 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ticagrelor | Myocardial Infarction | 1 Participants |
| Placebo | Myocardial Infarction | 0 Participants |
Secondary
Shock Free Days
Not requiring pressor support for hypotension
Time frame: 15 days
Population: 2 participants from the Ticagrelor arm and 1 from the placebo arm died during the 15 day period
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ticagrelor | Shock Free Days | 12.58 days |
| Placebo | Shock Free Days | 11.54 days |
Secondary
Stroke
Did the patient develop a stroke during the 90 day study?
Time frame: 90 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ticagrelor | Stroke | 1 Participants |
| Placebo | Stroke | 0 Participants |
Secondary
Stroke, Myocardial Infarct, Mortality
number of participants that suffered stroke, myocardial infarct, mortality
Time frame: 90 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ticagrelor | Stroke, Myocardial Infarct, Mortality | 5 Participants |
| Placebo | Stroke, Myocardial Infarct, Mortality | 2 Participants |
Secondary
Ventilator Free Days
Time frame: 29 days
Population: 2 participants from each arm died during the 29 day period
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ticagrelor | Ventilator Free Days | 24.16 days |
| Placebo | Ventilator Free Days | 22.3 days |
Other Pre-specified
Discharge Disposition
(Home, other facility, with or without assisted ventilation)
Time frame: 90 days
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ticagrelor | Discharge Disposition | Extended Care without Ventilator | 4 Participants |
| Ticagrelor | Discharge Disposition | In patient rehabilitation | 1 Participants |
| Ticagrelor | Discharge Disposition | Extended Care with Ventilator | 0 Participants |
| Ticagrelor | Discharge Disposition | Death prior to discharge | 2 Participants |
| Ticagrelor | Discharge Disposition | Home | 5 Participants |
| Placebo | Discharge Disposition | Death prior to discharge | 2 Participants |
| Placebo | Discharge Disposition | Home | 9 Participants |
| Placebo | Discharge Disposition | Extended Care without Ventilator | 2 Participants |
| Placebo | Discharge Disposition | Extended Care with Ventilator | 0 Participants |
| Placebo | Discharge Disposition | In patient rehabilitation | 0 Participants |
Other Pre-specified
Hospital Length of Stay
In days
Time frame: 29 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ticagrelor | Hospital Length of Stay | 14.83 days |
| Placebo | Hospital Length of Stay | 12.46 days |
Other Pre-specified
ICU Length of Stay
Includes ICU readmission if during same hospital stay
Time frame: 29 days
Population: 2 participants from each arm died during this period
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ticagrelor | ICU Length of Stay | 8.33 days |
| Placebo | ICU Length of Stay | 8.77 days |
Other Pre-specified
Need for Dialysis
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ticagrelor | Need for Dialysis | 1 Participants |
| Placebo | Need for Dialysis | 0 Participants |
Other Pre-specified
Need for Re-instituting Assisted or Mechanical Ventilation After Achieving 48 Consecutive Hours of Unassisted Breathing or Comfort Care Chosen (Withdrawal of Support)
Time frame: 90 days
Population: only participants that required mechanical ventilation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ticagrelor | Need for Re-instituting Assisted or Mechanical Ventilation After Achieving 48 Consecutive Hours of Unassisted Breathing or Comfort Care Chosen (Withdrawal of Support) | 0 Participants |
| Placebo | Need for Re-instituting Assisted or Mechanical Ventilation After Achieving 48 Consecutive Hours of Unassisted Breathing or Comfort Care Chosen (Withdrawal of Support) | 0 Participants |
Other Pre-specified
Time to Initiation of Unassisted Breathing
Only in patients on mechanical ventilation and assuming patient achieves 48 consecutive hours of unassisted breathing
Time frame: 29 days
Population: 2 participants from each arm died during this period
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ticagrelor | Time to Initiation of Unassisted Breathing | 136.9 hours |
| Placebo | Time to Initiation of Unassisted Breathing | 173.19 hours |