A Study of Plazomicin Compared with Colistin when combined with a second antibiotic (either meropenem or tigcycline) in the treatment of Patients with blood stream Infection (BSI) or nosocomial pneumonia due to Carbapenem-Resistant Enterobacteriaceae (CRE). Therapeutic Drug Managment (TDM) will be used to ensure that Plazomicin exposures lie within an acceptable range of the target mean steady-state area the curve (AUC).
- Conditions
- Bloodstream infections (BSI), hospital-acquired pneumonia (HABP) andventilator-associated bacterial pneumonia (VABP) due to carbapenemresistantEnterobacteriaceae (CRE)MedDRA version: 18.0Level: LLTClassification code 10018657Term: Gram-negative bacterial infection NOSSystem Organ Class: 100000004862Therapeutic area: Diseases [C] - Bacterial Infections and Mycoses [C01]
- Registration Number
- EUCTR2013-001997-18-DE
- Lead Sponsor
- Achaogen, Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 358
•Male and female patients age 18 to 85 years, inclusive
•APACHE II score between 15 and 30, inclusive
•Positive blood (for BSI) or lower respiratory tract (for HABP/VABP)
culture that was collected =96 hours prior to randomization meeting any of the following criteria;
a. Direct susceptibility testing or susceptibility testing on a purified
isolate suggesting a CRE (type 2 carbapenem [any one of: meropenem, imipenem or doripenem] MIC = 4 µg/mL or a disc diffusion zone = 19 mm)
b. Isolation of a carbapenemase-producing member of the
Enterobacteriaceae
c. Identification of a K. pneumoniae isolate from a qualifying culture in a patient from an intensive care unit or ward where =50% of clinical K. pneumoniae isolates are resistant to a type 2 carbapenem
d. Identification of an Enterobacteriaceae from a qualifying culture in a patient known to be colonized (urinary, respiratory or gastrointestinal tract) or infected by a CRE in the past 6 months
•Diagnosis of BSI, HABP, or VABP; all components defining the infection at baseline must have been present within 96 hours prior to randomization
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 179
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 179
•Receipt of more than 72 hours of potentially effective antibacterial
therapy prior to randomization
– Antibiotic therapy with a narrow spectrum of activity against Grampositive or anaerobic organisms is not restricted (eg, daptomycin, linezolid, metronidazole, nafcillin [or equivalent], cloxacillin, clindamycin, telavancin, teicoplanin, vancomycin, dalbavancin, oritavancin and tedizolid).
– Potentially effective antibacterial therapy is defined as the use of any antibiotic for which in vitro susceptibility testing against the index CRE isolate indicates full or intermediate susceptibility according to CLSI breakpoints (M100-S25, Performance
Standards for Anti-microbial Susceptibility Testing, January 2015).
Where CLSI breakpoints are not available, EUCAST breakpoints may be used (Clinical Breakpoints version 5.0, January 2015).
– If the study-qualifying infection occurred while the patient was
receiving antibiotics as prophylaxis or for treatment of an unrelated
infection, the antibacterial therapy will be considered ineffective
irrespective of the susceptibility profile of the study qualifying pathogen.
•Polymicrobial infections involving two or more aerobic Gram-negative pathogens (ie, not colonizers or contaminants) in the study qualifying culture, with the following exceptions:
– Up to two Enterobacteriaceae are permitted
– Polymicrobial infections involving CRE and Gram-positive or anaerobic Gram negative pathogens are permitted, provided that the infection can be treated using antibiotics permitted in Section 5.3.2.2
•Knowledge that the index CRE pathogen is resistant to colistin (MIC > 2 µg/mL) prior to randomization (including Enterobacteriaceae genera with intrinsic resistance to colistin, eg Serratia, Proteus and Providencia)
•Patients with a requirement for prohibited concomitant therapy
•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
•Receipt of high level vasopressors, defined as >0.5 µg/kg/min
norepinephrine or equivalent for > 36 hours prior to randomization or need for =2 vasopressors to maintain MAP = 65 mm Hg despite initial adequate fluid resuscitation (30 mL/kg crystalloid or 15 mL/kg of colloid within 6 hours of onset of hypotension) OR an initial serum or blood lactate level of =4 mmol/L that fails to decline >10%/h over the first 8 hours of resuscitation (where lactate results are available)
•Patients in acute renal failure or on intermittent hemodialysis (IHD) at the time of screening
•HABP/VABP patients only: Known bronchial obstruction or a history of post-obstructive pneumonia, tracheobronchitis in the absence of
concurrent pneumonia, primary lung cancer or malignancies metastatic to the lung, known or suspected active tuberculosis, and currently known or suspected fungal or viral pneumonia. Patients with chronic obstructive pulmonary disease (COPD) are eligible.
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: The primary objective of this study is to demonstrate the superiority of plazomicin (+ meropenem or tigecycline) compared with colistin (+ meropenem or tigecycline) in the treatment of BSI, HABP, or VABP due to CRE, with respect to the primary endpoint of all-cause mortality at Day 28 or significant disease-related complications .<br>;Secondary Objective: The secondary objectives of this study are:<br>- to compare additional efficacy outcomes and safety of a plazomicinbased regimen with a colistin-based regimen in the treatment of BSI, HABP or VABP due to CRE <br>- to evaluate the PK of intravenous (IV) plazomicin in patients with CRE infection.<br>- to evaluate the clinical utility of TDM for plazomicin dose adjustment;Primary end point(s): The primary efficacy endpoint is all-cause mortality at Day 28 or<br>significant disease-related complications;Timepoint(s) of evaluation of this end point: 28 days
- Secondary Outcome Measures
Name Time Method Secondary end point(s): Secondary efficacy parameters include all-cause mortality at day 28;<br>time to death through day 28; all cause mortatlity at day 28 or<br>significant disease related complications at end of treatment and test of cure; overall incidence of adverse events; plazomicin PK parameters; and frequency with which the use of TDM leads to a dose adjustment of<br>plazomicin.;Timepoint(s) of evaluation of this end point: 14 and 28 days