Study Evaluating Safety and Efficacy of Tigecycline Versus Imipenem/Cilastatin Subjects With Hospital-Acquired Pneumonia

A Phase 2, Multicenter, Randomized, Double-Blind, Comparative Study Of The Safety And Efficacy of 2 Doses Of Tigecycline Versus Imipenem/Cilastatin For The Treatment Of Subjects With Hospital-Acquired Pneumonia

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.

Study Overview

• Status: Terminated
• Conditions: Pneumonia, Bacterial
• Intervention / Treatment: Drug: tigecycline; Drug: tigecycline; Drug: imipenem/cilastatin

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.

• Study Type: Interventional
• Enrollment (Actual): 108
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Provincia de Buenos Aires, Argentina
    • Pfizer Investigational Site
  • Buenos Aires
    • La Plata, Buenos Aires, Argentina, 1900
      • Pfizer Investigational Site
  • Mendoza
    • Godoy Cruz, Mendoza, Argentina
      • Pfizer Investigational Site
  • Provincia de Buenos Aires
    • La Plata, Provincia de Buenos Aires, Argentina, B1900AVG
      • Pfizer Investigational Site
• Australia
  • Victoria, Australia, 3128
    • Pfizer Investigational Site
  • Queensland
    • Nambour, Queensland, Australia, 4560
      • Pfizer Investigational Site
• Brazil
  • MG
    • Belo Horizonte, MG, Brazil, 30150-221
      • Pfizer Investigational Site
  • RS
    • Porto Alegre, RS, Brazil, 90610-000
      • Pfizer Investigational Site
  • SP
    • Sao Jose do Rio Preto, SP, Brazil, 15090-000
      • Pfizer Investigational Site
• Canada
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 5H6
      • Pfizer Investigational Site
    • Trois-Rivieres, Quebec, Canada, G8Z 3R9
      • Pfizer Investigational Site
• Chile
  • Santiago, Chile
    • Pfizer Investigational Site
• Colombia
  • Bogota, Colombia
    • Pfizer Investigational Site
  • Antioquia
    • Medellin, Antioquia, Colombia
      • Pfizer Investigational Site
• Croatia
  • Zagreb, Croatia, 10000
    • Pfizer Investigational Site
• France
  • Argenteuil, France, 95100
    • Pfizer Investigational Site
• Hungary
  • Debrecen, Hungary, 4043
    • Pfizer Investigational Site
  • Nyiregyhaza, Hungary, 4400
    • Pfizer Investigational Site
  • Szekesfehervar, Hungary, 8000
    • Pfizer Investigational Site
  • Vac, Hungary, 2600
    • Pfizer Investigational Site
• Korea, Republic of
  • Korea
    • Seoul, Korea, Korea, Republic of, 135 710
      • Pfizer Investigational Site
    • Seoul, Korea, Korea, Republic of, 136-705
      • Pfizer Investigational Site
    • Seoul, Korea, Korea, Republic of, 138-736
      • Pfizer Investigational Site
    • Seoul, Korea, Korea, Republic of, 152-703
      • Pfizer Investigational Site
• Latvia
  • Daugavpils, Latvia, LV-5417
    • Pfizer Investigational Site
  • Riga, Latvia, 1001
    • Pfizer Investigational Site
  • Riga, Latvia, LV-1001
    • Pfizer Investigational Site
• Russian Federation
  • Moscow, Russian Federation, 119620
    • Pfizer Investigational Site
  • Moscow, Russian Federation, 121359
    • Pfizer Investigational Site
  • Novosibirsk, Russian Federation, 630051
    • Pfizer Investigational Site
  • St Petersburg, Russian Federation, 194354
    • Pfizer Investigational Site
  • St Petersburg, Russian Federation, 196247
    • Pfizer Investigational Site
  • Vsevolozhsk, Russian Federation, 188640
    • Pfizer Investigational Site
• Taiwan
  • Tainan, Taiwan, 407
    • Pfizer Investigational Site
  • Tainan, Taiwan
    • Pfizer Investigational Site
  • Taipei, Taiwan, 100
    • Pfizer Investigational Site
  • Taipei TOC, Taiwan, 100
    • Pfizer Investigational Site
• United States
  • Kentucky
    • Louisville, Kentucky, United States
      • Pfizer Investigational Site
  • Nebraska
    • Omaha, Nebraska, United States, 68131
      • Pfizer Investigational Site
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • Pfizer Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A	Drug: tigecycline; 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]).; Drug: tigecycline; An initial intravenous (IV) loading dose of 200 mg of tigecycline, followed by 100 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]).
Experimental: B	Drug: tigecycline; 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]).; Drug: tigecycline; An initial intravenous (IV) loading dose of 200 mg of tigecycline, followed by 100 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]).
Active Comparator: C	Drug: imipenem/cilastatin; 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]).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to Day 24 to 35 (10 to 21 days after last day of therapy [LDOT])

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to Day 24 to 35 (10 to 21 days after LDOT)
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.	Up to Day 24 to 35 (10 to 21 days after LDOT)
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.	Up to Day 24 to 35 (10 to 21 days after LDOT)
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.	Up to Day 24 to 35 (10 to 21 days after LDOT)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Experienced Nausea or Vomiting		Baseline up to Day 29 to Day 35 (15 to 21 days after LDOT)
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.	Baseline up to Day 24 to Day 35 (10 to 21 days after LDOT)
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).	Baseline up to Day 14 or LDOT
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
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.	Day 3, 4 or 5
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.	Day 3, 4 or 5
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.	Day 3, 4 or 5
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.	Baseline up to Day 29 to 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 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.	Up to Day 24 to 35 (10 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	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.	Up to Day 24 to 35 (10 to 21 days after LDOT)
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)

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• Ramirez J, Dartois N, Gandjini H, Yan JL, Korth-Bradley J, McGovern PC. Randomized phase 2 trial to evaluate the clinical efficacy of two high-dosage tigecycline regimens versus imipenem-cilastatin for treatment of hospital-acquired pneumonia. Antimicrob Agents Chemother. 2013 Apr;57(4):1756-62. doi: 10.1128/AAC.01232-12. Epub 2013 Jan 28.

Study record dates

Study Major Dates

• Study Start: December 1, 2008
• Primary Completion (Actual): June 1, 2011
• Study Completion (Actual): June 1, 2011

Study Registration Dates

• First Submitted: June 26, 2008
• First Submitted That Met QC Criteria: June 27, 2008
• First Posted (Estimate): June 30, 2008

Study Record Updates

• Last Update Posted (Estimate): July 10, 2012
• Last Update Submitted That Met QC Criteria: June 5, 2012
• Last Verified: June 1, 2012

More Information

Terms related to this study

• Keywords: Hospital-acquired pneumonia; Ventilator-associated pneumonia
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Disease Attributes; Bacterial Infections; Bacterial Infections and Mycoses; Cross Infection; Iatrogenic Disease; Healthcare-Associated Pneumonia; Pneumonia; Pneumonia, Bacterial; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Protease Inhibitors; Anti-Bacterial Agents; Protein Synthesis Inhibitors; Imipenem; Cilastatin; Tigecycline
• Other Study ID Numbers: 3074K6-2000; B1811004

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No