Pneumonia, Bacterial
Conditions
Keywords
Hospital-acquired pneumonia, Ventilator-associated pneumonia
Brief summary
This study will compare the safety and efficacy of a tigecycline regimen versus an imipenem/cilastatin regimen for the treatment of subjects who are hospitalized with hospital-acquired pneumonia (HAP). At least 70% of enrolled subjects will have ventilator-associated pneumonia (VAP). Two dose levels of tigecycline will be assessed and compared to imipenem/cilastatin in parallel. Subjects will receive intravenous therapy from a minimum of 7 & up to 14 consecutive days, the exact duration will be at the decision of the investigator based on the subject's condition. Additional protocol specified antibiotics may be given to ensure appropriate coverage. A final assessment at test-of-cure (TOC) visit will be done 10 to 21 days after the last day of therapy. The total duration of subject participation will be between 17 and 44 days, including a follow up period of 30 days after the last day of therapy for SAEs. Subjects will be followed for safety and efficacy. The safety assessment will include: physical examinations, vital signs, assessment of the clinical signs and symptoms of pneumonia, collection of adverse events, 12-lead ECG, collection of samples for hematology, serum chemistries, and coagulation parameters, & a serum or urine pregnancy test before study entry for women of childbearing potential. The clinical and microbiological efficacy will both be evaluated.
Detailed description
The sponsor internal decision has been taken to close the study on 15 of July 2011, due to difficulties in enrollment. This decision was not based on any safety issues.
Interventions
DRUGtigecycline
An initial intravenous (IV) loading dose of 150 mg of tigecycline, followed by 75 mg of IV tigecycline approximately every 12 hours (q12h), for up to 14 consecutive days. Ceftazidime 2 g IV approximately every 8 hours, an aminoglycoside (tobramycin 7mg/kg daily or amikacin 20 mg/kg daily) and vancomycin placebo given at the start of therapy (unless it is known at baseline that the subject does not have Pseudomonas aeruginosa or methicillin-resistant Staphylococcus aureus \[MRSA\]).
Imipenem/cilastatin 1g intravenous (IV) will be administered approximately every 8 hours, for up to 14 consecutive days. In addition vancomycin 15 mg/kg IV approximately every 12 hours (q12h), an aminoglycoside (tobramycin 7mg/kg daily or amikacin 20 mg/kg daily) and ceftazidime placebo will be given at the start of therapy (unless it is known at baseline that the subject does not have Pseudomonas aeruginosa or methicillin-resistant Staphylococcus aureus \[MRSA\]).
Sponsors
Pfizer
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
* Male or female subjects, greater than or equal to 18 years of age, known or suspected to have acute hospital-acquired pneumonia (HAP). * Acute HAP is defined as pneumonia with onset of symptoms: 1. Greater than or equal to 48 hours after admission to an acute care hospital or chronic care facility such as a skilled nursing home facility or rehabilitation unit. Or 2. Less than or equal to 7 days after the subject was discharged from the hospital. The initial hospitalization must have been greater than or equal to 3 days duration. * VAP is defined as: onset of symptoms of pneumonia greater than or equal to 48 hours after endotracheal intubation. * Presence of a new or evolving infiltrate on a chest x-ray film, presence of fever or leukocytosis, respiratory failure requiring mechanical ventilation or presence of 2 of the following clinical signs and symptoms: cough, dyspnea or tachypnea, pleuritic chest pain, rales and/or evidence of pulmonary consolidation, hypoxemia, or purulent sputum production.
Exclusion criteria
* Subjects with other significant underlying conditions that would make it difficult to evaluate the subjects or make it unlikely to complete the therapy or that would increase their risk by participating in the study, infection with organisms known to be resistant, contraindication, or hypersensitivity to any of the test articles.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Clinical Response in Clinically Evaluable (CE) Population at Test-of-Cure (TOC) Visit | Up to Day 24 to 35 (10 to 21 days after last day of therapy [LDOT]) | Clinical response: Cure=All initial signs/symptoms of pneumonia (SSx) improved; chest x-ray (CXR) improved/stable; no other antibiotics for pneumonia; no worsening or new SSx. Failure=Persistence or worsening SSx; no clinical improvement or initial improvement with clinically important worsening; other antimicrobials for pneumonia; CXR progression; death \> study day 2 due to pneumonia. Indeterminate=unable to determine outcome for non-study drug/infection reasons (e.g., lost to follow-up); death in 2 days after 1st dose for any reason, or \>2 days but before TOC visit for non-pneumonia reason. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Clinical Response in Clinical Modified Intent-to-treat (c-mITT) Population at Test-of-Cure (TOC) Visit | Up to Day 24 to 35 (10 to 21 days after LDOT) | Clinical response: Cure=All initial SSx improved; CXR improved/stable; no other antibiotics for pneumonia; no worsening or new SSx. Failure=Persistence or worsening SSx; no clinical improvement or initial improvement with clinically important worsening; other antimicrobials for pneumonia; CXR progression; death \> study day 2 due to pneumonia. Indeterminate=unable to determine outcome for non-study drug/infection reasons (e.g., lost to follow-up); death in 2 days after 1st dose for any reason, or \>2 days but before TOC visit for non-pneumonia reason. |
| Percentage of Participants With Clinical Response in Ventilator Associated Pneumonia (VAP) and Non-VAP Participants at Test-of-Cure (TOC) Visit | Up to Day 24 to 35 (10 to 21 days after LDOT) | Clinical response: Cure=All initial SSx improved; CXR improved/stable; no other antibiotics for pneumonia; no worsening or new SSx. Failure=Persistence or worsening SSx; no clinical improvement or initial improvement with clinically important worsening; other antimicrobials for pneumonia; CXR progression; death \> study day 2 due to pneumonia. Indeterminate=unable to determine outcome for non-study drug/infection reasons (e.g., lost to follow-up); death in 2 days after 1st dose for any reason, or \>2 days but before TOC visit for non-pneumonia reason. |
| Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Up to Day 24 to 35 (10 to 21 days after LDOT) | Eradication=baseline isolate not present in repeat culture from the original infection site; Presumed Eradication=clinical response of cure precluded the availability of a specimen for culture; Persistence=baseline isolate present in repeat culture from the original infection site; Presumed Persistence=culture data not available for participants with a clinical response of failure; Indeterminate=unable to determine outcome for non-study drug/infection reasons; no baseline isolate; death in 2 days after 1st dose for any reason, or \>2 days but before TOC visit for non-pneumonia reason. |
| Percentage of Participants With Microbiological Response at the Participant Level Population at Test-of-Cure (TOC) Visit | Up to Day 24 to 35 (10 to 21 days after LDOT) | Microbiological response assessed at participant level. Eradication = baseline isolate not present in repeat culture from the original infection site; Presumed Eradication = clinical response of cure precluded the availability of a specimen for culture; Persistence = baseline isolate present in repeat culture from the original infection site; Presumed Persistence = culture data not available for participants with a clinical response of failure; Superinfection = culture from the primary infection site had new pathogen not identified as a baseline isolate and clinical response was failure. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-12)] of Tigecycline | Day 3, 4 or 5 | AUC (0-12) = Area under the serum concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-12). Area under the serum concentration-time curve was derived from the population pharmacokinetic (PK) analysis by using each participant's dose and the post-hoc individual estimated systemic CL, AUC (0-12) = Dose divided by CL. |
| Clearance (CL) of Tigecycline | Day 3, 4 or 5 | Drug clearance (CL) is a quantitative measure of the rate at which a drug substance is removed from the blood. It is defined as the volume of serum from which drug can be completely removed per unit of time. |
| Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-24)] of Tigecycline | Day 3, 4 or 5 | AUC (0-24) = Area under the serum concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-24). Area under the serum concentration-time curve was derived from the population pharmacokinetic (PK) analysis by using each participant's dose and the post-hoc individual estimated systemic CL, AUC (0-12) = Dose divided by CL. Model-predicted AUC (0-24) was calculated by multiplying AUC (0-12) by 2. |
| Correlation of AUC (0-24) of Tigecycline With Nausea and Vomiting | Baseline up to Day 29 to 35 (15 to 21 days after LDOT) | AUC (0-24) = Area under the serum concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-24). Area under the serum concentration-time curve was derived from the population PK analysis by using each participant's dose and the post-hoc individual estimated systemic CL, AUC (0-12) = Dose divided by CL. Model-predicted AUC (0-24) was calculated by multiplying AUC (0-12) by 2. |
| Number of Participants Who Experienced Nausea or Vomiting | Baseline up to Day 29 to Day 35 (15 to 21 days after LDOT) | — |
| Correlation of AUC(0-24) to Minimum Inhibitory Concentration (MIC) Ratio (AUC [0-24]/MIC) of Tigecycline With Microbiological Outcome | Up to Day 24 to 35 (10 to 21 days after LDOT) | Microbiological response:Eradication=baseline isolate not present in repeat culture from original infection site;Presumed Eradication=clinical response of cure precluded availability of specimen for culture;Persistence=baseline isolate present in repeat culture from original infection site;Presumed Persistence=culture data not available for participants with clinical response of failure;Superinfection=culture from primary infection site had new pathogen not identified as baseline isolate, clinical response was failure. MIC=lowest drug concentration with no visible growth of microorganism. |
| Maximum Observed Plasma Concentration of Procalcitonin (Cmaxpd) and Predicted Procalcitonin Plasma Concentration at 24 Hours (Cpd,24) and 48 Hours (Cpd,48) | Baseline up to Day 6 | — |
| Time to Reach Half of the Maximum Observed Plasma Concentration and Time to Normalization of Concentrations (Tnorm) of Procalcitonin | Baseline up to Day 6 | — |
| Duration of Intravenous Antibiotic Treatment, Hospital and Intensive Care Unit (ICU) Stay | Baseline up to Day 44 (30 days after LDOT) | — |
| Correlation of AUC(0-24) to Minimum Inhibitory Concentration (MIC) Ratio (AUC [0-24]/MIC) of Tigecycline With Clinical Outcome | Up to Day 24 to 35 (10 to 21 days after LDOT) | Clinical response:Cure =Initial SSx improved;CXR improved/stable;no other antibiotic for pneumonia;no worsening/new SSx. Failure=Persistence/worsening SSx;no clinical improvement/initial improvement with worsening; other antibiotic;CXR progression;death \>study day 2 due to pneumonia. Indeterminate=unable to determine outcome for non-study drug/infection reason;death in 2 days after dose 1 for any reason or \>2 days but before TOC visit for non-pneumonia reason. MIC=lowest drug concentration with no visible growth of microorganism. AUC(0-24)/MIC:reported for cure and failure/indeterminate. |
| Number of Participants With Abnormal Laboratory Examinations | Baseline up to Day 24 to Day 35 (10 to 21 days after LDOT) | Participants were evaluated for following laboratory parameters: albumin, alkaline phosphatase, amylase, urea (blood urea nitrogen \[BUN\]), total bilirubin, calcium, magnesium, carbon dioxide, international normalized ratio (INR), chloride, creatinine, glucose, lipase, potassium, phosphorus, aspartate aminotransferase (AST), alanine aminotransferase (ALT), sodium, total protein, hemoglobin, hematocrit, white blood cells, eosinophils, neutrophils, lymphocytes, platelets, prothrombin time, prothrombin activity and partial thromboplastin time. |
| Number of Participants With Abnormal Electrocardiogram (ECG) | Baseline up to Day 14 or LDOT | Potentially clinically significant ECG data: Non-first values greater than 240 millisecond (msec) with increase of greater than or equal to 10 percent (%) from baseline for PR interval; Non-first values greater than or equal to 120 msec for QRS interval; Non-first values greater than 460 msec with increase of greater than or equal to 5% from baseline for corrected QT (QTc) interval; Non-first values greater than 460 msec with increase of greater than or equal to 5% from baseline for QTc using Framingham formula (QTc F). |
| Maximum Observed Serum Concentration (Cmax) of Tigecycline | Day 3, 4 or 5 | — |
| Time to Reach Maximum Observed Serum Concentration (Tmax) of Tigecycline | Day 3, 4 or 5 | — |
Countries
Argentina, Australia, Brazil, Canada, Chile, Colombia, Croatia, France, Hungary, Latvia, Russia, South Korea, Taiwan, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tigecycline 75 mg Tigecycline 150 milligram (mg) loading dose intravenously followed by tigecycline 75 mg maintenance dose intravenously approximately every 12 hours (hrs). Ceftazidime 2 gram intravenously approximately every 8 hrs, an aminoglycoside (tobramycin 7 mg/kilogram \[mg/kg\] or amikacin 20 mg/kg daily) and vancomycin placebo intravenously at the start of therapy unless participant did not have Pseudomonas aeruginosa (P. aeruginosa) or methicillin-resistant Staphylococcus aureus (MRSA). | 36 |
| Tigecycline 100 mg Tigecycline 200 mg loading dose intravenously followed by tigecycline 100 mg maintenance dose intravenously approximately every 12 hrs. Ceftazidime 2 gram intravenously approximately every 8 hrs, an aminoglycoside (tobramycin 7 mg/kg or amikacin 20 mg/kg daily) and vancomycin placebo intravenously at the start of therapy unless participant did not have P. aeruginosa or MRSA. | 35 |
| Imipenem/Cilastatin 1 Gram Imipenem/cilastatin 1 gram intravenously approximately every 8 hrs. Vancomycin 15 mg/kg intravenously approximately every 12 hrs, an aminoglycoside (tobramycin 7 mg/kg or amikacin 20 mg/kg daily) and ceftazidime placebo intravenously at the start of therapy unless participant did not have P. aeruginosa or MRSA. | 34 |
| Total | 105 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 3 | 2 |
| Overall Study | Death | 3 | 1 | 3 |
| Overall Study | Lack of Efficacy | 1 | 2 | 0 |
| Overall Study | Other | 8 | 3 | 5 |
| Overall Study | Physician Decision | 1 | 1 | 2 |
| Overall Study | Protocol Violation | 0 | 0 | 1 |
| Overall Study | Randomized, but not treated | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Tigecycline 75 mg | Tigecycline 100 mg | Imipenem/Cilastatin 1 Gram | Total |
|---|---|---|---|---|
| Age Continuous | 60.31 years STANDARD_DEVIATION 14.82 | 61.46 years STANDARD_DEVIATION 16.05 | 64.85 years STANDARD_DEVIATION 15.33 | 62.16 years STANDARD_DEVIATION 15.37 |
| Sex: Female, Male Female | 13 Participants | 16 Participants | 5 Participants | 34 Participants |
| Sex: Female, Male Male | 23 Participants | 19 Participants | 29 Participants | 71 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 28 / 36 | 25 / 35 | 26 / 34 |
| serious Total, serious adverse events | 12 / 36 | 9 / 35 | 10 / 34 |
Outcome results
Primary
Percentage of Participants With Clinical Response in Clinically Evaluable (CE) Population at Test-of-Cure (TOC) Visit
Clinical response: Cure=All initial signs/symptoms of pneumonia (SSx) improved; chest x-ray (CXR) improved/stable; no other antibiotics for pneumonia; no worsening or new SSx. Failure=Persistence or worsening SSx; no clinical improvement or initial improvement with clinically important worsening; other antimicrobials for pneumonia; CXR progression; death \> study day 2 due to pneumonia. Indeterminate=unable to determine outcome for non-study drug/infection reasons (e.g., lost to follow-up); death in 2 days after 1st dose for any reason, or \>2 days but before TOC visit for non-pneumonia reason.
Time frame: Up to Day 24 to 35 (10 to 21 days after last day of therapy [LDOT])
Population: CE population included those participants who met specified evaluability criteria for efficacy.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tigecycline 75 mg | Percentage of Participants With Clinical Response in Clinically Evaluable (CE) Population at Test-of-Cure (TOC) Visit | Cure | 69.6 percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Clinical Response in Clinically Evaluable (CE) Population at Test-of-Cure (TOC) Visit | Failure | 30.4 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Clinical Response in Clinically Evaluable (CE) Population at Test-of-Cure (TOC) Visit | Cure | 85.0 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Clinical Response in Clinically Evaluable (CE) Population at Test-of-Cure (TOC) Visit | Failure | 15.0 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Clinical Response in Clinically Evaluable (CE) Population at Test-of-Cure (TOC) Visit | Cure | 75.0 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Clinical Response in Clinically Evaluable (CE) Population at Test-of-Cure (TOC) Visit | Failure | 25.0 percentage of participants |
Comparison: Cure: Confidence interval (CI) was calculated using the Wilson score method, with continuity correction. Clinical response (rates of cure) by using a 2-sided 70 percent (%) CI for the true difference in efficacy (tigecycline regimen minus imipenem/cilastatin regimen) was calculated. Statistical testing was done at 15% alpha.70% CI: [-21.6, 10.9]
Comparison: Cure: CI was calculated using the Wilson score method, with continuity correction. Clinical response (rates of cure) by using a 2-sided 70% CI for the true difference in efficacy (tigecycline regimen minus imipenem/cilastatin regimen) was calculated. Statistical testing was done at 15% alpha.70% CI: [-6.1, 24.8]
Secondary
Percentage of Participants With Clinical Response in Clinical Modified Intent-to-treat (c-mITT) Population at Test-of-Cure (TOC) Visit
Clinical response: Cure=All initial SSx improved; CXR improved/stable; no other antibiotics for pneumonia; no worsening or new SSx. Failure=Persistence or worsening SSx; no clinical improvement or initial improvement with clinically important worsening; other antimicrobials for pneumonia; CXR progression; death \> study day 2 due to pneumonia. Indeterminate=unable to determine outcome for non-study drug/infection reasons (e.g., lost to follow-up); death in 2 days after 1st dose for any reason, or \>2 days but before TOC visit for non-pneumonia reason.
Time frame: Up to Day 24 to 35 (10 to 21 days after LDOT)
Population: c-mITT population included all participants who were randomly assigned to receive intravenous study medication and had clinical evidence of hospital-acquired pneumonia (HAP).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tigecycline 75 mg | Percentage of Participants With Clinical Response in Clinical Modified Intent-to-treat (c-mITT) Population at Test-of-Cure (TOC) Visit | Failure | 27.8 percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Clinical Response in Clinical Modified Intent-to-treat (c-mITT) Population at Test-of-Cure (TOC) Visit | Cure | 52.8 percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Clinical Response in Clinical Modified Intent-to-treat (c-mITT) Population at Test-of-Cure (TOC) Visit | Indeterminate | 19.4 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Clinical Response in Clinical Modified Intent-to-treat (c-mITT) Population at Test-of-Cure (TOC) Visit | Failure | 14.3 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Clinical Response in Clinical Modified Intent-to-treat (c-mITT) Population at Test-of-Cure (TOC) Visit | Cure | 71.4 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Clinical Response in Clinical Modified Intent-to-treat (c-mITT) Population at Test-of-Cure (TOC) Visit | Indeterminate | 14.3 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Clinical Response in Clinical Modified Intent-to-treat (c-mITT) Population at Test-of-Cure (TOC) Visit | Cure | 52.9 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Clinical Response in Clinical Modified Intent-to-treat (c-mITT) Population at Test-of-Cure (TOC) Visit | Indeterminate | 29.4 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Clinical Response in Clinical Modified Intent-to-treat (c-mITT) Population at Test-of-Cure (TOC) Visit | Failure | 17.6 percentage of participants |
Comparison: Cure: CI was calculated using the Wilson score method, with continuity correction. Clinical response (rates of cure) by using a 2-sided 70% CI for the true difference in efficacy (tigecycline regimen minus imipenem/cilastatin regimen) was calculated. Statistical testing was done at 15% alpha.70% CI: [-14.3, 14]
Comparison: Cure: CI was calculated using the Wilson score method, with continuity correction. Clinical response (rates of cure) by using a 2-sided 70% CI for the true difference in efficacy (tigecycline regimen minus imipenem/cilastatin regimen) was calculated. Statistical testing was done at 15% alpha.70% CI: [4.3, 31.8]
Secondary
Percentage of Participants With Clinical Response in Ventilator Associated Pneumonia (VAP) and Non-VAP Participants at Test-of-Cure (TOC) Visit
Clinical response: Cure=All initial SSx improved; CXR improved/stable; no other antibiotics for pneumonia; no worsening or new SSx. Failure=Persistence or worsening SSx; no clinical improvement or initial improvement with clinically important worsening; other antimicrobials for pneumonia; CXR progression; death \> study day 2 due to pneumonia. Indeterminate=unable to determine outcome for non-study drug/infection reasons (e.g., lost to follow-up); death in 2 days after 1st dose for any reason, or \>2 days but before TOC visit for non-pneumonia reason.
Time frame: Up to Day 24 to 35 (10 to 21 days after LDOT)
Population: CE population included those participants who met specified evaluability criteria for efficacy. 'n' is signifying those participants who were evaluable for this measure and included in VAP (suffering from VAP) and non-VAP group (not suffering from VAP) for each group respectively.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tigecycline 75 mg | Percentage of Participants With Clinical Response in Ventilator Associated Pneumonia (VAP) and Non-VAP Participants at Test-of-Cure (TOC) Visit | VAP: Cure (n = 7, 7, 9) | 71.4 percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Clinical Response in Ventilator Associated Pneumonia (VAP) and Non-VAP Participants at Test-of-Cure (TOC) Visit | VAP: Failure (n = 7, 7, 9) | 28.6 percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Clinical Response in Ventilator Associated Pneumonia (VAP) and Non-VAP Participants at Test-of-Cure (TOC) Visit | Non-VAP: Cure (n = 16, 13, 15) | 68.8 percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Clinical Response in Ventilator Associated Pneumonia (VAP) and Non-VAP Participants at Test-of-Cure (TOC) Visit | Non-VAP: Failure (n = 16, 13, 15) | 31.3 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Clinical Response in Ventilator Associated Pneumonia (VAP) and Non-VAP Participants at Test-of-Cure (TOC) Visit | Non-VAP: Failure (n = 16, 13, 15) | 15.4 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Clinical Response in Ventilator Associated Pneumonia (VAP) and Non-VAP Participants at Test-of-Cure (TOC) Visit | VAP: Cure (n = 7, 7, 9) | 85.7 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Clinical Response in Ventilator Associated Pneumonia (VAP) and Non-VAP Participants at Test-of-Cure (TOC) Visit | Non-VAP: Cure (n = 16, 13, 15) | 84.6 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Clinical Response in Ventilator Associated Pneumonia (VAP) and Non-VAP Participants at Test-of-Cure (TOC) Visit | VAP: Failure (n = 7, 7, 9) | 14.3 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Clinical Response in Ventilator Associated Pneumonia (VAP) and Non-VAP Participants at Test-of-Cure (TOC) Visit | Non-VAP: Failure (n = 16, 13, 15) | 26.7 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Clinical Response in Ventilator Associated Pneumonia (VAP) and Non-VAP Participants at Test-of-Cure (TOC) Visit | VAP: Failure (n = 7, 7, 9) | 22.2 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Clinical Response in Ventilator Associated Pneumonia (VAP) and Non-VAP Participants at Test-of-Cure (TOC) Visit | Non-VAP: Cure (n = 16, 13, 15) | 73.3 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Clinical Response in Ventilator Associated Pneumonia (VAP) and Non-VAP Participants at Test-of-Cure (TOC) Visit | VAP: Cure (n = 7, 7, 9) | 77.8 percentage of participants |
Secondary
Percentage of Participants With Microbiological Response at the Participant Level Population at Test-of-Cure (TOC) Visit
Microbiological response assessed at participant level. Eradication = baseline isolate not present in repeat culture from the original infection site; Presumed Eradication = clinical response of cure precluded the availability of a specimen for culture; Persistence = baseline isolate present in repeat culture from the original infection site; Presumed Persistence = culture data not available for participants with a clinical response of failure; Superinfection = culture from the primary infection site had new pathogen not identified as a baseline isolate and clinical response was failure.
Time frame: Up to Day 24 to 35 (10 to 21 days after LDOT)
Population: ME population included participants who met specified evaluability criteria for efficacy, had culture taken from the infected site before first dose of study medication and had at least 1 pathogen, and at least 1 baseline pathogen was susceptible to tigecycline and imipenem/cilastatin regimens.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tigecycline 75 mg | Percentage of Participants With Microbiological Response at the Participant Level Population at Test-of-Cure (TOC) Visit | Persistence | 38.5 percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Microbiological Response at the Participant Level Population at Test-of-Cure (TOC) Visit | Eradication | 61.5 percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Microbiological Response at the Participant Level Population at Test-of-Cure (TOC) Visit | Superinfection | 0.0 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Microbiological Response at the Participant Level Population at Test-of-Cure (TOC) Visit | Persistence | 20.0 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Microbiological Response at the Participant Level Population at Test-of-Cure (TOC) Visit | Eradication | 80.0 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Microbiological Response at the Participant Level Population at Test-of-Cure (TOC) Visit | Superinfection | 0.0 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Microbiological Response at the Participant Level Population at Test-of-Cure (TOC) Visit | Eradication | 80.0 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Microbiological Response at the Participant Level Population at Test-of-Cure (TOC) Visit | Superinfection | 6.7 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Microbiological Response at the Participant Level Population at Test-of-Cure (TOC) Visit | Persistence | 13.3 percentage of participants |
Comparison: Eradication: CI was calculated using the Wilson score method, with continuity correction. Microbiological response (rates of eradication) by using a 2-sided 70% CI for the true difference in efficacy (tigecycline regimen minus imipenem/cilastatin regimen) was calculated. Statistical testing was done at 15% alpha.70% CI: [-39.6, 4.2]
Comparison: Eradication: CI was calculated using the Wilson score method, with continuity correction. Microbiological response (rates of eradication) by using a 2-sided 70% CI for the true difference in efficacy (tigecycline regimen minus imipenem/cilastatin regimen) was calculated. Statistical testing was done at 15% alpha.70% CI: [-23.8, 20.9]
Secondary
Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit
Eradication=baseline isolate not present in repeat culture from the original infection site; Presumed Eradication=clinical response of cure precluded the availability of a specimen for culture; Persistence=baseline isolate present in repeat culture from the original infection site; Presumed Persistence=culture data not available for participants with a clinical response of failure; Indeterminate=unable to determine outcome for non-study drug/infection reasons; no baseline isolate; death in 2 days after 1st dose for any reason, or \>2 days but before TOC visit for non-pneumonia reason.
Time frame: Up to Day 24 to 35 (10 to 21 days after LDOT)
Population: Microbiologically Evaluable (ME) population:participants who met evaluability criteria for efficacy, had culture taken from infected site before dose 1 of study drug, had at least (\>=)1 pathogen, \>=1 pathogen was susceptible to tigecycline, imipenem/cilastatin regimen; 'n' = those participants who had specified pathogen for each group respectively.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tigecycline 75 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Streptococcus pneumonia: Eradication (n=1,1,0) | 100.0 percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | SA: Persistence (n=8,6,9) | 37.5 percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Haemophilus influenzae: Persistence (n=0,1,1) | NA percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Streptococcus mitis: Eradication (n=1,0,0) | 100.0 percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Staphylococcus aureus (SA): Eradication (n=8,6,9) | 62.5 percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Klebsiella oxytoca: Eradication (n=1,0,0) | 100.0 percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Streptococcus anginosus: Eradication (n=1,0,0) | 100.0 percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Serratia marcescens: Eradication (n=0,2,0) | NA percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Klebsiella pneumoniae: Eradication (n=2,2,5) | 50.0 percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Enterobacter cloacae: Persistence (n=0,0,2) | NA percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Klebsiella pneumoniae: Persistence (n=2,2,5) | 50.0 percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Acinetobacter calcoaceticus: Persistence (n=3,2,3) | 33.3 percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Methicillin-suseptible SA: Persistence (n=4,4,5) | 25.0 percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Escherichia coli: Eradication (n=1,1,2) | 0 percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Acinetobacter calcoaceticus: Eradication (n=3,2,3) | 66.7 percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Methicillin-suseptible SA: Eradication (n=4,4,5) | 75.0 percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Escherichia coli: Persistence (n=1,1,2) | 100.0 percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Streptococcus oralis: Eradication (n=0,0,1) | NA percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | MRSA:Persistence (n=4,2,4) | 50.0 percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Haemophilus: Eradication (n=1,0,0) | 100.0 percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Enterobacter cloacae: Eradication (n=0,0,2) | NA percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | MRSA:Eradication (n=4,2,4) | 50.0 percentage of participants |
| Tigecycline 75 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Haemophilus influenzae: Eradication (n=0,1,1) | NA percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Haemophilus influenzae: Persistence (n=0,1,1) | 0 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Acinetobacter calcoaceticus: Eradication (n=3,2,3) | 50.0 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Acinetobacter calcoaceticus: Persistence (n=3,2,3) | 50.0 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Enterobacter cloacae: Eradication (n=0,0,2) | NA percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Enterobacter cloacae: Persistence (n=0,0,2) | NA percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Escherichia coli: Eradication (n=1,1,2) | 0 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Escherichia coli: Persistence (n=1,1,2) | 100.0 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Haemophilus: Eradication (n=1,0,0) | NA percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Haemophilus influenzae: Eradication (n=0,1,1) | 100.0 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Klebsiella oxytoca: Eradication (n=1,0,0) | NA percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Klebsiella pneumoniae: Eradication (n=2,2,5) | 50.0 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Klebsiella pneumoniae: Persistence (n=2,2,5) | 50.0 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Serratia marcescens: Eradication (n=0,2,0) | 100.0 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Staphylococcus aureus (SA): Eradication (n=8,6,9) | 83.3 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | SA: Persistence (n=8,6,9) | 16.7 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | MRSA:Eradication (n=4,2,4) | 100.0 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | MRSA:Persistence (n=4,2,4) | 0 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Methicillin-suseptible SA: Eradication (n=4,4,5) | 75.0 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Methicillin-suseptible SA: Persistence (n=4,4,5) | 25.0 percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Streptococcus anginosus: Eradication (n=1,0,0) | NA percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Streptococcus mitis: Eradication (n=1,0,0) | NA percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Streptococcus oralis: Eradication (n=0,0,1) | NA percentage of participants |
| Tigecycline 100 mg | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Streptococcus pneumonia: Eradication (n=1,1,0) | 100.0 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Haemophilus: Eradication (n=1,0,0) | NA percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Acinetobacter calcoaceticus: Eradication (n=3,2,3) | 66.7 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | MRSA:Eradication (n=4,2,4) | 100.0 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Escherichia coli: Persistence (n=1,1,2) | 50.0 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Streptococcus mitis: Eradication (n=1,0,0) | NA percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | MRSA:Persistence (n=4,2,4) | 0 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Escherichia coli: Eradication (n=1,1,2) | 50.0 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Acinetobacter calcoaceticus: Persistence (n=3,2,3) | 33.3 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Methicillin-suseptible SA: Eradication (n=4,4,5) | 80.0 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Enterobacter cloacae: Persistence (n=0,0,2) | 50.0 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Streptococcus pneumonia: Eradication (n=1,1,0) | NA percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Klebsiella pneumoniae: Eradication (n=2,2,5) | 80.0 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Methicillin-suseptible SA: Persistence (n=4,4,5) | 20.0 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Klebsiella pneumoniae: Persistence (n=2,2,5) | 20.0 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Klebsiella oxytoca: Eradication (n=1,0,0) | NA percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Enterobacter cloacae: Eradication (n=0,0,2) | 50.0 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Serratia marcescens: Eradication (n=0,2,0) | NA percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Haemophilus influenzae: Persistence (n=0,1,1) | 100.0 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Streptococcus oralis: Eradication (n=0,0,1) | 100.0 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Staphylococcus aureus (SA): Eradication (n=8,6,9) | 88.9 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Haemophilus influenzae: Eradication (n=0,1,1) | 0 percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | Streptococcus anginosus: Eradication (n=1,0,0) | NA percentage of participants |
| Imipenem/Cilastatin 1 Gram | Percentage of Participants With Microbiological Response at the Pathogen Level Population at Test-of-Cure (TOC) Visit | SA: Persistence (n=8,6,9) | 11.1 percentage of participants |
Other Pre-specified
Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-12)] of Tigecycline
AUC (0-12) = Area under the serum concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-12). Area under the serum concentration-time curve was derived from the population pharmacokinetic (PK) analysis by using each participant's dose and the post-hoc individual estimated systemic CL, AUC (0-12) = Dose divided by CL.
Time frame: Day 3, 4 or 5
Population: CE population included those participants who met specified evaluability criteria for efficacy. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tigecycline 75 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-12)] of Tigecycline | 3.20 ng*hr/mL | Standard Deviation 1.28 |
| Tigecycline 100 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-12)] of Tigecycline | 5.04 ng*hr/mL | Standard Deviation 1.31 |
Other Pre-specified
Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-24)] of Tigecycline
AUC (0-24) = Area under the serum concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-24). Area under the serum concentration-time curve was derived from the population pharmacokinetic (PK) analysis by using each participant's dose and the post-hoc individual estimated systemic CL, AUC (0-12) = Dose divided by CL. Model-predicted AUC (0-24) was calculated by multiplying AUC (0-12) by 2.
Time frame: Day 3, 4 or 5
Population: CE population included those participants who met specified evaluability criteria for efficacy. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tigecycline 75 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-24)] of Tigecycline | 6.40 mg*hr/mL | Standard Deviation 2.55 |
| Tigecycline 100 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-24)] of Tigecycline | 10.07 mg*hr/mL | Standard Deviation 2.61 |
Other Pre-specified
Clearance (CL) of Tigecycline
Drug clearance (CL) is a quantitative measure of the rate at which a drug substance is removed from the blood. It is defined as the volume of serum from which drug can be completely removed per unit of time.
Time frame: Day 3, 4 or 5
Population: CE population included those participants who met specified evaluability criteria for efficacy. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Tigecycline 75 mg | Clearance (CL) of Tigecycline | 22.6 Liter/hr |
Other Pre-specified
Correlation of AUC (0-24) of Tigecycline With Nausea and Vomiting
AUC (0-24) = Area under the serum concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-24). Area under the serum concentration-time curve was derived from the population PK analysis by using each participant's dose and the post-hoc individual estimated systemic CL, AUC (0-12) = Dose divided by CL. Model-predicted AUC (0-24) was calculated by multiplying AUC (0-12) by 2.
Time frame: Baseline up to Day 29 to 35 (15 to 21 days after LDOT)
Population: CE population included those participants who met specified evaluability criteria for efficacy. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tigecycline 75 mg | Correlation of AUC (0-24) of Tigecycline With Nausea and Vomiting | Experienced nausea (n = 4) | 8.668 mg*hr/mL | Standard Deviation 4.401 |
| Tigecycline 75 mg | Correlation of AUC (0-24) of Tigecycline With Nausea and Vomiting | Did not experience nausea (n = 35) | 8.206 mg*hr/mL | Standard Deviation 3.102 |
| Tigecycline 75 mg | Correlation of AUC (0-24) of Tigecycline With Nausea and Vomiting | Experienced vomiting (n = 4) | 6.863 mg*hr/mL | Standard Deviation 3.065 |
| Tigecycline 75 mg | Correlation of AUC (0-24) of Tigecycline With Nausea and Vomiting | Did not experience vomiting (n = 35) | 8.412 mg*hr/mL | Standard Deviation 3.205 |
Comparison: Statistical analysis was carried out between categories, experienced nausea and did not experience nausea.p-value: 0.7895% CI: [0.754, 1.46]Regression, Logistic
Comparison: Statistical analysis was carried out between categories, experienced vomiting and did not experience vomiting.p-value: 0.35695% CI: [0.593, 1.21]Regression, Logistic
Other Pre-specified
Correlation of AUC(0-24) to Minimum Inhibitory Concentration (MIC) Ratio (AUC [0-24]/MIC) of Tigecycline With Clinical Outcome
Clinical response:Cure =Initial SSx improved;CXR improved/stable;no other antibiotic for pneumonia;no worsening/new SSx. Failure=Persistence/worsening SSx;no clinical improvement/initial improvement with worsening; other antibiotic;CXR progression;death \>study day 2 due to pneumonia. Indeterminate=unable to determine outcome for non-study drug/infection reason;death in 2 days after dose 1 for any reason or \>2 days but before TOC visit for non-pneumonia reason. MIC=lowest drug concentration with no visible growth of microorganism. AUC(0-24)/MIC:reported for cure and failure/indeterminate.
Time frame: Up to Day 24 to 35 (10 to 21 days after LDOT)
Population: CE population included those participants who met specified evaluability criteria for efficacy. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tigecycline 75 mg | Correlation of AUC(0-24) to Minimum Inhibitory Concentration (MIC) Ratio (AUC [0-24]/MIC) of Tigecycline With Clinical Outcome | Cure (n = 17) | 24.3 ratio | Standard Deviation 20.4 |
| Tigecycline 75 mg | Correlation of AUC(0-24) to Minimum Inhibitory Concentration (MIC) Ratio (AUC [0-24]/MIC) of Tigecycline With Clinical Outcome | Failure/indeterminate (n = 8) | 22.8 ratio | Standard Deviation 9.59 |
Comparison: Statistical analysis was carried out between categories, cure and failure/indeterminate.p-value: 0.83695% CI: [0.956, 1.06]Regression, Logistic
Other Pre-specified
Correlation of AUC(0-24) to Minimum Inhibitory Concentration (MIC) Ratio (AUC [0-24]/MIC) of Tigecycline With Microbiological Outcome
Microbiological response:Eradication=baseline isolate not present in repeat culture from original infection site;Presumed Eradication=clinical response of cure precluded availability of specimen for culture;Persistence=baseline isolate present in repeat culture from original infection site;Presumed Persistence=culture data not available for participants with clinical response of failure;Superinfection=culture from primary infection site had new pathogen not identified as baseline isolate, clinical response was failure. MIC=lowest drug concentration with no visible growth of microorganism.
Time frame: Up to Day 24 to 35 (10 to 21 days after LDOT)
Population: Data was not analyzed because correlation analysis could not be performed due to insufficient number of participants for whom data for both microbiological outcomes and tigecycline concentration was available.
Other Pre-specified
Duration of Intravenous Antibiotic Treatment, Hospital and Intensive Care Unit (ICU) Stay
Time frame: Baseline up to Day 44 (30 days after LDOT)
Population: mITT population included all randomized participants who received at least 1 dose of study medication. Here, 'n' signifies those participants who were evaluable for intravenous antibiotic treatment, hospital or ICU stay for each reporting group respectively.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Tigecycline 75 mg | Duration of Intravenous Antibiotic Treatment, Hospital and Intensive Care Unit (ICU) Stay | ICU stay (n = 25, 25, 29) | 8.00 days |
| Tigecycline 75 mg | Duration of Intravenous Antibiotic Treatment, Hospital and Intensive Care Unit (ICU) Stay | Hospital stay (n = 36, 35, 34) | 13.00 days |
| Tigecycline 75 mg | Duration of Intravenous Antibiotic Treatment, Hospital and Intensive Care Unit (ICU) Stay | Intravenous antibiotic treatment (n = 36, 35, 34) | 8.00 days |
| Tigecycline 100 mg | Duration of Intravenous Antibiotic Treatment, Hospital and Intensive Care Unit (ICU) Stay | Hospital stay (n = 36, 35, 34) | 13.00 days |
| Tigecycline 100 mg | Duration of Intravenous Antibiotic Treatment, Hospital and Intensive Care Unit (ICU) Stay | Intravenous antibiotic treatment (n = 36, 35, 34) | 9.00 days |
| Tigecycline 100 mg | Duration of Intravenous Antibiotic Treatment, Hospital and Intensive Care Unit (ICU) Stay | ICU stay (n = 25, 25, 29) | 9.00 days |
| Imipenem/Cilastatin 1 Gram | Duration of Intravenous Antibiotic Treatment, Hospital and Intensive Care Unit (ICU) Stay | Intravenous antibiotic treatment (n = 36, 35, 34) | 8.50 days |
| Imipenem/Cilastatin 1 Gram | Duration of Intravenous Antibiotic Treatment, Hospital and Intensive Care Unit (ICU) Stay | ICU stay (n = 25, 25, 29) | 10.00 days |
| Imipenem/Cilastatin 1 Gram | Duration of Intravenous Antibiotic Treatment, Hospital and Intensive Care Unit (ICU) Stay | Hospital stay (n = 36, 35, 34) | 15.50 days |
Comparison: Intravenous antibiotic treatment: One-way analysis of variance (ANOVA) with treatment as factor was used to calculate p-value.p-value: 0.245ANOVA
Comparison: Hospital stay: One-way ANOVA with treatment as factor was used to calculate p-value.p-value: 0.484ANOVA
Comparison: ICU stay: One-way ANOVA with treatment as factor was used to calculate p-value.p-value: 0.192ANOVA
Other Pre-specified
Maximum Observed Plasma Concentration of Procalcitonin (Cmaxpd) and Predicted Procalcitonin Plasma Concentration at 24 Hours (Cpd,24) and 48 Hours (Cpd,48)
Time frame: Baseline up to Day 6
Population: mITT population included all randomized participants who received at least 1 dose of study medication. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tigecycline 75 mg | Maximum Observed Plasma Concentration of Procalcitonin (Cmaxpd) and Predicted Procalcitonin Plasma Concentration at 24 Hours (Cpd,24) and 48 Hours (Cpd,48) | Cmax | 2.83 ng/mL | Standard Deviation 8.29 |
| Tigecycline 75 mg | Maximum Observed Plasma Concentration of Procalcitonin (Cmaxpd) and Predicted Procalcitonin Plasma Concentration at 24 Hours (Cpd,24) and 48 Hours (Cpd,48) | Cpd,24 | 1.86 ng/mL | Standard Deviation 4.54 |
| Tigecycline 75 mg | Maximum Observed Plasma Concentration of Procalcitonin (Cmaxpd) and Predicted Procalcitonin Plasma Concentration at 24 Hours (Cpd,24) and 48 Hours (Cpd,48) | Cpd,48 | 1.74 ng/mL | Standard Deviation 4.12 |
Other Pre-specified
Maximum Observed Serum Concentration (Cmax) of Tigecycline
Time frame: Day 3, 4 or 5
Population: CE population included those participants who met specified evaluability criteria for efficacy. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tigecycline 75 mg | Maximum Observed Serum Concentration (Cmax) of Tigecycline | 479 nanogram/milliliter (ng/mL) | Standard Deviation 327 |
| Tigecycline 100 mg | Maximum Observed Serum Concentration (Cmax) of Tigecycline | 1217 nanogram/milliliter (ng/mL) | Standard Deviation 1070 |
Other Pre-specified
Number of Participants Who Experienced Nausea or Vomiting
Time frame: Baseline up to Day 29 to Day 35 (15 to 21 days after LDOT)
Population: Modified intent-to-treat (mITT) population included all randomized participants who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tigecycline 75 mg | Number of Participants Who Experienced Nausea or Vomiting | Nausea | 1 participants |
| Tigecycline 75 mg | Number of Participants Who Experienced Nausea or Vomiting | Vomiting | 3 participants |
| Tigecycline 100 mg | Number of Participants Who Experienced Nausea or Vomiting | Nausea | 3 participants |
| Tigecycline 100 mg | Number of Participants Who Experienced Nausea or Vomiting | Vomiting | 1 participants |
| Imipenem/Cilastatin 1 Gram | Number of Participants Who Experienced Nausea or Vomiting | Nausea | 1 participants |
| Imipenem/Cilastatin 1 Gram | Number of Participants Who Experienced Nausea or Vomiting | Vomiting | 4 participants |
Comparison: Nausea: p-value was calculated using 2-tail Fischer's exact test.p-value: 0.527Fisher Exact
Comparison: Vomiting: p-value was calculated using 2-tail Fischer's exact test.p-value: 0.39Fisher Exact
Other Pre-specified
Number of Participants With Abnormal Electrocardiogram (ECG)
Potentially clinically significant ECG data: Non-first values greater than 240 millisecond (msec) with increase of greater than or equal to 10 percent (%) from baseline for PR interval; Non-first values greater than or equal to 120 msec for QRS interval; Non-first values greater than 460 msec with increase of greater than or equal to 5% from baseline for corrected QT (QTc) interval; Non-first values greater than 460 msec with increase of greater than or equal to 5% from baseline for QTc using Framingham formula (QTc F).
Time frame: Baseline up to Day 14 or LDOT
Population: mITT population included all randomized participants who received at least 1 dose of study medication. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tigecycline 75 mg | Number of Participants With Abnormal Electrocardiogram (ECG) | 14 participants |
| Tigecycline 100 mg | Number of Participants With Abnormal Electrocardiogram (ECG) | 14 participants |
| Imipenem/Cilastatin 1 Gram | Number of Participants With Abnormal Electrocardiogram (ECG) | 14 participants |
Comparison: p-value was calculated using 2-tail Fischer's exact test.p-value: 1Fisher Exact
Other Pre-specified
Number of Participants With Abnormal Laboratory Examinations
Participants were evaluated for following laboratory parameters: albumin, alkaline phosphatase, amylase, urea (blood urea nitrogen \[BUN\]), total bilirubin, calcium, magnesium, carbon dioxide, international normalized ratio (INR), chloride, creatinine, glucose, lipase, potassium, phosphorus, aspartate aminotransferase (AST), alanine aminotransferase (ALT), sodium, total protein, hemoglobin, hematocrit, white blood cells, eosinophils, neutrophils, lymphocytes, platelets, prothrombin time, prothrombin activity and partial thromboplastin time.
Time frame: Baseline up to Day 24 to Day 35 (10 to 21 days after LDOT)
Population: mITT population included all randomized participants who received at least 1 dose of study medication. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tigecycline 75 mg | Number of Participants With Abnormal Laboratory Examinations | 34 participants |
| Tigecycline 100 mg | Number of Participants With Abnormal Laboratory Examinations | 31 participants |
| Imipenem/Cilastatin 1 Gram | Number of Participants With Abnormal Laboratory Examinations | 31 participants |
Comparison: p-value was calculated using 2-tail Fischer's exact test.p-value: 1Fisher Exact
Other Pre-specified
Time to Reach Half of the Maximum Observed Plasma Concentration and Time to Normalization of Concentrations (Tnorm) of Procalcitonin
Time frame: Baseline up to Day 6
Population: Data was not analyzed because there was no apparent change in procalcitonin concentration over time.
Other Pre-specified
Time to Reach Maximum Observed Serum Concentration (Tmax) of Tigecycline
Time frame: Day 3, 4 or 5
Population: CE population included those participants who met specified evaluability criteria for efficacy. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tigecycline 75 mg | Time to Reach Maximum Observed Serum Concentration (Tmax) of Tigecycline | 0.5 hrs |
| Tigecycline 100 mg | Time to Reach Maximum Observed Serum Concentration (Tmax) of Tigecycline | 0.5 hrs |