| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 5.2 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052596 |
|
| 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 |
| To demonstrate the noninferiority of ceftobiprole plus placebo compared with linezolid plus ceftazidime with respect to the clinical cure rate in subjects with nosocomial pneumonia (NP) at the test-of-cure (TOC) visit. |
|
| E.2.2 | Secondary objectives of the trial |
- To compare the microbiological eradication rate following treatment with ceftobiprole plus placebo with linezolid plus ceftazidime in subjects with NP at the TOC visit.
- To compare the clinical cure rate and microbiological eradication rate following treatment with ceftobiprole plus placebo with linezolid plus ceftazidime in subjects with NP at the late follow-up (LFU) visit.
- To compare the 30-day pneumonia-specific mortality rates following treatment with ceftobiprole plus placebo with linezolid plus ceftazidime in subject with NP. |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1) Written informed consent provided. 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 patient information sheet and informed consent form approved by the responsible Ethics Committee.
2) Male or female patients aged ≥ 18 years.
3) Femal subjects must be postmenopausal (for at least 1 year), surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of of pregnancy), or practicing an effective method of birth control (e.g. prescription oral contraceptives, contraceptive injections or patch, intrauterine device, double-barrier method (e.g. condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), male partner sterilization or, at the discretion of the investigator, abstinence), before entry and throughout the study; and have a negative serum or urine pregnancy test (depending on local regulations) at screning.
4) Subject suffering from NP or VAP defined as follows:
Nosocomial Pneumonia (subject must have a, b, c and d)
a) Clinical diagnosis of pneumonia after a minimum of 72 hours of hospitalization or in a chronic care facility
Excemptions would include:
- ≥48 to <72 hours of hospitalization or in a chronic care facility if at admission no acute inflammatory pulmonary infiltrate was present, WBC and differential blood count was normal, and the reason for admission was not an infection, OR
- discharge from hospital or chronic care facility ≤48 hours after a stay of ≥72 hours
b) Clinical signs or symptoms of pneumonia with AT LEAST 2 of the following criteria:
- New onset of purulent sputum production or respiratory secretions or a worsening in character of sputum.
- Tachypnea (respiratory rate ≥20/minute), particularly if progressive in nature.
- Hypoxemia with a P02≤60 mmHg while subject is breathing on room air, as determined by pulse oximetry or arterial blood gas, or alveoloar arterial O2 gradient, or respiratory failure requiring mechanical ventilation.
c) New or persistent (persistance is defined as the infiltrate being radiographically visible for at least 72 Hours) radiographic infiltrates (not related to another disease process)
d) Fever or leukocytosis/leukopenia consistent with a diagnosis of pneumonia with AT LEAST 1 of the follosing:
- Fever ((in the absence of anti-pyretics), increase in core temperature of >1°C OR an oral temperature >38°C, a tympanic temperature >38.5°C, a rectal/core temperature >39°C, OR hypothermia, defined as a rectal/core body temperature of <35°C)
- Leukocytosis (a total WBC count ≥10 x 10exp9/L or ≥15% immature neutrophils (bands), regardless of total peripheral white count; or leucopenia with total WBC ≤4.5 x 10exp9/L )
Ventilator- Associated Pneumonia
Subjects with NP (as defined above) who developed pneumonia more than 48 hours after onset of mechanical ventilation.
5) Microbiological samples (respiratory secretions) suitable for culture and microscopy.
6) APACHE II score ≥ 8 and ≤ 25. |
|
| E.4 | Principal exclusion criteria |
1) Female patients who are pregnant or lactating.
2) Known or suspected hypersensitivity to any related antiinfective (including beta-lactam antibiotics such as penicillins, cephalosporins, oxazolidinone, or monobactams)
3) Any known or suspected condition or concurrent treatment that would be contraindicated by the prescribing information for linezolid (any medicinal product which inhibits monoamine oxidases A or B, [e.g., phenelzine, isocarboxazid, selegiline, moclobemide] or within 2 weeks of taking any such medicinal product) or ceftazidime. Exception: Subjects with underlying conditions and/or on concomitant medications that might put them at risk from MAO inhibition can only be enrolled if they are hospitalized.
4) Known or suspected severe renal impairment, (calculated creatinine clearance [CrCl] < 30 mL/minute, or oliguria < 20 mL/h unresponsive to fluid challenge) or any form of dialysis.
5) Known or suspected hepatic dysfunction (total bilirubin, or alanine aminotransferase [ALT], or aspartate aminotransferase [AST] ≥ 3 x upper limit of the normal range [ULN]).
6) QTcB (Bazett's correction) > 450 msac at baseline.
7) Previous enrollment in this study.
8) Treatment with any investigational drug within 30 days before enrollment.
9) Any other known or suspected condition of the patient that may jeopardize adherence to protocol requirements (e.g.severe chronic obstructive pulmonary disease [COPD], NYHA Class 4 cardiac disease, burn subjects with >15% total body burn or any significant third degree burn).
10) Known to be HIV-positive with CD4 counts of ≤0.2x10exp9/L (≤200 cells/mm³). Subjects with HIV and >0.2x10exp9/L [>200 cells/mm³] may be included).
11) Presence of myelosuppression or neutropenia (absolute neutrophil count [ANC] ≤0.5x10exp9/L [<500 PMNs/mm³]), severe anemia (hemoglobin <6.5 g/dL), or severe thrombocytopenia (<49.9x10exp9/cm). Note; subjects receiving immunosuppressive therapy who are expected to reach a nadir of <500PMNs/mm³ during administration of study drug should not be enrolled.
12) Children or other family members of the investigator or of emplyees of the study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center.
Clinical conditions that may interfere with assessment of efficacy:
13) Sustained shock (e.g., systolic BP < 90 mmHg for > 2 hours despite adequate fluid resuscitation, with evidence of hypoperfusion or need for sympathomimetic agents).
14) Subjects with either- known bronchial obstruction or a history of post-obstructive pneumonia (mild and moderate chronic obstructive pulmonary disease [COPD] patients are allowed) including primary lung cancer or another malignancy metastatic to the lungs, - cystic fibrosis, - lung abscess, - pleural effusion as a primary source of infection- active tuberculosis, or - subjects requiring antibiotic cover for aspiration pneumonia, atypical pneumonia (including Legionella pneumophila) or Pneumocystis jiroveci (carinii) pneumonia.
Microbiological conditions that may interfere with assessment of efficacy:
15) Systemic antimicrobial therapy for > 24 hours is permitted in case of any of the following: a) the infection is caused by microbiologically-confirmed pathogens that are resistant to the previous antimicrobial agents. b) the patient is clinically deteriorating despite at least 72 hours of antibiotic therapy and is documented to be infected or colonized with a pathogen that is suspectible to both ceftobiprole and the comparator regimen. c)the subject has received antibiotic therapy for prophylaxis (i.e., surgical prophylaxis, trauma) greater that 72 hours prior to enrollment.
16) Evidence from available surveillance cultures of (co-)infection with pathogen(s) such as: - Extended Spectrum Beta-lactamase producers, - Proteus vulgaris, or - Ceftazidime- or ceftobiprole-resistant nonfermenters |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Clinical cure rate, defined as the ratio of the number of clinically cured subjects to the total number of subjects in the population at TOC visit. |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| 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) | 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 | 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.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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 | |
| 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 months | 14 |
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