E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult Subjects with Community-Acquired Pneumonia |
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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 | 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 |
Determine the non-inferiority in the clinical cure rate for ceftaroline compared to that for ceftriaxone at the Test-of-Cure (TOC) visit in the Clinically Evaluable (CE) and Modified Intent-to-Treat Efficacy (MITTE) Populations in adult subjects with community-acquired pneumonia (CAP) |
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E.2.2 | Secondary objectives of the trial |
• Evaluate the clinical response at the End-of-Therapy (EOT) visit • Evaluate the microbiological favorable outcome rate at the TOC visit • Evaluate the overall (clinical and radiographic) success rate at the TOC visit • Evaluate the clinical and microbiological response by pathogen at the TOC visit • Evaluate clinical relapse at the Late Follow-up (LFU) visit • Evaluate microbiological reinfection/recurrence at the LFU visit • Evaluate safety |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
'A Population Pharmacokinetics Study in Adult Subjects Participating in Phase 3 Studies Evaluating the Safety and Efficacy of Ceftaroline'. 120-140 patients will be randomly selected from either the Ceftaroline of Ceftriaxone groups in this protocol or protocol P903-08 (which is running in parallel in several EU territories). Four additional blood samples will be taken on study day 3 to evaluate the population PK of IV Ceftaroline in adult subjects. |
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E.3 | Principal inclusion criteria |
•Subjects are required to meet the following inclusion criteria:
1. Males and females 18 or more years of age 2. Community-acquired pneumonia meeting the following criteria:
I. Radiographically-confirmed pneumonia (new or progressive pulmonary infiltrate(s) on chest radiograph (CXR) or chest computed tomography (CT) scan consistent with bacterial pneumonia)
AND
II. Acute illness (≤7 days’ duration) with at least three of the following clinical signs or symptoms consistent with a lower respiratory tract infection: • New or increased cough • Purulent sputum or change in sputum character • Auscultatory findings consistent with pneumonia (e.g. rales, egophony, findings of consolidation) • Dyspnea, tachypnea, or hypoxemia (O2 saturation <90% on room air or pO2 <60 mm Hg) • Fever greater than 38ºC oral (>38.5ºC rectally or tympanically) or hypothermia (<35ºC) • White blood cell (WBC) count greater than 10,000 cells/mm3 or less than 4,500 cells/mm3 • Greater than 15% immature neutrophils (bands) irrespective of WBC count
AND
III. PORT score greater than 70 and less than or equal to 130 (i.e. PORT Risk Class II, III, or IV)
3. The subject must require initial hospitalization, or treatment in an emergency room or urgent care setting, by the standard of care. 4. The subject’s infection would require initial treatment with IV antimicrobials. 5. Female subjects of child-bearing potential, and those who are fewer than 2 years post-menopausal must agree to, and comply with, using highly effective methods of birth control (i.e. condom plus spermicide, combined oral contraceptive, implant, injectable, indwelling intrauterine device, sexual abstinence, or a vasectomized partner) while participating in this study. 6. Written informed consent, willingness, and ability to comply with all study procedures. |
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E.4 | Principal exclusion criteria |
1. PORT score less than or equal to 70 (PORT Risk Class I and II), PORT score greater than 130 (PORT Risk Class V), or requiring admission to an intensive care unit 2. CAP suitable for outpatient therapy with an oral antimicrobial agent 3. Confirmed or suspected respiratory tract infections attributable to sources other than community-acquired bacterial pathogens (e.g. ventilator-associated pneumonia, hospital-acquired pneumonia, visible/gross aspiration pneumonia, suspected viral, fungal, or mycobacterial infection of the lung) 4. Non-infectious causes of pulmonary infiltrates (e.g. pulmonary embolism, chemical pneumonitis from aspiration, hypersensitivity pneumonia, congestive heart failure) 5. Pleural empyema (not including sterile parapneumonic effusions) 6. Microbiologically-documented infection with a pathogen known to be resistant to ceftriaxone, or epidemiological or clinical context suggesting high likelihood of a ceftriaxone-resistant “typical” bacterial pathogen (eg, Pseudomonas aeruginosa, MRSA). Epidemiological clues to potential MRSA infection include residence in a nursing home or assisted living facility, existence of an ongoing local MRSA infection outbreak, known skin colonization with MRSA, recent skin or skin structure infection due to MRSA, intravenous drug use, and concomitant influenza. Subjects with risk factors for MRSA infection who have predominance of gram-positive cocci in clusters on sputum Gram’s stain should also be excluded. 7. Infection with an atypical organism (M. pneumoniae, C. pneumoniae, Legionella spp.) is confirmed, or suspected based upon the epidemiological context, or infection with Legionella pneumophila is confirmed by the urinary antigen test at baseline. 8. Previous treatment with an antimicrobial for treatment of CAP within 96 hours leading up to randomization
EXCEPTIONS: subjects may be eligible despite prior antimicrobial therapy if they meet the following conditions:
EITHER:
• A single dose of an oral or intravenous short-acting antibiotic for CAP
OR BOTH OF THE FOLLOWING: • Unequivocal clinical evidence of treatment failure (e.g. worsening signs and symptoms) following at least 48 hours of prior systemic antimicrobial therapy • Isolation of an organism resistant to the prior, systemic, antimicrobial therapy
9. Failure of ceftriaxone (or other third-generation cephalosporin) as therapy for this episode of CAP, or prior isolation of an organism resistant in vitro to ceftriaxone 10. History of any hypersensitivity or allergic reaction to any ß-lactam antimicrobial 11. Past or current history of epilepsy or seizure disorder
EXCEPTIONS: well-documented febrile seizure of childhood
12. Requirement for concomitant antimicrobial or systemic antifungal therapy for any reason
EXCEPTIONS: topical antifungal or antimicrobial therapy, single oral dose of any antifungal for treatment of vaginal candidiasis
13. Neoplastic lung disease, cystic fibrosis, progressively fatal disease, chronic neurological disorder preventing clearance of pulmonary secretions, or life expectancy of less than or equal to 3 months 14. Probenecid administration within 3 days prior to initiation of study drug therapy or requirement for concomitant therapy with probenecid 15. Infections or conditions requiring concomitant systemic corticosteroids
EXCEPTIONS: the corticosteroid dose equivalent is less than 40 mg prednisone per day
16. Severely impaired renal function (CrCl ≤ 30 mL/min) estimated by the Cockroft-Gault formula 17. Evidence of significant hepatic, hematological, or immunologic disease (see definitions) 18. Evidence of immediately life-threatening disease, including, but not limited to, current or impending respiratory failure, acute heart failure, shock, acute coronary syndrome, unstable arrhythmias, hypertensive emergency, acute hepatic failure, active gastrointestinal bleeding, profound metabolic abnormalities (e.g. diabetic ketoacidosis), or acute cerebrovascular events 19. Residence in a nursing home or assisted living facility that provides 24-hour medical supervision (not including extended living facilities for ambulatory elderly persons) or hospitalization within 14 days prior to onset of symptoms (i.e. healthcare-associated pneumonia) 20. Women who are pregnant or nursing 21. Participation in any study involving administration of an investigational agent or device within 30 days prior to randomization into this study or previously participated in the current study 22. Previous participation in a study of ceftaroline 23. Unable or unwilling to adhere to the study-specified procedures and restrictions 24. Any condition that, in the opinion of the Investigator, would compromise the safety of the subject or the quality of the data |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy outcome measure is the per-subject clinical response rate at the TOC visit in the CE and MITTE Populations. Subjects will be considered clinically cured at the TOC visit if they have total resolution of all signs and symptoms of the baseline infection, or improvement of the infection to such an extent that no further antimicrobial therapy is necessary. Clinical improvement includes the absence of fever (temperature ≤38°C oral or ≤38.5°C rectally or tympanically) for at least 24 continuous hours, with temperature recorded twice daily, in addition to a substantial improvement in signs and symptoms of CAP. Substantial improvement includes a return to pre-CAP baseline levels for subjects with decreased pulmonary function (eg, subjects with chronic obstructive pulmonary disease). The outcome measures in the CE and MITTE Populations are regarded as co-primary, however no adjustment is needed for multiple comparisons. The number and percentage of subjects in each treatment group determined to be a clinical cure, clinical failure, or indeterminate (by definition, indeterminates are excluded from the CE Population) will be tabulated for all subjects.
Secondary: • Per-subject clinical cure rate at the EOT visit in the MITTE and CE Populations • Per-subject microbiological favorable outcome rate at the TOC visit in the mMITT, mMITTE and ME Populations • Per-subject overall success rate at the TOC visit in the MITTE and CE Populations • Per-pathogen clinical cure rate at the TOC visit in the mMITTE and ME Populations • Per-pathogen microbiological favorable outcome rate at the TOC visit in the mMITTE and ME Populations • Per-subject relapse rate at the LFU visit in the subset of subjects in the CE and MITTE Populations who were clinically cured at the TOC visit • Per-subject reinfection or recurrence rate at the LFU visit in the subset of subjects in the ME and mMITTE Populations who had a favorable microbiological outcome (eradication or presumed eradication) at the TOC visit |
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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 | 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.8.4.1 | Number of sites anticipated in Member State concerned | 18 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 42 |
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 | 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
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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 | |
E.8.9.1 | In the Member State concerned days | |