| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Community-acquired bacterial
pneumonia (CABP) |
|
| E.1.1.1 | Medical condition in easily understood language |
Community-acquired bacterial
pneumonia |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010120 |
| E.1.2 | Term | Community acquired pneumonia |
| E.1.2 | System Organ Class | 100000004862 |
|
| 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 |
- Evaluate the efficacy of ceftaroline and azithromycin versus ceftriaxone and azithromycin plus vancomycin in adult subjects with community-acquired bacterial pneumonia (CABP) at risk for infection due to methicillin-resistant Staphylococcus aureus (MRSA).
- Evaluate the safety of ceftaroline and azithromycin versus ceftriaxone and azithromycin plus vancomycin in adult subjects with CABP at risk for infection due to MRSA
- Evaluate the pharmacokinetics of ceftaroline in adult subjects with CABP at risk for infection due to MRSA |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects are required to meet the following iinclusion criteria:
1. Provides written informed consent, and has the willingness and ability to comply with all study procedures
2. Male or female, 18 years old
3. Presence of CABP warranting 3 days of initial hospitalization, a minimum of 3 days of intravenous (IV) antibacterial therapy, and a minimum of 5 days but no more than 14 days total of study therapy (IV and oral combined)
4. Presence of CABP 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 daysf duration) with at least 3 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
. Chest pain
. Auscultatory findings consistent with pneumonia (eg, rales or crackles, egophony, findings of consolidation)
. Dyspnea, tachypnea (respiratory rate > 24 breaths/min), or hypoxemia (oxygen saturation < 90% on room air or PaO2 < 60 mmHg)
. Fever (temperature > 38?C) or hypothermia (temperature < 36?C) (Note: temperature should not be measured by the axillary method)
. > 10,000 white blood cells [WBC]/mm3 or < 4,500 WBC/mm3
. > 15% immature neutrophils (bands) regardless of total peripheral WBC count
5. At least 1 major or at least 2 minor risk factors for CABP due to MRSA, as defined by the following:
Major MRSA Risk Factors
. Gram-positive cocci in clusters identified on Gram stain of an adequate baseline sputum specimen (defined as < 10 squamous epithelial cells and > 25 polymorphonuclear cells/low power field [LPF]) or other respiratory specimen (eg, pleural fluid, deep bronchial, deep tracheal)
. MRSA-positive blood culture or respiratory specimen from current episode of CABP (including induced or expectorated sputum, pleural fluid, deep bronchial, or deep tracheal sample) by culture or diagnostic test
Minor MRSA Risk Factors
. Confirmed or suspected pleural empyema, pulmonary abscess, or necrotizing pneumonia, based on chest radiography characteristics (eg, CXR or CT scan) or diagnostic testing (eg, thoracentesis with pleural fluid analysis)
. Severe CABP, defined as:
A. Requirement for management in an intensive care unit
OR
B. Meets modified American Thoracic Society criteria for severe community-acquired pneumonia:
- At least 1 major criterion: either a requirement for invasive mechanical ventilation or septic shock with the need for vasopressor therapy
OR
- At least 3 minor criteria: respiratory rate >= 30 breaths/min, PaO2/FiO2 ratio < 250, oxygen saturation < 90% on room air, multilobar
infiltrates, confusion/disorientation, blood urea nitrogen (BUN) >= 20 mg/dL, < 4000 WBC/mm3, < 100,000 platelets/mm3, body temperature < 36?C, systolic blood pressure < 90 mmHg, or hypotension requiring aggressive fluid resuscitation
. Prior documentation of MRSA colonization by culture or diagnostic test within 1 year of randomization
. Prior documentation of an invasive MRSA infection (eg, acute skin or skin structure infection) within 1 year of randomization
. Previous influenza-like illness (defined as temperature >= 38 C plus cough or sore throat in the absence of a known cause other than influenza) or documented influenza infection (eg, by culture or diagnostic test) within 28 days of
randomization
6. Subjects with healthcare-associated pneumonia (eg, subjects from nursing homes or long-term care facilities, antibiotic exposure in the prior 90 days) may be enrolled;
however, such subjects must also have at least 1 of the Major MRSA Risk Factors listed above
7. Sufficient IV access to receive study drug(s) and ability to take or receive oral study drug(s)
8. If female:
. Not breastfeeding
. Not planning to become pregnant during the study
. Surgically sterile or at least 2-years postmenopausal, or if of child bearing potential, has a negative pregnancy test
. Willing to practice sexual abstinence or dual methods of contraception (eg, condom or diaphragm plus spermicidal foam or gel) during treatment and for at least 30 days after the last dose of any study drug (IV or oral), if of childbearing potential (including being < 2 years postmenopausal) |
|
| E.4 | Principal exclusion criteria |
Subjects must NOT meet any of the following exclusion criteria:
1. History of any hypersensitivity or allergic reaction to any Beta-lactam antimicrobial,
vancomycin, azithromycin, linezolid, or amoxicillin clavulanate
2. Diagnosed with CABP suitable for outpatient therapy with an oral antimicrobial agent,
initial outpatient parenteral antimicrobial therapy (OPAT), or initial IV therapy in a
home care setting
3. Suspected or microbiologically-documented infection with a pathogen known to be
resistant to any of the study drugs (eg, Pseudomonas aeruginosa, extended-spectrum
?-lactamase [ESBL]-producing gram-negative rods)
4. Confirmed or suspected respiratory tract infection attributable to sources other than
community-acquired bacterial pathogens (eg, ventilator-associated pneumonia,
hospital-acquired pneumonia, visible/gross aspiration pneumonia, suspected viral,
fungal, or mycobacterial infection of the lung [eg, cavitation due to tuberculosis])
5. Non-infectious causes of pulmonary infiltrates (eg, pulmonary embolism, chemical
pneumonitis from aspiration, hypersensitivity pneumonia, congestive heart failure)
6. Positive Legionella pneumophila urinary antigen test
7. More than 24 hours of any potentially effective systemic antibacterial therapy for
CABP within 96 hours before randomization. Exception: Unequivocal clinical
evidence of treatment failure (eg, worsening signs and symptoms) following at least
48 hours of prior systemic antimicrobial therapy (not including failure to any of the
study drugs), PLUS documented isolation of MRSA from blood or respiratory culture
from current episode of CABP that is resistant to the prior systemic antimicrobial
therapy.
8. Requirement for any potentially effective concomitant systemic antibacterial therapy
9. Requirement for high-dose (eg, equivalent to > 40 mg of prednisone per day) or
prolonged (ie, > 14 days) systemic corticosteroid therapy
10. Past or current history of epilepsy or seizure disorder. Exception: well-documented
febrile seizure of childhood.
11. End-stage renal disease (creatinine clearance < 15), including hemodialysis
12. Evidence of significant hepatic, hematological, or immunocompromising condition
(any of the following):
? Known acute viral hepatitis
? Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level
> 10 times the upper limit of normal (× ULN) or total bilirubin > 3 × ULN
? Manifestations of end-stage liver disease, such as ascites or hepatic
encephalopathy
? Neutropenia defined as < 500 neutrophils/mm3
? Thrombocytopenia defined as < 60,000 platelets/mm3
? If human immunodeficiency virus (HIV)-positive, has either a CD4 count of
? 200 cells/mm3 at the last measurement or current diagnosis of another
AIDS-defining illness
13. Participation in any study involving administration of an investigational agent or device
within 30 days before randomization into this study or previously participated in the
current study or in another study of ceftaroline fosamil (in which an active agent was
taken or received)
14. Unable or unwilling to adhere to the study-specified procedures and restrictions
15. Evidence of immediately life-threatening disease, including, but not limited to,
neoplastic lung disease, cystic fibrosis, acute heart failure, acute coronary syndrome,
unstable arrhythmias, acute cerebrovascular events, chronic neurological disorder
preventing clearance of pulmonary secretions, or life expectancy of 3 months or less
16. Any condition that would make the subject, in the opinion of the Investigator,
unsuitable for the study (eg, would place a subject at risk or compromise the quality of
the data) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoints for this study are efficacy, safety and pharmacokinetics of ceftaroline fosamil versus ceftriaxone plus vancomycin in adult subjects with CABP at risk for infection due to MRSA.
Efficacy
- Symptom improvement at Study Day 4 in the Modified Intent-to-Treat (MITT) and Microbiological Modified Intent-to-Treat (mMITT) Populations
- Clinical stability at Study Day 4 in the MITT and mMITT Populations
- Clinical success (both symptom improvement and clinical stability) at Study Day 4 in
the MITT and mMITT Populations
-Symptom improvement, clinical stability, and clinical success at Study Day 4 by baseline pathogen in the mMITT Population
- Clinical outcome at End-of-Intravenous Study Drug (EOIV), End-of-Therapy (EOT),
and Test-of-Cure (TOC) in the MITT and Clinically Evaluable (CE) Populations
-Clinical and microbiological outcomes by subject and by baseline pathogen at TOC in
the mMITT and Microbiologically Evaluable (ME) Populations
-Clinical relapse at Late Follow-up (LFU) in the MITT Population
-Emergent infections at EOT and TOC in the MITT and mMITT Populations
-30-day all-cause mortality in the MITT Population
Safety
-Adverse events (AEs), serious adverse events (SAEs), deaths, and discontinuations due to AEs
-Vital signs, hematology parameters, and chemistry parameters
Pharmacokinetic:Plasma concentrations of ceftaroline, ceftaroline fosamil (prodrug), and ceftaroline M-1
(inactive metabolite)
Refer to Schedule of Assessments and Procedures within the protocol |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Day 4 for efficacy and according to protocol. |
|
| E.5.2 | Secondary end point(s) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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) | 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 | 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 | No |
| 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 |
| Georgia |
| Hungary |
| Poland |
| Romania |
| Russian Federation |
| Spain |
| Ukraine |
| United States |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
