| 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 | 13.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065153 |
| E.1.2 | Term | Ventilator associated pneumonia |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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-cilastatin 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-cilastatin with respect to the clinical cure rate at the EOT in ME subjects.
·superiority of doripenem relative to imipenem-cilastatin with regard to clinical cure rate at EOT in ME subjects from whom P. aeruginosa are isolated from LRT specimen at baseline, or at least one of the following specific serious gram negative organisms is isolated at baseline: any Enterobacteriaceae, P. aeruginosa, and Acinetobacter spp.
·that for P. aeruginosa, emergent resistance is lower in doripenem subjects compared with imipenem-cilestatin treated subjects.
·Compare other clinical/microbiologic responses between the 2 groups.
·Explore correlation of diagnostic and early markers of efficacy with clinical outcome & exposure-response relationships for doripenem microbiologic and clinical outcomes using PK/PD modeling.
·Evaluate medical resource utilization, safety of 1-g 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. 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): defined as a tympanic temperature > 38.5°C or a rectal or core body temperature > 39,0°C
–Hypothermia, defined as a rectal/core body temperature of < 35,0°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.
·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 and tracheal aspirate may be performed up to 36 hours before the first dose of study drug. Note: subjects maybe enrolled before the results of the culture are known (refer to section 4.5 Treatment Continuation Criteria)
·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 >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 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 (e.g., vulnerable populations like prisoners or the mentally impaired)
·Have received an experimental medication or used an experimental therapeutic 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 | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| 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) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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
| No |
| 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
|
| The study is considered completed with the last visit of the last subject undergoing the study |
|
| 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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