| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Community-acquired Bacterial Pneumonia |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | PT |
| E.1.2 | Classification code | 10035664 |
| E.1.2 | Term | Pneumonia |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 | 10004051 |
| E.1.2 | Term | Bacterial pneumonia, unspecified |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10060946 |
| E.1.2 | Term | Pneumonia bacterial |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 | 10021881 - Infections and infestations |
|
| 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 evaluate the safety and tolerability of ceftaroline versus ceftriaxone in pediatric subjects ages 2 months to < 18 years with CABP requiring hospitalization. |
|
| E.2.2 | Secondary objectives of the trial |
• Evaluate the efficacy of ceftaroline versus ceftriaxone in pediatric subjects with CABP requiring hospitalization.
• Evaluate the pharmacokinetics of ceftaroline in pediatric subjects ages 2 months to < 18 years with CABP requiring hospitalization. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Informed consent in writing from parent(s) or other legally acceptable representative(s) and informed assent from subject (if age appropriate according to local requirements).
2. Male or female 2 months to < 18 years of age.
3. Presence of CABP warranting 3 days of initial hospitalization and a minimum of 3 days of IV antibacterial therapy and a minimum of 5 days but no more than 14 days total of study therapy (IV and PO combined).
4. Presence of CABP meeting each of the following criteria:
I. Fever (temperature > 38.0°C) or hypothermia (temperature <35.0°C). Note that temperature should not be measured by the axillary method.
II. New infiltrate(s) compatible with bacterial pneumonia, including a new alveolar/lobar infiltrate or consolidation (based on imaging results or diagnostic testing)
III. Acute onset or worsening within the previous 5 days before randomization of at least 2 of the following clinical signs or symptoms:
- Cough
- Tachypnea, defined as (World Health Organization, 2011):
- 2 months to < 12 months: ≥ 50 breaths/min
- 12 months to < 5 years: ≥ 40 breaths/min
- ≥ 5 years: ≥ 20 breaths/min
- Dyspnea
- Grunting
- Sputum production
- Chest pain
- Cyanosis
- Evidence of pneumonia with parenchymal consolidation (eg, dullness on percussion, diminished breath sounds, egophony, bronchial breath sounds, rales or crackles)
- Increased work of breathing (eg, nasal flaring, chest wall retractions)
IV. Presence of at least 1 of the following:
- Organism consistent with a typical respiratory pathogen identified or isolated from a respiratory or blood culture
- Leukocytosis (> 15,000 white blood cells [WBC]/mm3)
- >15% immature neutrophils (bands) regardless of total peripheral WBC
- Leukopenia (< 4500 WBC/mm3) likely due to the bacterial infection
- Hypoxemia (oxygen saturation < 92% on room air)
5. Female subjects who have reached menarche must have a negative urine pregnancy test.
6. Female subjects who have reached menarche and are sexually active must be willing to practice sexual abstinence or dual methods of birth control (eg, condom or diaphragm with spermicidal foam or gel) during treatment and for at least 28 days after the last dose of any study drug (IV or PO).
7. Sufficient IV access to receive medication.
|
|
| E.4 | Principal exclusion criteria |
1. Documented history of any hypersensitivity or allergic reaction to any β-lactam antimicrobial.
2. Confirmed or suspected infection with a pathogen known to be resistant to ceftriaxone (eg, Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus [MRSA]) or known infection at baseline with a sole atypical organism (eg, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Chlamydia trachomatis, Legionella pneumophila). Epidemiological clues to potential MRSA infection include necrotizing pneumonia, existence of an ongoing local MRSA infection outbreak, known skin colonization with MRSA, recent invasive MRSA infection, and recent influenza. Subjects with risk factors for MRSA infection who have predominance of gram-positive cocci in clusters on sputum Gram stain should also be excluded.
3. Confirmed or suspected respiratory tract infection attributable to sources other than community-acquired bacterial pathogens (eg, ventilator-associated pneumonia; hospital-acquired pneumonia [occurring 48 hours or more after admission, which was not incubating at the time of admission (Niederman, 1996; Tablan et al, 2004)]; visible/gross aspiration pneumonia; suspected sole viral [eg, respiratory syncytial virus], fungal, Mycobacterium tuberculosis infection of the lung); chronic lung disease or neurologic disease preventing normal clearance of secretions.
4. Non-infectious causes of pulmonary infiltrates (eg, cystic fibrosis, chemical pneumonitis from aspiration, hypersensitivity pneumonia) on chest radiography.
5. More than 24 hours of any potentially effective systemic antibacterial therapy for CABP within 96 hours before randomization.
EXCEPTIONS:
a) Microbiological or clinical treatment failure with a nonstudy antibacterial therapy that was administered for at least 72 hours. Failure must be confirmed by either a microbiological laboratory report or documented worsening clinical signs or symptoms.
b) Low-dose tetracycline derivative for acne (eg, doxycycline 50 mg q12h)
6. Requirement for any potentially effective concomitant systemic antibacterial therapy
7. Requirement for high-dose (eg, equivalent to > 20 mg of prednisone per day) or prolonged (ie, >14 days) systemic corticosteroid therapy; short courses of corticosteroids, such as those for currently worsening asthma, are permitted.
8. History of seizures, excluding febrile seizure of childhood.
9. Creatinine clearance < 50 mL/min/1.73 m2 as calculated using the updated Schwartz “bedside” formula (Schwartz et al, 2009):
CrCl (mL/min/1.73 m2) = 0.413 × height (length) (cm)/serum creatinine (mg/dL).
10. Clinical signs or suspicion of bacterial meningitis.
11. Evidence of significant hepatic, hematologic, or immunocompromising condition (any of the following):
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the upper limit of normal (× ULN) or total bilirubin level > 2 × ULN
- Known acute viral hepatitis
- Neutropenia (< 500 neutrophils/mm3)
- Thrombocytopenia (< 60,000 platelets/mm3)
- If human immunodeficiency virus (HIV)-positive, has CD4 count < 250 cells/mm3 at the last measurement or history of AIDS-defining illness
- Bone marrow ablative therapy, including bone marrow transplantation, within the last 12 months
- Bone marrow or solid organ recipients who have had an episode of graft versus host disease or acute rejection episode, respectively, within the last 6 months
- Severe combined immunodeficiency disorder (SCID)
12. Evidence of immediately life-threatening disease, progressively fatal disease, or life expectancy of 3 months or less.
13. Females who are currently pregnant or breastfeeding.
14. Participation in any study involving administration of an investigational agent or device within 30 days before randomization or previously participated in the current study or in another study of ceftaroline fosamil (in which an active agent was taken or received).
15. Unable or unwilling to adhere to the study-specified procedures and restrictions.
16. Any condition (eg, septic shock, acute hemodynamic instability including those conditions requiring pressor support) 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 objective is to evaluate the safety and tolerability of ceftaroline versus ceftriaxone in pediatric subjects ages 2 months to < 18 years with CABP requiring hospitalization. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
• Adverse events: AEs, SAEs, deaths, and discontinuations due to AEs will be evaluated. Cephalosporin class effects and additional AEs (including, but not limited to, seizures, Clostridium difficile-associated diarrhea, allergic reactions, hemolytic anemia, hepatic abnormalities, and changes in renal function) will be closely monitored at Treatment, EOIV, EOT, TOC, LFU.
• Clinical: vital signs (pulse, blood pressure, respiratory rate, oxygen saturation, and temperature) at Treatment, EOIV, EOT, TOC, LFU
• Laboratory: complete blood count with differential (at treatment day 7, EOIV, TOC), direct Coombs test (at TOC), and chemistry panel (at treatment day 2 and 3, EOIV)
Refer to Schedule of Assessments and Procedures within the protocol
|
|
| E.5.2 | Secondary end point(s) |
1. Evaluate the efficacy of ceftaroline versus ceftriaxone in pediatric subjects with CABP requiring hospitalization.
2. Evaluate the pharmacokinetics of ceftaroline in pediatric subjects ages 2 months to < 18 years with CABP requiring hospitalization.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
•Clinical response at Study Day4 by subject and by baseline pathogen in the Modified Intent-to-Treat and the Microbiological Modified Intent-to-Treat Populations
•Clinical stability at Study Day4 by subject and by baseline pathogen in the MITT and mMITT Populations
•Clinical outcome at End-of-Intravenous Study Drug, EOT, and TOC in the MITT and CE Populations
•Clinical and microbiological outcomes by subject and by baseline pathogen at TOC in the mMITT and Microbiologically Evaluable Populations
•Clinical relapse at Late Follow-up in the MITT Population
•Emergent infections in the mMITT Population
•Concentrations of ceftaroline fosamil, ceftaroline, and ceftaroline M1 in plasma
•If available, concentrations of ceftaroline fosamil, ceftaroline, and ceftaroline M1 in cerebrospinal fluid |
|
| 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 | No |
| 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 |
|
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| 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 |
| Argentina |
| Brazil |
| Greece |
| Hungary |
| Poland |
| Spain |
| Ukraine |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| 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 | 2 |
| 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 |
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