A Study of Plazomicin Compared With Colistin in Patients With Infection Due to Carbapenem-Resistant Enterobacteriaceae (CRE)

NCT ID: NCT01970371

Last Updated: 2018-10-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 69 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-09-16
• Study Completion Date: 2016-09-15

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).

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Plazomicin in Combination with Meropenem or Tigecycline

Cohort 1: Patients received 15 milligram per killogram (mg/kg) plazomicin therapy (plus meropenem or tigecycline) as a 30-minute intravenous (IV) infusion once daily for 7 to 14 days.

Group Type: EXPERIMENTAL

plazomicin

Intervention Type: DRUG

meropenem

Intervention Type: DRUG

tigecycline

Intervention Type: DRUG

Colistin in Combination with Meropenem or Tigecycline

Cohort 1: Patients received a 5 mg/kg IV loading dose (300 mg maximum) colistin (plus meropenem or tigecycline) followed by a 5 mg/kg/d maintenance dose divided into every 8 hours (q8h) or every 12 hours (q12h) for 7 to 14 days.

Group Type: ACTIVE_COMPARATOR

colistin

Intervention Type: DRUG

meropenem

Intervention Type: DRUG

tigecycline

Intervention Type: DRUG

Plazomicin in Combination with Adjunctive Antibiotic

Cohort 2: Patients received 15 mg/kg as a 30 minute IV infusion once daily. BSI, HABP or VABP patients received plazomicin and any supplemental antibiotic therapy, according to Investigator's choice, for 7 to 14 days. cUTI or AP patients received plazomicin monotherapy only for 4 to 7 days with an option to switch to oral therapy on or after Day 5.

Group Type: EXPERIMENTAL

plazomicin

Intervention Type: DRUG

antibiotic of Investigator's choice

Intervention Type: DRUG

Interventions

plazomicin

Intervention Type: DRUG

colistin

Intervention Type: DRUG

meropenem

Intervention Type: DRUG

tigecycline

Intervention Type: DRUG

antibiotic of Investigator's choice

Intervention Type: DRUG

Other Intervention Names

colistimethate sodium

Eligibility Criteria

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

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Department of Health and Human Services

FED

Sponsor Role: collaborator

Achaogen, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Lynn E Connolly, MD, PhD

Role: STUDY_DIRECTOR

Achaogen, Inc.

References

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.

Reference Type: DERIVED

PMID: 31254273 (View on PubMed)

Other Identifiers

2013-001997-18

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

U1111-1151-2686

Identifier Type: OTHER

Identifier Source: secondary_id

ACHN-490-007

Identifier Type: -

Identifier Source: org_study_id