E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult subjects with Community-Acquired Pneumonia |
|
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 |
|
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 overall (clinical and radiographic) success 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 (MITT) Populations in adult subjects with community-acquired pneumonia (CAP) |
|
E.2.2 | Secondary objectives of the trial |
• Evaluate the clinical response at the End-of-Therapy (EOT) and TOC visits • Evaluate the microbiological 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 re-infection/recurrence at the LFU visit • Evaluate safety |
|
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 |
Pharmacokinetic Blood Sample Substudy: The pharmacokinetic (PK) data acquisition and analysis strategy entails the use of a sparse PK sampling schedule, performed only at selected investigational sites. Sites will be selected based on location, ability to perform PK procedures with high quality, and ability to efficiently store and ship PK samples. Efforts will be made to obtain PK samples from approximately 120 to 140 subjects treated with IV ceftaroline or IV ceftriaxone on Study Day 3. The PK samples will be collected for both IV ceftaroline and IV ceftriaxone treatment groups for the purpose of maintaining the blind, but only PK samples from the ceftaroline group will be analyzed (using a validated assay) by the unblinded central bioanalytical laboratory. Analysis of the PK data will be described in a separate statistical analysis plan. |
|
E.3 | Principal 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 III, or IV) (see Section 9.1) 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. |
|
E.4 | Principal exclusion criteria |
1. PORT score less than or equal to 70 (PORT Risk Class I or 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. 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 nonpurulent 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. epidemiological clues to potential MRSA infection include residence in a nursing home or assisted living facility, existence of an ongiong local MRSA infection ourbreak, know skin colonization with MRSA, recent skin or skin structure infection due to MRSA, IV drug use, and concomitant influenza. Subjects with risk factors for MRSA infection who have predominance of G+ 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 penumophilla is confirmed by the urinary antigene 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 associated with this episode of CAP and resistant in vitro to ceftriaxone 10. History of any hypersensitivity or allergic reaction to any ß-lactam antimicrobial 11. History of any hypersensitivity or allergic reaction to clarithromycin or any macrolide/ ketolide 12. Inability to take oral clarithromycin 13. Requirement for concomitant therapy with any drug known to exhibit a contraindicated drug-drug interaction with clarithromycin; or labeled contraindication to use of clarithromycin 14. Past or current history of epilepsy or seizure disorder- EXCEPTION: well-documented febrile seizure of childhood 15. Requirement for concomitant antimicrobial or systemic antifungal therapy for any reason. EXCEPTIONS: topical antifungal or antimicrobial therapy, a single oral dose of any antifungal for treatment of vaginal candidiasis 16. 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. 17. Probenecid administration within 3 days prior to initiation of the study treatment regimen or requirement for concomitant therapy with probenecid 18. Infections or conditions requiring concomitant systemic corticosteroids. EXCEPTION: the corticosteroid dose equivalent is less than 40 mg prednisone per day 19. Severely impaired renal function (CrCl ≤ 30 mL/min) estimated by the Cockroft-Gault formula. 20. Evidence of significant hepatic, hematological, or immunologic disease. 21. Evidence of immediately life-threatening disease. 22. 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) 23. Women who are pregnant or nursing 24. 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 25. Previous participation in a study of ceftaroline 26. Unable or unwilling to adhere to the study-specified procedures and restrictions 27. Any condition that, in the opinion of the Investigator, would compromise the safety of the subject or the quality of the data |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The Investigator will assess clinical outcome at the EOT and TOC visits, and radiographic outcomes at the TOC and LFU visits. The primary efficacy outcome measure will be the per-subject overall (combined clinical and radiographic) success rate at the TOC visit in the CE and MITT Populations. Overall response is defined as the combined clinical and radiographic responses. 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. Radiographic success will be determined if the TOC visit CXR or chest CT scan is resolved, improved, or stable compared to the baseline CXR or CT scan. The overall response will be assessed programmatically by combining the clinical response with the radiographic response. To be an overall success the subject must be deemed a clinical cure and either a radiographic success or a radiographic indeterminate. |
|
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 | 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 | 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 | Yes |
E.8.1.7.1 | Other trial design description |
adjunctive therapy : in both treatment groups 2 doses of oral Clarithromycin (500mg) q12h on day 1 |
|
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 80 |
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
| |
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |