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

NCT01970371 | Completed Phase 3 Results DMC

• 3 other identifiers: ACHN-490-0072013-001997-18U1111-1151-2686
• Study Type: interventional
• Target: 69
• Locations: 0 countries
• Sites: N/A

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

Keywords

Gram-negative; bacterial infection; antibacterial; antimicrobial; CRE; CPE; BSI; pneumonia; HABP; VABP; AP; cUTI; UTI

Outcome Measures

Primary Outcomes (1)

• 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

  ACM at Day 28: confirmed date of death within 28 days of the first dose of study drug, irrespective of causality. SDRCs for all patients: presence of 1 or more of the following complications within 7 days of randomization: new or worsening acute respiratory distress syndrome (ARDS), new lung abscess, new empyema, new onset of septic shock, new carbapenem-resistant Enterobacteriaceae (CRE) (HABP/VABP patients only); persistent bacteremia on study Day ≥5 (BSI patients only). Note: Although it is generally expected that results for primary and secondary endpoints will be presented for all arms included at baseline, results for Cohort 2 are not presented here as this Cohort was not part of the primary or key secondary endpoints per the protocol and statistical analysis plan (SAP).

  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 (9)

• Percentage of Patients With ACM at Day 28 in the mMITT Population in Cohort 1

  Up to Day 28

• Percentage of Patients With Adjudicated Clinical Cure at the Test of Cure (TOC) Visit in the mMITT Population in Cohort 1

  Up to TOC (Day 23)

• Time to Death Through Day 28 in the mMITT Population in Cohort 1

  Up to Day 28

• Percentage of Patients With ACM at Day 14 in the mMITT Population in Cohort 1

  Day 14

• Percentage of Patients With Dose Adjustment Due to Therapeutic Drug Management (TDM)

  Up to Day 14

Study Arms (3)

Plazomicin in Combination with Meropenem or Tigecycline

EXPERIMENTAL

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.

Drug: plazomicin; Drug: meropenem; Drug: tigecycline

Colistin in Combination with Meropenem or Tigecycline

ACTIVE COMPARATOR

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.

Drug: colistin; Drug: meropenem; Drug: tigecycline

Plazomicin in Combination with Adjunctive Antibiotic

EXPERIMENTAL

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.

Drug: plazomicin; Drug: antibiotic of Investigator's choice

Interventions

plazomicin DRUG

Plazomicin in Combination with Adjunctive Antibiotic; Plazomicin in Combination with Meropenem or Tigecycline

colistin DRUG

Also known as: colistimethate sodium

Colistin in Combination with Meropenem or Tigecycline

meropenem DRUG

Colistin in Combination with Meropenem or Tigecycline; Plazomicin in Combination with Meropenem or Tigecycline

tigecycline DRUG

Colistin in Combination with Meropenem or Tigecycline; Plazomicin in Combination with Meropenem or Tigecycline

antibiotic of Investigator's choice DRUG

Plazomicin in Combination with Adjunctive Antibiotic

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Achaogen, Inc.: lead
• Department of Health and Human Services: collaborator

Related Publications (1)

• 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.

  PMID: 31254273 DERIVED

MeSH Terms

Conditions

Sepsis; Bacterial Infections; Pneumonia

Interventions

plazomicin; Colistin; colistinmethanesulfonic acid; Meropenem; Tigecycline

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Bacterial Infections and Mycoses; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Polymyxins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Lipopeptides; Lipids; Antimicrobial Cationic Peptides; Peptides; Amino Acids, Peptides, and Proteins; Antimicrobial Peptides; Pore Forming Cytotoxic Proteins; Membrane Proteins; Proteins; Thienamycins; Carbapenems; beta-Lactams; Lactams; Amides; Organic Chemicals; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Tetracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons

Results Point of Contact

• Title: Clinical Trials Registration Group
• Organization: Achaogen, Inc.

clinical-trials@achaogen.com

Study Officials

• Lynn E Connolly, MD, PhD

  Achaogen, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 23, 2013
• First Posted: October 28, 2013
• Study Start: September 16, 2014
• Primary Completion: August 18, 2016
• Study Completion: September 15, 2016
• Last Updated: October 16, 2018
• Results First Posted: October 16, 2018

Record last verified: 2018-09