E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Bloodstream infections (BSI) and nosocomial pneumonia due to carbapenem-resistant Enterobacteriaceae (CRE) |
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E.1.1.1 | Medical condition in easily understood language |
Infection due to Carbapenem Resistant Enterobacteriaceae (CRE) |
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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 | 10018657 |
E.1.2 | Term | Gram-negative bacterial infection NOS |
E.1.2 | System Organ Class | 100000004862 |
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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 demonstrate the superiority, in terms of all-cause mortality at 28 days, of a plazomicin-based regimen compared with a colistin-based regimen in the treatment of BSI or nosocomial pneumonia due to CRE. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are:
- to compare additional efficacy outcomes and safety of a plazomicin-based regimen with a colistin-based regimen in the treatment of BSI or nosocomial pneumonia due to CRE
- to evaluate the PK of intravenous (IV) plazomicin in patients with CRE infection.
- to evaluate the clinical utility of TDM for plazomicin dose adjustment |
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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 |
Full Title: "Evaluation of the ARK™ Plazomicin Assay for the
Determination of Plazomicin Plasma Concentrations in the Phase 3 Clinical Study ACHN-490-007"
Date: 01Oct2013
Version: Original
Objective: "The objective of this study is to assess the correlation of the plasma concentrations of plazomicin as measured by the ARK Plazomicin Assay and the reference method, LC/MS/MS in patient plasma samples collected prospectively from study ACHN-490-007." |
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E.3 | Principal inclusion criteria |
•Male and female patients age 18 to 85 years, inclusive
•APACHE II score between 15 and 30, inclusive
•Presumptive identification of a carbapenem resistant-member of the Enterobacteriaceae as defined by rapid testing methods from an appropriate culture specimen ≤ 72 hours prior to study OR definitive identification of a carbapenem resistant-member of the Enterobacteriaceae as defined by local lab identification and susceptibility testing from an appropriate culture specimen ≤ 72 hours prior to study entry
•Diagnosis of BSI as defined by at least one positive blood culture meeting the above microbiological criteria associated with at least one of the following signs of infection: Fever or hypothermia; New onset arterial hypotension; Elevated total peripheral white blood cell (WBC) count > 10,000 cells/mm3, > 15% immature neutrophils (band forms) regardless of total peripheral WBC count, or leukopenia with total WBC count < 4500 cells/mm3
•Or, diagnosis of nosocomial pneumonia in a patient on mechanical ventilation, as defined by lower respiratory tract or pleural fluid culture meeting the above defined microbiological criteria, and associated with the following clinical signs of pneumonia: A chest X-ray or computed tomography (CT) scan with findings consistent with a diagnosis of pneumonia; Worsening gas exchange; Purulent deep respiratory specimen; AND one of the following: Elevated total peripheral WBC count > 10,000 cells/mm3, > 15% immature neutrophils (band forms) regardless of total peripheral WBC count, or leukopenia with total WBC count < 4500 cells/mm3; Fever or hypothermia
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E.4 | Principal exclusion criteria |
•Patient has received more than 72 hours of empirical therapy
•Infection with CRE isolate with reduced susceptibilty to colistin
•Presence of refractory septic shock
•Objective clinical evidence for any of the following clinical syndromes that necessitates antimicrobial therapy for greater than 14 days: endovascular infection including endocarditis, osteomyelitis, prosthetic joint infection, meningitis and/or other central nervous system infections
•Objective clinical evidence of infectious involvement of intravascular material not intended to be removed within 4 calendar days of initial positive culture
•Pulmonary disease that precludes evaluation of therapeutic response including known bronchial obstruction or a history of post-obstructive pneumonia, tracheobronchitis, primary lung cancer or malignancies metastatic to the lung, bronchiectasis, known or suspected active tuberculosis
•Patients with severe liver disease (Child-Pugh score of Class C)
•Patients in acute renal failure or on intermittent hemodialysis (IHD) at the time of screening
•Patients with a history of seizure disorder and who are receiving anti-convulsive therapy
•Diagnosis of myasthenia gravis or any other neuromuscular disorder |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is all-cause mortality |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Secondary efficacy parameters include time to death through Day 28; allcause mortality at 14 days after randomization; assessment of clinical response (as determined by the adjudication committee) at end of treatment, test of cure, and end of study; overall incidence of adverse events; plazomicin PK parameters; and frequency with which the use of TDM leads to a dose adjustment of plazomicin. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
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 | Yes |
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 | 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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 41 |
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 |
France |
Germany |
Greece |
Israel |
Italy |
Mexico |
Poland |
Ukraine |
Korea, Republic of |
Spain |
Taiwan |
Turkey |
United States |
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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
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Last follow-up call for the last patient |
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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 | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |