| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hospitalized community acquired pneumonia |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010120 |
| E.1.2 | Term | Community acquired pneumonia |
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| 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 ceftobiprole medocaril compared with ceftriaxone with/without linezolid (comparator) with respect to the clinical cure rate in subjects hospitalized with community-acquired pneumonia (CAP) at the test-of-cure (TOC) visit. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
to compare the microbiological eradication rate at the TOC visit;
to compare the clinical cure rate in subjects requiring mechanical ventilation within 48h of enrollment;
to compare the microbiological eradication rate in subjects that require mechanical ventilation with 48h of enrollment;
to compare the clinical and microbiological relapse rates at the late-follow-up visit.
Further objectives:
to assess the PK of Ceftobiprole in subjects treated with Ceftobiprole
to collect MRU data
to characterize the safety and tolerability of Ceftobiprole in CAP patients |
|
| 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 (for at least 1 year), surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy), abstinent, or, if sexually active, be practicing an effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, double-barrier method [e.g., condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel], contraceptive patch, male partner sterilization) before entry and continue to use the same method of contraception throughout the study
- Women must have a negative serum β-human chorionic gonadotropin
(b-hCG) or urine pregnancy test (depending on local regulations) before enrollment
- Willing to adhere to the prohibitions and restrictions specified in this protocol
- Subjects (or their legally acceptable representatives) 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
Disease Specific
Subjects with CAP severe enough to require hospitalization and treatment with i.v. antibiotics for at least 3 days (72 hours) defined as follows:
Subjects must have a, b, c, d, AND e
a) Clinical diagnosis of acute bacterial pneumonia acquired in the community. Subjects must have resided in the community (i.e., NOT in a chronic care facility such as a nursing home or rehabilitation facility) and NOT have been hospitalized during the 14 days before the onset of symptoms of pneumonia. Residence in an assisted-living facility where the subject has regular access to the community is allowed.
b) Clinical signs or symptoms of acute bacterial pneumonia with AT LEAST 2 of the following criteria:
- Cough (new or increased over usual state)
- Production of purulent sputum or a worsening in the character of sputum
- Auscultatory findings on pulmonary examination of rales or evidence of pulmonary consolidation (dullness on percussion, bronchial breath sounds, or egophony)
- Dyspnea or tachypnea (respiratory rate ³20 breaths per minute), that is new or worse than usual state
- New onset hypoxemia on room air (PO2 <60 mmHg on arterial blood gas or O2 saturation <90% by pulse oximetry), or respiratory failure requiring mechanical ventilation.
c) New radiographic infiltrates (not related to another disease process) consistent with the diagnosis of bacterial pneumonia
d) Fever or leukocytosis/leukopenia (temporally associated with the onset of pneumonia symptoms) with AT LEAST 1 of the following:
- Fever (in the absence of antipyretics) defined as an axillary temperature >37.5°C, oral temperature >38°C, a tympanic temperature >38.5°C, a rectal temperature >39°C, OR hypothermia, defined as a rectal body temperature of <35°C
- Leukocytosis defined as an elevated total peripheral WBC count ³10 x 109/L or ³15% immature neutrophils (bands), regardless of total peripheral white count; OR leukopenia with total WBC £4.5 x 109/L.
e) Severity of pneumonia requiring intravenous antibiotic therapy.
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|
| E.4 | Principal exclusion criteria |
Potential subjects who meet any of the following criteria will be excluded from participating in the study:
- History of or suspected condition that may jeopardize adherence to protocol requirements (e.g., severe cardiac disease such that even minimal physical activity causes discomfort, New York Heart Association [NYHA] Class 4)44
- History of or suspected hypersensitivity to any related anti-infective (including beta lactam antibiotics such as penicillins and cephalosporins, oxazolidinones). Subjects in whom cephalosporins would be used as part of normal clinical practice are not excluded.
- History of or suspected condition or concurrent treatment that would be contraindicated by the prescribing information for ceftriaxone or linezolid
- History of or suspected severe renal impairment, (i.e., ClCr £30 mL/min or oliguria <20 mL/h unresponsive to fluid challenge) or any form of dialysis
- History of or suspected hepatic dysfunction (total bilirubin, or alanine aminotransferase [ALT], or aspartate aminotransferase [AST] ³3 times the upper limit of the normal range [ULN]).
- History of suspected extra-pulmonary infection, including concomitant meningitis, endocarditis, septic arthritis, or osteomyelitis
- Known to be human immunodeficiency virus (HIV) positive with CD4 counts of £0.2x109/L (£200 cells/mm3). (Subjects with HIV and >0.2x109/L [>200 cells/mm3] may be included)
- Presence of neutropenia, (absolute neutrophil count [ANC] £0.5x109/L [<500 Neutrophils [polymorphonuclear leukocytes] [PMNs/mm3]) severe anemia (hemoglobin <6.5 g/dL), or severe thrombocytopenia (<49.9x109/cm)
Note: Subjects receiving immunosuppressive therapy who are expected to reach a nadir of <500 PMNs/mm3 during administration of study drug should not be enrolled
- Previous enrollment in this study or any other ceftobiprole protocol
- Have received an experimental drug or used an experimental medical device within 30 days before the planned start of treatment
- Is pregnant or 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
Clinical conditions that may interfere with assessments of efficacy:
· Sustained shock
· Subjects with any of the following pulmonary conditions:
– known bronchial obstruction or a history of postobstructive pneumonia
– primary lung cancer or another malignancy to the lungs unless surgically resected
– cystic fibrosis
– lung abscess
– pleural effusion as a primary source of infection
– active tuberculosis
– suspected or known pneumonia due to aspiration, atypical bacteria (Legionella spp, Mycoplasma pneumoniae, and Chlamydia pneumoniae), viruses, or Pneumocystis jiroveci (carinii).
Microbiological conditions that may interfere with assessments of efficacy:
· Systemic antimicrobial therapy for more than 24 hours in the 3 days before enrollment.
Exception: Systemic antimicrobial therapy for more than 24 hours is permitted in case of a subject with an infection caused by microbiologically confirmed pathogen(s) that are resistant to the previous antimicrobial agents (e.g., pneumonia due to a macrolide resistant staphylococci or pneumococci being treated with a macrolide).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The clinical cure rate is defined as the ratio of the number of clinically cured subjects to the total number of subjects in the population at the 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 | 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) | 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 | No |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| 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 |
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| 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
|
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| 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 | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 13 |
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