Clinical trial NCT01970371: A Study of Plazomicin Compared With Colistin in Patients With Infection Due to Carbapenem-Resistant Enterobacteriaceae (CRE)
Official title: A Phase 3, Multicenter, Randomized, Open-Label Study to Evaluate the Efficacy and Safety of Plazomicin Compared With Colistin in Patients With Infection Due to Carbapenem-Resistant Enterobacteriaceae (CRE)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Bloodstream Infections (BSI) Due to CRE
Hospital-Acquired Bacterial Pneumonia (HABP) Due to CRE
Ventilator-Associated Bacterial Pneumonia (VABP) Due to CRE
Complicated Urinary Tract Infection (cUTI) Due to CRE
Acute Pyelonephritis (AP) Due to CRE
Keywords: Gram-negative
bacterial infection
antibacterial
antimicrobial
CRE
CPE
BSI
pneumonia
HABP
VABP
AP
cUTI
UTI
Lead sponsor: Achaogen, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Department of Health and Human Services
First posted: 2013-10-28
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This was a Phase 3 study containing a randomized open-label superiority cohort (Cohort 1) comparing the efficacy and safety of plazomicin with colistin when combined with a second antibiotic (either meropenem or tigecycline) in the treatment of patients with bloodstream infection (BSI), hospital acquired bacterial pneumonia (HABP), or ventilator-associated bacterial pneumonia (VABP) due to CRE. An additional cohort of patients with BSI, HABP, VABP, complicated urinary tract infection (cUTI), or acute pyelonephritis (AP) due to CRE, not eligible for inclusion in the other cohort, were enrolled into a single arm (Cohort 2) and treated with plazomicin-based therapy. Therapeutic drug management (TDM) was used to help ensure that plazomicin exposures lie within an acceptable range of the target mean steady-state area under the curve (AUC).


Eligibility criteria: Key Inclusion Criteria:

* Cohort 1: APACHE II score between 15 and 30, inclusive; Cohort 2: BSI, HABP, VABP patients with an APACHE II score ≤30 (cUTI and AP patients do not need to have their APACHE II score calculated)
* Positive culture that was collected ≤96 hours prior to randomization indicating a CRE infection, or a high likelihood of a CRE infection
* Diagnosis of BSI as defined by at least one of the following: fever, hypothermia, new onset arterial hypotension, elevated total peripheral white blood cell (WBC) count, increased immature neutrophils (band forms), or leukopenia
* Or, diagnosis of HABP defined as clinical signs and symptoms consistent with pneumonia acquired after at least 48 hours of continuous stay in an inpatient acute or chronic-care facility, or acquired within 7 days after being discharged from a hospitalization of ≥3 days duration
* Or, diagnosis of VABP defined by clinical signs and symptoms consistent with pneumonia acquired after at least 48 hours of continuous mechanical ventilation
* Or, diagnosis of cUTI or AP defined by clinical signs and symptoms consistent with cUTI or AP assessed within 24 hours prior to enrollment

Key Exclusion Criteria:

* Cohorts 1 and 2 BSI, HABP, and VABP patients: receipt of more than 72 hours of potentially effective antibacterial therapy; Cohort 2: cUTI and AP patients: receipt of any potentially effective antibacterial therapy in the 48 hours prior to enrollment
* Cohort 1 only: knowledge that index CRE infection is resistant to colistin prior to randomization
* Objective clinical evidence for any of the following clinical syndromes that necessitates study 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 potentially due to the study qualifying pathogen and not intended to be removed within 4 calendar days of the initial positive culture
* HABP or VABP patients only: 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
* cUTI or AP patients only: renal abscess, chronic bacterial prostatitis, orchitis or epididymitis, polycystic kidney disease, one functional kidney, vesicoureteral reflux, renal transplant, cystectomy or ileal loop surgery, fungal UTI or complete, permanent obstruction of the urinary tract
* Patients in acute renal failure at the time of randomization
* Patients receiving intermittent hemodialysis (IHD) at the time of screening
* Pregnant or breastfeeding female patient

Primary outcomes:
measure: Percentage of Patients With All Cause Mortality (ACM) at Day 28 or Significant Disease-Related Complication (SDRC) in the Microbiological Modified Intent to Treat (mMITT) Population in Cohort 1
timeFrame: Up to Day 28 for ACM, up to 7 Days for SDRCs in all patients, on or after Day 5 for BSI patients only.
Secondary outcomes:
measure: Percentage of Patients With ACM at Day 28 in the mMITT Population in Cohort 1
timeFrame: Up to Day 28
measure: Percentage of Patients With Adjudicated Clinical Cure at the Test of Cure (TOC) Visit in the mMITT Population in Cohort 1
timeFrame: Up to TOC (Day 23)
measure: Time to Death Through Day 28 in the mMITT Population in Cohort 1
timeFrame: Up to Day 28
measure: Percentage of Patients With ACM at Day 14 in the mMITT Population in Cohort 1
timeFrame: Day 14
measure: Percentage of Patients With Dose Adjustment Due to Therapeutic Drug Management (TDM)
timeFrame: Up to Day 14
measure: Percentage of Patients With Treatment-Emergent Adverse Events (TEAEs)
timeFrame: Up to Day 67
measure: Plasma Pharmacokinetics (PK): Area Under the Curve From 0 to 24 Hours (AUC 0-24h)
timeFrame: 48 hours
measure: Plasma Pharmacokinetics (PK): Maximum Observed Plasma Drug Concentration (Cmax)
timeFrame: 48 hours
measure: Plasma Pharmacokinetics (PK): Minimum Observed Plasma Drug Concentration (Cmin)
timeFrame: 48 hours
Other outcomes:
Locations:
Study officials:
affiliation: Achaogen, Inc.
name: Lynn E Connolly, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Kuti JL, Kim A, Cloutier DJ, Nicolau DP. Evaluation of Plazomicin, Tigecycline, and Meropenem Pharmacodynamic Exposure against Carbapenem-Resistant Enterobacteriaceae in Patients with Bloodstream Infection or Hospital-Acquired/Ventilator-Associated Pneumonia from the CARE Study (ACHN-490-007). Infect Dis Ther. 2019 Sep;8(3):383-396. doi: 10.1007/s40121-019-0251-4. Epub 2019 Jun 28.