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

Conditions: Ventilator-Associated Pneumonia
MedDRA version: 9.1Level: LLTClassification code 10065153Term: <Manually entered code. Term in E.1.1>

Registration Number: EUCTR2007-004646-33-HU

Lead Sponsor: Janssen-Cilag International NV

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 524

Inclusion Criteria

·Men or women 18 years of age or older
·Have new or progressive radiographic infiltrates consistent with VAP that is not related to cardiac or other disease processes. Chest X-rays obtained within 36 hours before the first dose of study drug are acceptable for the screening examination. A CT scan may be used in place of a chest X-ray if the chest X-ray is not sufficiently interpretable.
·Have at least 1 of the following:
–Fever (in the absence of antipyretics): a rectal temperature greater than 39°C OR an increase in core temperature of greater than 1°C above normal
–Hypothermia, defined as a rectal/core body temperature of less than 35°C
–Leukocytosis (WBC count >10x109/L or >15% immature neutrophils, regardless of the total peripheral white cell count; or leukopenia with total WBC count less than 4x109/L
·Have been mechanically ventilated for >48 hours and on mechanical ventilation at the time of randomization. (Subjects who failed prior antibiotic treatment for the current VAP may be considered if: a) they received the prior antibiotic for >48 hours; b) they have been ventilated for at least 72 hours; c) they have persistent signs and symptoms of VAP; d) they have a repeat BAL performed before first dose of study drug. Subjects enrolled as failures of prior therapy must meet t, both of the following criteria to continue on study drug:
·The isolate(s) from the quantitative culture of the BAL must be >10*4 CFU/mL
·At least 1 pathogen that grows from the quantitative culture of the BAL
specimen at =10*4CFU/mL must be susceptible to imipenem-cilastatin and
resistant to the prior failed antibiotic therapy(ies) administered for the
current episode of VAP.
At least 1 qualifying pathogen (i.e. =10*4 CFU/mL and imipenem MIC
=8µg/mL) from the quantitative culture of the baseline BAL is required for a
subject to continue on study drug irrespective of whether he/she was enrolled
as a prior failure or not.
·Have been hospitalized for a minimum of 5 consecutive days before signing the informed consent form (residents of chronic health care facilities do not have to fulfill this 5-day requirement. Residency in a chronic health care facility is defined as having spent any 5 days in the facility in the past 90 days)
·Have a baseline CPIS of >6
·Have an APACHE II Score of >8 and <35
·Have a bronchoscopic BAL/mini-BAL plus tracheal aspirate performed at baseline. (A bronchoscopic BAL/mini-BAL may be performed up to 36 hours before the first dose of study drug.
·Women must be postmenopausal (for at least 1 year), surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy), abstinent (at the discretion of the investigator), or, if sexually active, be practicing an effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double-barrier method [e.g., condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel], male partner sterilization) before entry and must agree to continue to use the same method of contraception throughout the study; have a negative serum beta-human chorionic gonadotropin (b hCG] or urine pregnancy test at screening (depending on local regulations)
·Willing to adhere to the prohibitions and restrictions specified in this protocol
·Subjects must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study

Exclusion Criteria

·Received >24 hours of prior antibiotics (before the first dose of study drug) for the current episode of VAP. Note: Subjects will not be excluded if all of the following criteria are met:
–this prior antibiotic therapy has been given for >48 hours
–the subject is failing on the prior antibiotic as shown by clinical assessments
–the failing antibiotic has not been changed in the 24-hour period between signing the informed consent form and the administration of the first dose of study drug.
·Known presence at baseline of only MRS or Stenotrophomonas infection from the quantitative culture of the baseline BAL
·Have acute respiratory distress syndrome (ARDS defined by diffuse radiographic infiltrates and PaO2 to FiO2 ratio <200)
·Has any of the following conditions that interfere with the assessment or interpretation of the diagnosis or response to therapy:
–Chest trauma with severe lung contusion or flail chest. (A CT scan is recommended in subjects with a history of traumatic chest injury when pneumonia cannot be clearly distinguished from severe lung contusion on the chest X-ray).
–Pleural effusion(s) requiring drainage or empyema
–Active lung cancer-primary or secondary within the last 2 years
–Chronic bronchitis with an exacerbation within the last 30 days
–Bronchiectasis
–Lung abscess(s)
–Anatomical bronchial obstruction
–Respiratory tuberculosis on treatment
–Suspected atypical pneumonia
–Chemical pneumonitis (e.g., aspiration of gastric contents, inhalation injury)
–Cystic fibrosis
–Congestive Heart Failure as noted by the New York Heart Association Classification IV
–Active seizure disorder within the last 2 years or brain injury such that imipenem-cilastatin would not be administered to the subject in usual practice
–Severe full thickness burns to greater than 15% of the body
–Cirrhotic liver disease.
·Severe impairment of renal function defined as a CLCR <10 mL/min requiring either continuous renal replacement therapy (CRRT), peritoneal dialysis, hemodialysis, hemofiltration, OR oliguria, defined as a urine output <20 mL of urine/hour over 24 hours
·History of active immunosuppression, including: acquired immunodeficiency syndrome (AIDS), organ (including bone marrow) transplant recipients who have received immunosuppressive therapy within the past 60 days, active hematologic malignancy, OR chronic use of high-dose corticosteroids, defined as >40 mg/d of systemic prednisone (or equivalent per day) for more than2 weeks during the current admission. (Subjects with a history of non-chronic rapid tapering of steroid therapy will be considered for enrollment.)
·History of any rapidly progressing disease or immediately life-threatening illness (defined as imminent death within 24 hours) that in the opinion of the investigator makes the subject very unlikely to survive the 5-to -6 week study period
·History of hypersensitivity reactions to carbapenems, penicillins, other b lactam antibiotics, or b lactamase inhibitors (subjects with a history of mild skin rash, documented not to have been caused by previous b lactam use are permitted to enroll)
·Have previously received doripenem, meropenem, or imipenem-cilastatin in the last week
·Have any other known or suspected condition that may jeopardize adherence to protocol requirements or interpretation of adverse events
·Suspicion of pulmonary edema as a cause of the acute illness
·Hematocrit of less than 22% or hemoglobin of less than 7 g/dL
·Neutropenia with absolute neutrophil count