| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hospital-acquired pneumonia or community-acquired pneumonia requiring hospitalisation. |
| Вътреболнична пневмония или придобита в обществото пневмония, изискващи хоспитализация. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pneumonia acquired infectiously from contact with other people or from hospital |
| Пневмония придобита инфекциозно от контакт с други хора или от болница |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052596 |
| E.1.2 | Term | Nosocomial 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 |
| To characterise the safety profile of ceftobiprole in paediatric patients with HAP or CAP requiring hospitalisation and intravenous (IV) antibiotic therapy |
|
| E.2.2 | Secondary objectives of the trial |
In paediatric patients with HAP or CAP requiring hospitalisation:
- To compare the clinical cure rate and microbiological eradication rate at the test-of-cure (TOC) visit between ceftobiprole and IV standard-of-care cephalosporin treatment (± vancomycin)
- To compare the clinical and microbiological relapse rates at the last follow-up (LFU) visit between ceftobiprole and IV standard-of-care cephalosporin treatment (± vancomycin)
- To characterise other efficacy measures of ceftobiprole (e.g., improvement in signs and symptoms of pneumonia, length of hospital stay)
- To assess the pharmacokinetics (PK) of ceftobiprole |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients meeting all of the following at Screening:
1. Male or female aged 3 months to < 18 years
2. Body weight of at least 5 kg
3. Diagnosis of either HAP (pneumonia occurring after ≥ 48 hours of hospitalisation) or CAP requiring hospitalisation and administration of IV antibiotic therapy, characterised by:
Fever (> 38.5 °C) or hypothermia (< 35 °C), and
Leucocytosis or leucopenia (relevant to patient age and
institutional normal ranges), and
At least two of the following signs or symptoms: cough, lower respiratory tract secretions, auscultatory findings of pneumonia, dyspnea/tachypnea, increased work of breathing (retractions, nasal flaring, or grunting), hypoxaemia/oxygen saturation < 92% (on room air)
Patients with CAP must present with at least one of the following conditions:
Admission to an intensive care unit, intermediate care unit,
or a unit with the ability to provide constant and close
monitoring and care
Suspected infection with multi-drug resistant pneumococci or methicillin-resistant Staphylococcus aureus (MRSA)
History of absent or incomplete pneumococcal vaccination (did not receive all vaccinations as per schedule)
Recent clinical diagnosis of influenza with exacerbation of fever and respiratory symptoms after initial improvement in the symptoms of acute influenza
Failure to clinically improve on initial antibiotic therapy for at least 48 hours and need for antibiotic treatment change
Oxygen saturation on room air ≤ 90%
4. New or progressive imaging findings consistent with bacterial pneumonia (e.g., X-ray, ultrasound, or computer tomography)
5. Requirement for IV antibacterial treatment for pneumonia
6. Sufficient vascular access to receive IV study drug
7. Informed consent from the parent or legally acceptable representative (LAR) to participate in the study, and child’s assent as appropriate
8. Female patients who are not pregnant or breast-feeding and meet one of the following conditions:
Pre-menarcheal, or
A negative serum or urine pregnancy test and willing to use a highly reliable method of contraception during the study until the LFU visit |
|
| E.4 | Principal exclusion criteria |
Patients meeting any one of the following at Screening:
1. Known resistance of the causative pathogen to ceftobiprole or IV standard-of-care cephalosporin treatment (± vancomycin)
2. On mechanical ventilation at Screening for more than 48 hours
3. Chest trauma with severe lung contusion or flail chest
4. Acute respiratory distress syndrome
5. Empyema or lung abscess
6. Anatomical bronchial obstruction
7. Documented or suspected active or currently-treated pulmonary tuberculosis
8. Documented or suspected atypical bacterial pneumonia, or viral pneumonia without bacterial superinfection, or need for antibiotic coverage with a macrolide
9. Known positive result from a rapid diagnostic test for influenza or respiratory syncytial virus, unless bacterial pneumonia secondary to viral respiratory illness is suspected based on a clinical history of exacerbation of fever and respiratory symptoms after initial improvement in the symptoms of an acute respiratory infection
10. Documented or suspected pertussis, chemical pneumonitis (e.g., aspiration of gastric contents, inhalation injury), or cystic fibrosis
11. Severe immunodeficiency (HIV infection, or congenital or acquired immunodeficiency syndrome)
12. Significant laboratory abnormalities (based on local laboratory results) including:
Hematocrit < 20%
Absolute neutrophil count < 0.5 × 109/L
Platelet count < 50 × 109/L
Alanine aminotransferase, aspartate aminotransferase, or total bilirubin > 5 × the age-specific upper limit of normal
Creatinine clearance of < 50 mL/min/1.73 m2, or requirement for any form of renal dialysis therapy
13. Use of systemic antimicrobial therapy for more than 24 hours in the 48 hours before randomization for the current episode of pneumonia
Exception: CAP patients with failure to clinically improve on initial antibiotic therapy for at least 48 hours and need for antibiotic treatment change (see Inclusion criterion 3)
14. History of a previous clinically-relevant hypersensitivity or serious adverse reaction to beta-lactam antibiotics or to vancomycin
15. Poorly-controlled seizure disorder (˃ 1 seizure in the month preceding randomization) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Analysis of adverse events (AEs) assessed on each of the first 3 days of study-drug treatment, and at the end-of-treatment (EOT), TOC, and LFU visits (Safety population). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Days 1, 2, 3, end of treatment (EOT), 7-14 days after EOT, 28-35 days after EOT (other timepoints may also be analyzed) |
|
| E.5.2 | Secondary end point(s) |
1. Efficacy: Comparison of clinical cure rates (ITT and CE populations) and microbiological eradication rates (mITT and ME populations) between ceftobiprole and the comparator at the TOC visit; and cure of pneumonia, defined as clinical improvement or lack of progression of X-ray abnormalities, as well as resolution of clinical pneumonia findings, at study Day 4 and the EOT visit (ITT and CE populations). The clinical and microbiological relapse rates at the LFU visit will also be compared (ITT, CE, mITT and ME populations).
2. Pharmacokinetics: Descriptive analysis of ceftobiprole plasma concentration per time point, based on PK sampling in at least 15 patients in each of the two age categories of < 6 years and ≥ 6 years (PK population) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy: Day 4, EOT, 7-14 days after EOT, 28-35 days after EOT; Pharmacokinetics: On Day 3 at the following time points:
Children aged 2 years and older: pre-dose, and at 2h (end of infusion), 4h, 6h, and 8h after start of infusion
Children aged less than 2 years: pre-dose and at 4h (end of infusion), 6h, and 8h after start of infusion
|
|
| 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) | 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 | Yes |
| E.8.1.4 | Double blind | No |
| 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 | 14 |
| 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 |
| Bulgaria |
| Georgia |
| Hungary |
| Romania |
| Ukraine |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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