To Compare Safety and Efficacy of Doripenem Versus Imipenem-Cilastatin in Patients With Ventilator-Associated Pneumonia

This study has been terminated.
(Observed lower cure rates and higher mortality rates in one of the treatment groups.)
Sponsor:
Information provided by (Responsible Party):
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
ClinicalTrials.gov Identifier:
NCT00589693
First received: December 21, 2007
Last updated: December 24, 2012
Last verified: December 2012

December 21, 2007
December 24, 2012
April 2008
June 2011   (final data collection date for primary outcome measure)
Clinical Cure Rate at the End-of-treatment (EOT) Visit [ Time Frame: End-of-treatment (Day 10 or Day 11) ] [ Designated as safety issue: Yes ]
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.
The primary endpoint of this study is to show that doripenem is as effective as imipenem with respect to clinical cure rate in clinically-evaluable patients [ Time Frame: End of Treatment (Day 10), Clinical Cure based on Clinical Evaluability. ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00589693 on ClinicalTrials.gov Archive Site
  • Clinical Cure Rate at the End-of-treatment (EOT) Visit in Patients From Whom a Qualifying P. Aeruginosa Was Isolated at Baseline [ Time Frame: End-of-treatment (Day 10 or Day 11) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: End-of-treatment (Day 10 or Day 11) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Up to 6 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to 28 days ] [ Designated as safety issue: Yes ]
    Number of deaths which occured up to 28 days of the study period due to all causes
The secondary endpoint of this study is to show that doripenem is as effective as imipenem with respect to clinical cure rate microbiologically-evaluable patients. [ Time Frame: End of Treatment (Day 10): Clinical Cure based on Microbiogical Evaluability and Clinical Cure rate in those that have relatively resistant bacteria in their lung such as Pseudomonas aeruginosa. Bacterial resistance at baseline or on study drug. ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
To Compare Safety and Efficacy of Doripenem Versus Imipenem-Cilastatin in Patients With Ventilator-Associated Pneumonia
A Prospective, Randomized, Double-Blind, Double-Dummy, Multicenter Study to Assess the Safety and Efficacy of Doripenem Compared With Imipenem-Cilastatin in the Treatment of Subjects With Ventilator-Associated Pneumonia

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.

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.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Ventilator-Associated Pneumonia
  • Drug: Doripenem
    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.
    Other Name: Doripenem
  • Drug: Imipenem-Cilastatin
    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.
    Other Name: Imipenem-Cilastatin
  • Drug: Placebo
    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.
    Other Name: Placebo
  • Experimental: Doripenem
    Doripenem from Days 1 to 7 and imipenem-cilastatin placebo from Days 1 to 10
    Interventions:
    • Drug: Doripenem
    • Drug: Placebo
  • Active Comparator: Imipenem-Cilastatin
    Imipenem-Cilastatin Days 1 to 10 and doripenem placebo from Days 1 to 7
    Interventions:
    • Drug: Imipenem-Cilastatin
    • Drug: Placebo
Kollef MH, Chastre J, Clavel M, Restrepo MI, Michiels B, Kaniga K, Cirillo I, Kimko H, Redman R. A randomized trial of 7-day doripenem versus 10-day imipenem-cilastatin for ventilator-associated pneumonia. Crit Care. 2012 Nov 13;16(6):R218. doi: 10.1186/cc11862.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Terminated
274
June 2011
June 2011   (final data collection date for primary outcome measure)

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
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
Germany,   United States,   Argentina,   Australia,   Belgium,   Brazil,   Canada,   France,   Ukraine,   Guatemala,   Hungary,   India,   Israel,   Mexico,   Philippines,   Portugal,   Romania,   Russian Federation,   Spain,   Thailand,   Turkey
 
NCT00589693
CR014038, DORINOS3008, 2007-004646-33
Yes
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Not Provided
Study Director: Johnson & Johnson Pharmaceutical Research & Development, L.L. C. Clinical Trial Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
December 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP