| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
Pneumonia, Bacterial
Community-Acquired Infections
Nosocomial Infection
Pneumonia, Ventilator-Associated |
|
| 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 | 10004051 |
| E.1.2 | Term | Bacterial pneumonia, unspecified |
| 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 of this study is to establish the safety and tolerability of doripenem compared with that of cefepime in hospitalized children 3 months to <18 years of age with suspected bacterial pneumonia including NP (Nosocomial Pneumonia), VAP (Ventilator-Assiociated Pneumonia), and severe CAP (Community-Acquired Pneumonia). |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
•To determine the clinical cure rate of doripenem compared with that of cefepime at the test-of-cure (TOC) visit
•To determine the clinical improvement rate of doripenem compared with that of cefepime at the end-of-treatment for IV study drug therapy (EIV) visit
•To determine the clinical relapse rate of doripenem compared with that of cefepime at the late follow-up (LFU) visit
•To characterize the pharmacokinetics of doripenem in hospitalized children with pneumonia based on a sparse pharmacokinetic sampling scheme |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1 - Have new or progressive radiographic infiltrate(s) (alveolar, lobar, or consolidation) consistent with a bacterial pneumonia that is not related to cardiac or other disease processes. (Note: subjects with clinically significant pleural effusions may be included if an empyema has been ruled out by a diagnostic sampling of pleural fluid. Chest X-rays obtained within 48 hours before the start of the infusion of the first dose of IV study drug therapy are acceptable for the screening examination. A computed tomography (CT) scan/magnetic resonance imaging (MRI) may be used to supplement a chest X-ray if the chest X-ray is not sufficiently interpretable).
2 - Have a clinical presentation compatible with bacterial pneumonia with ALL of the
following:
o Fever (oral temperature >38.0C, tympanic temperature >38.3C, or rectal or core temperature >38.8C) or hypothermia (rectal or core temperature <35.0C) AND
o Leukocytosis defined as WBC count > or = 15,000 cells/μL OR > or = 15% immature neutrophils, regardless of the total peripheral white cell count OR neutrophil count >1.2 times (x) the upper limit of normal (ULN); OR leucopenia with total WBC count <4500 cells/μL AND
o Non-intubated subjects must have at least 2 of the following clinical signs or symptoms:
– Cough
– New onset of LRT secretions, change in character of secretions, or increase in the quantity of secretions or suctioning requirements
– Auscultatory findings of pneumonia or consolidation (rales, rhonchi bronchial breath sounds, decreased breath sounds, wheezing, egophony)
– Dyspnea
– Increased work of breathing expressed as presence of retractions, nasal flaring, or grunting
– Hypoxemia (partial pressure of oxygen (PO2) <60mm Hg on room air) or oxygen saturation less than 90% on room air
– Tachypnea defined as follows:
> or = 50 breaths/minute for ages > or = 3 months to < or = 12 months
> or = 40 breaths/minute for ages >12 months to < or = 5 years
> or = 20 breaths/minute for ages >5 years of age
OR
apnea in infants <12 months of age
3 - Have a diagnosis of NP ,VAP, or severe CAP defined by the disease-specific criteria
specified below:
Nosocomial Pneumonia:
Subjects with NP must not be intubated or mechanically ventilated and must be hospitalized or reside in a chronic care facility for a minimum of
48 hours before being diagnosed with pneumonia.
Ventilator-associated pneumonia:
Subjects with VAP must be intubated and mechanically ventilated for > or = 48 hours before being diagnosed with pneumonia.
Severe community-acquired pneumonia:
Subjects with severe CAP must have pneumonia that is neither NP or VAP and must have at least ONE of the following risk factors for more severe disease or infection with a less susceptible pathogen:
– a mild to moderately immunocompromised condition including but not limited to diabetes or other metabolic disorder associated with immunosuppression, asplenia, sickle cell disease, mild to moderate neutropenia (ANC of 500 – 1500 cells/mm3), HIV infection not requiring Pneumocystis jirovicei prophylaxis, antibody deficiency syndromes not requiring chronic immunoglobulin replacement therapy, T-cell deficiencies not requiring prophylactic antibiotics or other chronic therapy for the immunodeficiency, phagocytic disorders, and receipt of non-inhaled corticosteroid therapy equivalent to <1 mg/kg of prednisone daily for 14 or more days during the 30 days before randomization,
– a documented tracheoesophageal fistula, or oropharyngeal incoordination with swallowing dysfunction predisposing to aspiration syndrome
– gastroesophageal reflux documented by either barium swallow or pH manometry,
– a condition associated with significant respiratory muscle dysfunction including but not limited to congenital or acquired cervical spinal cord defects, spinal muscular atrophy, peripheral nerve neuromuscular junction defects, and muscular dystrophies or myopathies,
– a congenital cardiac defect involving left to right shunting or a patent ductus arteriosus,
– prior admission to a health care facility (either a hospital, overnight acute care setting, or chronic care facility) for more than 24 consecutive hours during the 30 days before randomization,
– receipt of more than 24 consecutive hours of systemic (IV, IM or oral) antibacterial therapy for treatment of infection other than the current episode of pneumonia during the 30 days before randomization
– suspected gram negative pathogen causing pneumonia.
4 - Must, based on the judgment of the investigator, require hospitalization initially and
antibacterial therapy for 10 to 14 days for the treatment of the current pneumonia. (Note that the subject must require at least 3 days of IV antibiotic therapy initially). |
|
| E.4 | Principal exclusion criteria |
1 - Have a history of hypersensitivity reactions to carbapenems, cephalosporins, penicillins, or other β-lactam antibiotics. Note: Subjects with a history of mild non-urticarial skin rash temporally related to but considered not associated with the previous use of β-lactam antibiotics are permitted to enroll in the study. For such subjects, there must be a description of the rash and documentation by the investigator that upon review of the history it is his/her opinion that the rash was unlikely due to any of the above-mentioned classes of drugs for the subject to qualify for inclusion in the study.
2 - Concomitant infection including but not limited to suspected or confirmed meningitis, or other CNS infection, requiring systemic antibiotic or antifungal therapy at the time of randomization. (Clarification: possible bacteremia with a presumed respiratory pathogen is acceptable).
3 - Have received more than 24 hours of systemic antibacterial therapy in the 48 hours before the start of the infusion of the first dose of IV study drug therapy.
4 - Known presence at baseline of Stenotrophomonas maltophilia or Burkholderia cepacia pulmonary infection
5 - Known at the time of randomization to have mono-microbial pneumonia caused by a single pathogen that is nonsusceptible to doripenem or cefepime, including but not limited to MRSA or atypical bacteria.
6 - Have acute respiratory distress syndrome (defined by either diffuse bilateral radiographic infiltrates and/or a PaO2 to fraction of inspired oxygen (FiO2) ratio of <200)
7 - Acute or chronic renal insufficiency with a baseline CLCR <60 mL/minute or requires dialysis therapy for any reason.
8 - Are profoundly immunodeficient and require prophylactic antimicrobial therapy to
prevent infection with Pneumocystis jirovicei, Toxoplasma gondii, or herpes viruses,
and/or required chronic or intermittent immunoglobulin replacement therapy. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1 - Changes in adverse events
2 - Clinical laboratory tests
3 - Vital signs measurements |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1 - Baseline up to 42 days after the last dose of study drug
2 - Baseline up to 42 days after the last dose of study drug
3 - Baseline up to 42 days after the last dose of study drug |
|
| E.5.2 | Secondary end point(s) |
1 - To determine the clinical cure rate of doripenem compared with that of cefepime at the test of cure (TOC) visit
2 - To determine the clinical improvement rate of doripenem compared with that of cefepime at the end of treatment for IV study drug therapy (EIV) visit
3 - To determine the clinical relapse rate of doripenem compared with that of cefepime at the late follow-up (LFU) visit
4 - To characterize the pharmacokinetics of doripenem in hospitalized children with pneumonia based on a sparse pharmacokinetic sampling scheme |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 - 7 to 14 days after the last dose of iv study drug including oral antibiotic therapy
2 - Within 24 hours after completion of the last dose of iv study drug
3 - 28 to 42 days after the last dose of iv study drug including oral antibiotic therapy
4 - 1, 2, 4 and 6 hours after the 4th, 5th, 6th, or 7th dose administrations of doripenem/doripenem placebo |
|
| 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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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.8.2.4 | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| 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 |
| Colombia |
| India |
| Latvia |
| Lithuania |
| Mexico |
| Panama |
| Poland |
| Uganda |
| 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
|
| End of trial is last visit of the last subject (Late Follow Up visit) (LFU) |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | 24 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 24 |
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