| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
ventilator-associated pneumonia
complicated intra-abdominal infections |
|
| 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 | 10056570 |
| E.1.2 | Term | Intra-abdominal infection |
|
| 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 | Ventilator associated pneumonia |
|
| 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 assess the safety and tolerability of doripenem 1 g infused over 4 hours at 8-hour intervals. |
|
| E.2.2 | Secondary objectives of the trial |
·To compare the clinical cure rate of doripenem compared with imipenem after 7 days of study drug therapy and at the TOC visit in subjects with VAP
·To compare the clinical response of doripenem compared with imipenem in subjects with cIAI at the TOC visit
·To determine the PK profile of doripenem 1 g infused over 4 hours in subjects with VAP and cIAI
·To compare mortality rates in subjects treated with doripenem compared with imipenem. "Thirty-day all-cause mortality" will be assessed for all subjects.
·To determine the per-pathogen microbiologic and clinical response of subjects with VAP and cIAI by the MIC of the baseline pathogen
·To explore the exposure-response relationships for microbiologic and clinical outcomes using PK/PD modeling
·To collect medical resource utilization data to be used in the possible development of an economic model that will be analyzed and reported separately
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
· Men or women 18 years of age or older
· Women must be postmenopausal , surgically sterile, abstinent, or, if sexually active, be practicing an effective method of birth control before entry and throughout the study; have a negative serum beta-human chorionic gonadotropin or urine pregnancy test at screening (depending on local regulations).
· 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 their next of kin, guardian, or legal representative, according to local regulatory and ethical practice using a subject information sheet and informed consent form approved by the responsible Ethics Committee.
Subjects with VAP must also:
· Have been hospitalized (or been in a chronic care facility) for greater than or equal to 5 days.
· Have received mechanical ventilation for greater than or equal to 48 hours
· Have a Clinical Pulmonary Infection Score (CPIS) of greater than or equal to 5
· Have new or progressive radiographic infiltrates (not related to another disease process).
· Have at least one of the following:
– Fever (in the absence of antipyretics), increase in core temperature of greater than 1°C OR an oral temperature greater than 38°C, a tympanic temperature of 38.5°C, a rectal/core temperature greater than 39°C, a temporal temperature greater than 38.5°C
– Hypothermia, defined as a rectal/core body temperature of less than 35°C (axillary temperature measurements are not acceptable)
– Leukocytosis (a total white blood cell [WBC] count greater than or equal to 10 x 109/L or greater than or equal to 15% immature neutrophils [bands], regardless of total peripheral white count; or leukopenia with total WBC less than 4.5 x 109/L)
· Have microbiologic samples (quantitative BAL and tracheal aspirate) suitable for culture
· Have an Acute Physiology and Chronic Health Evaluation (APACHE) II score of 8 to 29, inclusive
Subjects with cIAI must also:
· Have clinical evidence of intra-abdominal infection
– If enrolled preoperatively, must have evidence of a systemic infection, with at least 1 of the following:
· Fever (oral temperature greater than 38°C) or hypothermia (core body temperature less than 35°C)
· Elevated WBC count (greater than 10,500 cells/mm3)
· Decrease in blood pressure relative to baseline of greater than 15 mmHg systolic (however systolic blood pressure should not be less than 90 mmHg and subject should not have required continued pressor support)
· Increased pulse (greater than 100 beats per minute [bpm]) and respiratory rates (greater than 20 bpm)
· Hypoxemia (partial pressure of oxygen [PaO2] less than 60 mmHg or pulse oximetry less than 90% on room air)
– In addition, if preoperative, must have at least one of the following physical signs consistent with IAI:
· Abdominal pain or tenderness
· Localized or diffuse abdominal wall rigidity
· Mass
· Ileus
· Have a requirement for surgical intervention (e.g., laparotomy, laparoscopic surgery, or percutaneous draining of an abscess) within 24 hours of study entry
· Require antibacterial therapy, in addition to surgical intervention
· Have one of the following eligible diagnoses:
– Cholecystitis (including gangrenous cholecystitis) with rupture, perforation, or progression of the infection beyond the gallbladder wall
– Diverticular disease with perforation or abscess
– Appendiceal perforation only if associated with generalized peritonitis
– Acute gastric and duodenal perforations, only if operated upon more than 24 hours after perforation occurred
– Traumatic perforation of the intestines, only if operated upon more than 12 hours after perforation occurred
– Peritonitis; due to perforated viscus, that is postoperative or due to other focus of infection (but not spontaneous bacterial peritonitis associated with cirrhosis and chronic ascites). Subjects with inflammatory bowel disease or ischemic bowel disease are eligible, provided there is bowel perforation.
– Intra-abdominal abscess (including liver and spleen) not due to appendiceal perforation
A subject enrolled as a failure of a prior antibacterial treatment must:
· Have a positive culture (from an intra-abdominal site)
· Require surgical intervention
Such subjects can be enrolled before the results of the culture are known. However, if the culture is negative, the subject must be removed from study therapy, but remain in the safety population.
|
|
| E.4 | Principal exclusion criteria |
•· History of subjects with acute hepatic failure or acute decompensation of chronic hepatic failure
· History of severe impairment of renal function requiring peritoneal dialysis, hemodialysis, hemofiltration, or oliguria
· History of immunocompromising illness, acquired immunodeficiency syndrome, or human immunodeficiency virus with a CD4 count less than 200 cells/mL within the past 6 months, organ (including bone marrow) transplant recipients, hematologic malignancy, and use of immunosuppressive therapy at screening, including use of high-dose corticosteroids (e.g., greater than 40 mg prednisone or equivalent per day for greater than 2 weeks)
· History of any rapidly progressing disease or immediately life-threatening illness (including acute hepatic failure and septic shock. Sustained 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 imipenem or meropenem in the past week
· Have any other known or suspected condition that may jeopardize adherence to protocol requirements
· Active seizure disorder or brain injury such that imipenem would not be administered to the subject in usual practice
· Hematocrit of less than 25% or hemoglobin of less that 8 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
· Is unlikely to survive the 6- to 8-week study period
· Current use of probenecid or valproic acid
· Have received an experimental drug or used an experimental medical device within 1 month before the planned start of treatment.
· Is breast-feeding
·
Additional exclusion criteria for subjects with VAP:
· Subjects with either:
– Known bronchial obstruction or a history of postobstructive pneumonia
– Primary lung cancer or another metastatic malignancy to the lungs
– Cystic fibrosis
– Lung abscess
– Empyema
– Acute respiratory distress syndrome (diffuse radiographic infiltrates and PaO2 to fraction of inspired oxygen [FiO2] ratio less than 200)
– Active pulmonary tuberculosis
– Subjects requiring antibiotic cover for aspiration pneumonia, atypical pneumonia (including known Legionella pneumophila), or Pneumocystis jiroveci (carinii) pneumonia, fungal pneumonia, or known or suspected gastric aspiration (i.e., chemical pneumonitis)
· Subjects with prior antibiotic therapy (active against likely causative pathogens of respiratory infection) will be excluded if the prior antibiotic:
– Was started or added for the current infection
AND
– This new antibiotic has been given for more than 24 hours before the first dose of i.v. study drug therapy.
Note that subjects will not be excluded if their prior antibiotic therapy has been given for more than 48 hours and remains unchanged before the first dose of i.v. study therapy.
Additional exclusion criteria for subjects with cIAI:
· Diagnosis of abdominal wall abscess, small bowel obstruction or ischemic bowel disease without perforation, traumatic bowel perforation with surgery within 12 hours, perforation of gastroduodenal ulcers with surgery within 24 hours (these are considered situations of peritoneal soiling before infection has become established)
· Appendicitis in the absence of generalized peritonitis, or any intra abdominal processes in which the primary etiology is not likely to be infectious
· History of uncomplicated intra-abdominal infection, (e.g., simple cholecystitis, i.e., gangrenous or suppurative cholecystitis without rupture or extension beyond the gallbladder wall), or acute suppurative cholangitis
. Have an APACHE score > 30
· Necrotizing pancreatitis or pancreatic abscess
· Intra-abdominal infection where planned management is by staged abdominal repair or an open abdomen technique
· The need for concomitant systemic antibacterial agents (other than vancomycin) in addition to study drug(s)
· Use of systemic antibiotic therapy for cIAI for 24 or more hours immediately preceding the first dose of i.v. study drug therapy (unless there is a documented lack of response to such therapy)
· No more than 1 dose of an active nonstudy antibacterial regimen was given postoperatively. For subjects enrolled preoperatively, including those enrolled as failures of previous antibacterial therapy, no postoperative nonstudy antibacterial therapy is allowed.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint of this study is the assessment of safety as
measured by the overall incidence of treatment-emergent adverse events. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| 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 | Yes |
| E.6.13 | Others | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 | No |
| 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
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
Print
