| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Ventilator-Associated Pneumonia |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065153 |
| E.1.2 | Term | <Manually entered code. Term in E.1.1> |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective is to demonstrate the noninferiority of a 7-day course
of doripenem to a 10-day course of imipenem with respect to the clinical
cure rate at the EOT visit in clinically evaluable subjects with VAP. |
|
| E.2.2 | Secondary objectives of the trial |
Demonstrate:
•noninferiority of doripenem to imipenem with respect to the clinical cure rate at the EOT visit in ME subjects
•superiority of doripenem relative to imipenem with regard to clinical cure rate at EOT in ME subjects from whom:
-P. aeruginosa are isolated from lower respiratory tract (LRT) specimen at
baseline
-at least one of the following specific serious gram-negative organisms is isolated at baseline:Enterobacteriaceae, P. aeruginosa, and Acinetobacter spp
•that baseline and emergent resistance at an MIC level of
≥8 μg/mL to study drug received is lower in P. aeruginosa to doripenem
than imipenem
•Explore:early markers of efficacy;relationship between the imipenem concentration over MIC with their clinical outcome;exposure-response relationships for doripenem microbiologic and their clinical outcomes using PK/PD modeling;medical resource utilization
•Evaluate the safety of 1 gram dose of doripenem |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 taken within 12 hours before screening. A CT scan may be required to evaluate parenchymal disease 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
–Hypothermia, defined as a rectal/core body temperature of less than 35°C
–Leukocytosis (WBC count ³10x109/L or ³15% immature neutrophils, regardless of the total peripheral white cell count; or leukopenia with total WBC count less than 4x109/L
·Have developed VAP and have been on mechanical ventilation for ³48 hours and on mechanical ventilation at the time of randomization. They may have been treated for VAP with antibiotics and have clinical deterioration associated with a probable new pathogen if they have been on a ventilator for >72 hours
·Have been hospitalized or been in a chronic care facility for a total of 5 or more days within the last 90 days
·Have a baseline CPIS of ³6
·Have an APACHE II Score of >8 and <35
·Have microbiologically suitable LRT sample available (BAL/mini BAL)within 12 hours
before screening
·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 and are willing to participate in the study. Consent may be given for unconscious/incapacitated subjects by a legally authorized representative, according to local regulatory and ethical practice using a subject information sheet and informed consent form approved by the responsible Ethics Committee. When a subject is no longer incapacitated, informed consent will be obtained from the subject at that time.
|
|
| E.4 | Principal exclusion criteria |
·Received antibiotics for this episode of VAP for >24 hours before randomization. Subjects will not be excluded if their prior antibiotic therapy has been given for more than 48 hours, are failing therapy by clinical assessments and the antibiotic has not been changed within the 24-hour period before the first dose of i.v. study drug is given.
·Known presence at baseline of only MRSA or Stenotrophomonas infection
·Acute respiratory distress syndrome (ARDS defined by diffuse radiographic infiltrates and PaO2 to fraction of inspired oxygen [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 lung contusion or flail chest. A CT scan may be required to
distinguish pneumonia from severe lung contusion on the chest X-ray
–Pleural effusion(s) requiring drainage or empyema
–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 year or brain injury such that imipenem would not be administered to the subject in usual practice
–Severe burns to greater than 15% of the body
–Pre-morbid evidence of stigmata of severe and chronic liver disease indicating cirrhosis in the opinion of the investigator
·History of severe impairment of renal function (i.e., a calculated creatinine clearance (CLCR) of less than 10 mL/minute) requiring continuous renal replacement therapy (CRRT), peritoneal dialysis, hemodialysis, hemofiltration, or oliguria (less than 20 mL urine output per hour over 24 hours)
·History of immunocompromising illness, acquired immunodeficiency syndrome (AIDS), or human immunodeficiency virus (HIV) with a CD4 count less than 200 cells/mL within the past 6 months, antiretroviral therapy within the last 60 days, organ (including bone marrow) transplant recipients, hematologic malignancy, and use of immunosuppressive therapy within 60 days, or use of high-dose corticosteroids (e.g greater than 40 mg of systemic prednisone or equivalent per day) in the last 2 weeks. History of rapid tapering steroids completed over 2 weeks before enrollment will be allowed.
·History of any rapidly progressing disease or immediately life-threatening illness (including acute hepatic failure and septic shock. Shock is defined as a systolic blood pressure less than 90 mmHg for greater than 2 hours, despite adequate fluid resuscitation, with evidence of hypoperfusion or need for sympathomimetic agents.)
·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
·Have previously received meropenem or imipenem 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 of less than 1,000 cell/mm3. Subjects with neutrophil counts as low as 500 cells/mm3 are permitted if the reduction is due to the acute infection process.
·Platelet count of less than 50,000 cells/mm3
·Current use of probenecid or valproic acid
·Are hospitalized involuntarily
·Have received an experimental medication or used an experimental medical device within 30 days.Subjects in clinical studies for approved products will not be excluded.
·Is breast-feeding
·Employees of the investigator or study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center, as well as family members of the employees or the investigator.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy endpoint
·Clinical cure rate at the EOT visit in clinically evaluable subjects.
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Microbiologic Efficacy Assessments |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Information not present in EudraCT |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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