Ventilator-Associated Pneumonia
Conditions
Keywords
Ventilator-Associated Pneumonia, Pneumonia, hospital-acquired, Doripenem, Imipenem-cilastatin
Brief summary
The purpose of this study is to show that doripenem is as effective as imipenem-cilastatin in the treatment of patients with ventilator-associated pneumonia.
Detailed description
This is a randomized (the study medication is assigned by chance), double-blind (neither physician nor patient knows the treatment that the patient receives), active-controlled (agent that is compared with a study medication to test whether the study medication has a real effect in a clinical study), double-dummy (placebo \[inactive substance that is compared with a medication to test whether the medication has a real effect in a clinical study\] is administered to maintain the blind when the comparator medication cannot be made identical to the study medication), parallel-group (each group of patients will be treated at the same time), multicenter study to assess the effectiveness and safety of 7 day course of doripenem, compared with 10 day course of imipenem-cilastatin in patients with ventilator-associated pneumonia. This study will consists of 3 phases: (1) a pretreatment phase with a maximum of 24 hours for the screening/baseline visit, (2) a double blind, double dummy, treatment phase of 10 days (Day 1 to Day 10) and an end-of-treatment (EOT) assessment within 24 hours after the last dose of study medication therapy administered on Day 10 or at the time of early withdrawal from study medication, and (3) a post treatment (follow-up) phase consisting of an early follow-up (EFU) visit within 7 to 14 days after the last dose of study medication, and last follow-up (LFU) visit within 28 to 35 days after the last dose of study medication for all patients including those who discontinued study medication early. Two hundred and seventy four patients will be randomly assigned to receive either doripenem or imipenem with placebo of the other medication given simultaneously to maintain the blind (eg, 1 group will receive blinded doripenem from Days 1 to 7 and imipenem placebo Days 1 to 10, other group will receive blinded imipenem Days 1 to 10 and doripenem placebo Days 1 to 7). A sample of secretions from the lower respiratory tract will be obtained by bronchoalveolar lavage (BAL) or mini-BAL within 36 hours prior to administration of study medication from the enrolled patients and sent for culture. Patients, whose baseline BAL or mini-BAL culture results will yield at least 1 qualifying pneumonia pathogen will continue to receive study medication therapy and patients, whose baseline BAL or mini-BAL culture results did not yield at least 1 qualifying pneumonia pathogen will be discontinued from study medication therapy but will remain enroll in the study and will be followed for safety. Safety evaluations including adverse events, clinical laboratory evaluations, vital signs and physical examinations will be monitored throughout the study period. The total duration of an individual patient's participation in the study will be approximately 5 to 6 weeks.
Interventions
DRUGDoripenem
Type=exact number, number=1, unit=g, form=solution for injection, route=intravenously. 1 gram 4-hour infusion of doripenem will be administered every 8 hours for 7 days.
Type=exact number, number=1, unit=g, form=solution for injection, route=intravenously. 1 gram 1-hour infusion of imipenem-cilastatin will be administered every 8 hours for 10 days.
DRUGPlacebo
Form=solution, route=intravenous. Doripenem pacebo will be administered from Days 1 to 7 in imipenem-cilastatin arm and imipenem-cilastatin placebo will be administered in doripenem arm.
Sponsors
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have new or worsening radiographic infiltrates consistent with ventilator-associated pneumonia that was not related to cardiac or other disease processes * Have at least 1 of the following: fever (core body temperature greater than 39.0°C); hypothermia (core body temperature of less than 35.0°C); leukocytosis (increased WBC count); and leukopenia (decreased WBC count) * Have developed ventilator-associated pneumonia and have been on mechanical ventilation for more than or equal to 48 hours and on mechanical ventilation at the time that study medication is assigned * Have been hospitalized or been in a chronic care facility for consecutive 5 days or more within the last 90 days * Have a baseline Clinical Pulmonary Infection Score (CPIS) more than or equal to 6 and an Acute Physiology and Chronic Health Evaluation (APACHE) II score more than 8 and less than 35
Exclusion criteria
* Have received antibiotics for this episode of ventilator-associated pneumonia for more than 24 hours before study medication administration * Known presence at baseline of only methicillin-resistant Staphylococcus aureus or Stenotrophomonas infection * Acute respiratory distress syndrome * Has any of the following conditions: chest trauma with severe lung bruising or loss of stability of the thoracic cage following a fracture of the sternum, ribs, or both, increased amounts of fluid in the lung cavities requiring drainage or pus in the cavity * Has active seizure disorder within the last 2 years or brain injury such that imipenem cilastatin would not be administered to the patient in usual practice * Has lung cancer within the last 2 years, chronic bronchitis with an increase in severity within the last 30 days, chronic enlargement of the bronchi or bronchioles related to inflammatory disease or obstruction, lung abscess(s), anatomical bronchial obstruction, respiratory tuberculosis on treatment, suspected atypical pneumonia, chemical pneumonitis, cystic fibrosis, congestive heart failure, severe burns to greater than 15% of the body, evidence of severe and chronic liver disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Cure Rate at the End-of-treatment (EOT) Visit | End-of-treatment (Day 10 or Day 11) | The number of patients who achieved clinical cure at the EOT visit on Day 10. The patient's were classified as clinical cure if they had resolution of signs and symptoms and objective findings of pneumonia to such an extent that no further antimicrobial therapy was necessary. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Cure Rate at the End-of-treatment (EOT) Visit in Patients From Whom a Qualifying P. Aeruginosa Was Isolated at Baseline | End-of-treatment (Day 10 or Day 11) | The clinical cure rate at the EOT visit in patients, whose bronchoalveolar lavage (BAL) or mini-BAL culture results yielded qualifying pneumonia pathogen P. aeruginosa at baseline. |
| Clinical Cure Rate at the End-of-treatment (EOT) Visit in Patients From Whom at Least 1 of the Gram-negative Qualifying Pneumonia Pathogens (Enterobacteriaceae, P. Aeruginosa, and Acinetobacter Spp) Was Isolated at Baseline | End-of-treatment (Day 10 or Day 11) | The clinical cure rate at the EOT visit in patients whose BAL or mini-BAL culture results yielded at least 1 of the following Gram-negative qualifying pneumonia pathogens was isolated at baseline: any Enterobacteriaceae, P. aeruginosa, and Acinetobacter Spp. |
| Number of Patients Who Had Emergence of P. Aeruginosa Resistance | Up to 6 weeks | Number of patients who had P. aeruginosa isolates with a 4 fold or greater increase in minimum inhibitory concentration (MIC) at anytime during the study (after the study medication is received) from baseline |
| 28-day All-cause Mortality Rate | Up to 28 days | Number of deaths which occured up to 28 days of the study period due to all causes |
Countries
Argentina, Australia, Belgium, Brazil, Canada, France, Germany, Guatemala, Hungary, India, Israel, Mexico, Philippines, Portugal, Romania, Russia, Spain, Thailand, Turkey (Türkiye), Ukraine, United States
Participant flow
Recruitment details
274 enrolled patients were randomnly assigned to the 127 study centers. 524 patients were to be enrolled, however as the study was terminated early only 274 patients were actually enrolled.
Pre-assignment details
Out of 274 randomized patients, 41 patients were excluded (as their sites were GCP Non-Compliant) and 6 patients were not treated. Treated patients=227 (115 doripenem and 112 imipenem-cilastatin).
Participants by arm
| Arm | Count |
|---|---|
| Doripenem 1 g 4-hour infusion intravenously every 8 hour for 7 days | 115 |
| Imipenem-cilastatin 1 g 1-hour infusion intravenously every 8 hour for 10 days | 112 |
| Total | 227 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 4 |
| Overall Study | Death | 26 | 16 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | randomized in error | 12 | 6 |
Baseline characteristics
| Characteristic | Doripenem | Imipenem-cilastatin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical >=65 years | 43 Participants | 39 Participants | 82 Participants |
| Age, Categorical Between 18 and 65 years | 72 Participants | 72 Participants | 144 Participants |
| Age Continuous | 57.5 years STANDARD_DEVIATION 16.53 | 54.6 years STANDARD_DEVIATION 18.46 | 56.1 years STANDARD_DEVIATION 17.53 |
| Region Enroll EUROPE | 69 participants | 71 participants | 140 participants |
| Region Enroll NORTH AMERICA | 16 participants | 12 participants | 28 participants |
| Region Enroll REST OF WORLD | 9 participants | 6 participants | 15 participants |
| Region Enroll SOUTH AMERICA | 21 participants | 23 participants | 44 participants |
| Sex: Female, Male Female | 43 Participants | 37 Participants | 80 Participants |
| Sex: Female, Male Male | 72 Participants | 75 Participants | 147 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 82 / 115 | 80 / 112 |
| serious Total, serious adverse events | 55 / 115 | 45 / 112 |
Outcome results
Primary
Clinical Cure Rate at the End-of-treatment (EOT) Visit
The number of patients who achieved clinical cure at the EOT visit on Day 10. The patient's were classified as clinical cure if they had resolution of signs and symptoms and objective findings of pneumonia to such an extent that no further antimicrobial therapy was necessary.
Time frame: End-of-treatment (Day 10 or Day 11)
Population: Microbiological Intent-to-Treat (MITT) - subset of all ITT (all randomized patients who received at least a partial dose of study medication) patients who had at least 1 qualifying pneumonia pathogen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Doripenem | Clinical Cure Rate at the End-of-treatment (EOT) Visit | 36 Participants |
| Imipenem-cilastatin | Clinical Cure Rate at the End-of-treatment (EOT) Visit | 50 Participants |
Comparison: Null Hypothesis: The clinical cure rate of doripenem assessed at the EOT visit is more than 15% inferior to that of imipenem-cilastatin95% CI: [-26.3, 3.8]Normal approximation of 2 proportions
Secondary
28-day All-cause Mortality Rate
Number of deaths which occured up to 28 days of the study period due to all causes
Time frame: Up to 28 days
Population: Microbiological Intent-to-Treat (MITT) - subset of all ITT (all randomized patients who received at least a partial dose of study medication) patients who had at least 1 qualifying pneumonia pathogen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Doripenem | 28-day All-cause Mortality Rate | 17 Participants |
| Imipenem-cilastatin | 28-day All-cause Mortality Rate | 13 Participants |
95% CI: [-5, 18.5]Normal approximation of 2 proportions
Secondary
Clinical Cure Rate at the End-of-treatment (EOT) Visit in Patients From Whom a Qualifying P. Aeruginosa Was Isolated at Baseline
The clinical cure rate at the EOT visit in patients, whose bronchoalveolar lavage (BAL) or mini-BAL culture results yielded qualifying pneumonia pathogen P. aeruginosa at baseline.
Time frame: End-of-treatment (Day 10 or Day 11)
Population: Microbiological Intent-to-Treat (MITT) - subset of all ITT (all randomized patients who received at least a partial dose of study medication) patients who had at least 1 qualifying pneumonia pathogen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Doripenem | Clinical Cure Rate at the End-of-treatment (EOT) Visit in Patients From Whom a Qualifying P. Aeruginosa Was Isolated at Baseline | 7 Participants |
| Imipenem-cilastatin | Clinical Cure Rate at the End-of-treatment (EOT) Visit in Patients From Whom a Qualifying P. Aeruginosa Was Isolated at Baseline | 6 Participants |
95% CI: [-57.2, 19.5]Normal approximation of 2 proportions
Secondary
Clinical Cure Rate at the End-of-treatment (EOT) Visit in Patients From Whom at Least 1 of the Gram-negative Qualifying Pneumonia Pathogens (Enterobacteriaceae, P. Aeruginosa, and Acinetobacter Spp) Was Isolated at Baseline
The clinical cure rate at the EOT visit in patients whose BAL or mini-BAL culture results yielded at least 1 of the following Gram-negative qualifying pneumonia pathogens was isolated at baseline: any Enterobacteriaceae, P. aeruginosa, and Acinetobacter Spp.
Time frame: End-of-treatment (Day 10 or Day 11)
Population: Microbiological Intent-to-Treat (MITT) - subset of all ITT (all randomized patients who received at least a partial dose of study medication) patients who had at least 1 qualifying pneumonia pathogen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Doripenem | Clinical Cure Rate at the End-of-treatment (EOT) Visit in Patients From Whom at Least 1 of the Gram-negative Qualifying Pneumonia Pathogens (Enterobacteriaceae, P. Aeruginosa, and Acinetobacter Spp) Was Isolated at Baseline | 32 Participants |
| Imipenem-cilastatin | Clinical Cure Rate at the End-of-treatment (EOT) Visit in Patients From Whom at Least 1 of the Gram-negative Qualifying Pneumonia Pathogens (Enterobacteriaceae, P. Aeruginosa, and Acinetobacter Spp) Was Isolated at Baseline | 34 Participants |
95% CI: [-23, 11.7]Normal approximation of 2 proportions
Secondary
Number of Patients Who Had Emergence of P. Aeruginosa Resistance
Number of patients who had P. aeruginosa isolates with a 4 fold or greater increase in minimum inhibitory concentration (MIC) at anytime during the study (after the study medication is received) from baseline
Time frame: Up to 6 weeks
Population: Microbiological Intent-to-Treat (MITT) - subset of all ITT (all randomized patients who received at least a partial dose of study medication) patients who had at least 1 qualifying pneumonia pathogen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Doripenem | Number of Patients Who Had Emergence of P. Aeruginosa Resistance | 3 Participants |
| Imipenem-cilastatin | Number of Patients Who Had Emergence of P. Aeruginosa Resistance | 6 Participants |
p-value: 0.14Fisher Exact