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

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ClinicalTrials.gov Identifier: NCT01970371
Recruitment Status : Completed
First Posted : October 28, 2013
Results First Posted : October 16, 2018
Last Update Posted : October 16, 2018
Sponsor:
Collaborator:
Department of Health and Human Services
Information provided by (Responsible Party):
Achaogen, Inc.

Tracking Information
First Submitted Date  ICMJE October 23, 2013
First Posted Date  ICMJE October 28, 2013
Results First Submitted Date  ICMJE July 24, 2018
Results First Posted Date  ICMJE October 16, 2018
Last Update Posted Date October 16, 2018
Actual Study Start Date  ICMJE September 16, 2014
Actual Primary Completion Date August 18, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 19, 2018)
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 [ Time Frame: Up to Day 28 for ACM, up to 7 Days for SDRCs in all patients, on or after Day 5 for BSI patients only. ]
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).
Original Primary Outcome Measures  ICMJE
 (submitted: October 23, 2013)
All-cause mortality at 28 days [ Time Frame: 28 days ]
Change History Complete list of historical versions of study NCT01970371 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 19, 2018)
  • Percentage of Patients With ACM at Day 28 in the mMITT Population in Cohort 1 [ Time Frame: Up to Day 28 ]
    ACM at Day 28: confirmed date of death within 28 days of the first dose of study drug, irrespective of causality. 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 SAP.
  • Percentage of Patients With Adjudicated Clinical Cure at the Test of Cure (TOC) Visit in the mMITT Population in Cohort 1 [ Time Frame: Up to TOC (Day 23) ]
    Clinical response (CR) was assessed at end of treatment (EOT) in all patients and at TOC for those who were a clinical cure or had an indeterminate outcome at the most recent visit. Assessment of CR at TOC was not needed for those who were a clinical failure at an earlier visit. Clinical outcomes at both EOT and TOC were independently adjudicated by an external committee. The assessment was confounded by comorbidities and the occurrence of additional infections; thus, adjudicating CR of the baseline CRE infection was influenced by confounding signs and symptoms of unrelated infections or conditions. The difficulty assessing CR supports greater reliance on the more objective mortality-based primary endpoint in these patients. 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 endpoints per the protocol and SAP.
  • Time to Death Through Day 28 in the mMITT Population in Cohort 1 [ Time Frame: Up to Day 28 ]
    Time to death through Day 28 is defined as days from first dose of study drug to death from any cause on or before Day 28. Patients who were alive at Day 28 were censored on Day 28. Any patient whose survival status was not known at Day 28 was censored on the last known date alive. 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 SAP.
  • Percentage of Patients With ACM at Day 14 in the mMITT Population in Cohort 1 [ Time Frame: Day 14 ]
    ACM at Day 14 was defined as a confirmed date of death within 14 days of the first dose of study drug, irrespective of causality. 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 SAP.
  • Percentage of Patients With Dose Adjustment Due to Therapeutic Drug Management (TDM) [ Time Frame: Up to Day 14 ]
    After the initial plazomicin dose, subsequent doses were adjusted, as directed, with the use of TDM on Day 1, 4, and 8 as needed. 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 1: Colistin are not presented here as TDM collection does not apply to and was not collected for patients in the colistin arm, as only plazomicin levels were measured.
  • Percentage of Patients With Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Up to Day 67 ]
    An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in humans, whether or not it is considered to be drug related. An AE (also referred to as an adverse experience) can be any unfavorable and unintended sign (eg, an abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, and it does not imply any judgment about causality. Adverse events also include the exacerbation or worsening of a condition present at screening other than the index infection for which the patient was enrolled in the study. A TEAE is any AE that newly appeared, increased in frequency, or worsened in severity following initiation of study drug. The safety population included all randomized patients who received any amount of study drug.
  • Plasma Pharmacokinetics (PK): Area Under the Curve From 0 to 24 Hours (AUC 0-24h) [ Time Frame: 48 hours ]
    PK specimens were collected on Days 1 and 4 using a sparse sampling scheme, and concentration-time data from these PK specimens were pooled with data from specimens collected for TDM. The pooled data were analyzed by population PK modeling, which described PK over the entire course of plazomicin treatment. The protocol allowed dose adjustments based on creatinine clearance; therefore, various dose regimens were used in the study, including regimens with dosing intervals of 12, 24, and 48 hours. To enable a combined summation of exposures across dose regimens, PK exposure parameters for the study were summarized for the first 48 hours of treatment. Thus, while exposures are summarized for the first 48 hours, the reported results considered patient data over the course of plazomicin treatment.
  • Plasma Pharmacokinetics (PK): Maximum Observed Plasma Drug Concentration (Cmax) [ Time Frame: 48 hours ]
    PK specimens were collected on Days 1 and 4 using a sparse sampling scheme, and concentration-time data from these PK specimens were pooled with data from specimens collected for TDM. The pooled data were analyzed by population PK modeling, which described PK over the entire course of plazomicin treatment. The protocol allowed dose adjustments based on creatinine clearance; therefore, various dose regimens were used in the study, including regimens with dosing intervals of 12, 24, and 48 hours. To enable a combined summation of exposures across dose regimens, PK exposure parameters for the study were summarized for the first 48 hours of treatment. Thus, while exposures are summarized for the first 48 hours, the reported results considered patient data over the course of plazomicin treatment.
  • Plasma Pharmacokinetics (PK): Minimum Observed Plasma Drug Concentration (Cmin) [ Time Frame: 48 hours ]
    PK specimens were collected on Days 1 and 4 using a sparse sampling scheme, and concentration-time data from these PK specimens were pooled with data from specimens collected for TDM. The pooled data were analyzed by population PK modeling, which described PK over the entire course of plazomicin treatment. The protocol allowed dose adjustments based on creatinine clearance; therefore, various dose regimens were used in the study, including regimens with dosing intervals of 12, 24, and 48 hours. To enable a combined summation of exposures across dose regimens, PK exposure parameters for the study were summarized for the first 48 hours of treatment. Thus, while exposures are summarized for the first 48 hours, the reported results considered patient data over the course of plazomicin treatment.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 23, 2013)
  • Time to death through 28 days [ Time Frame: 28 days ]
  • All-cause mortality at 14 days [ Time Frame: 14 days ]
  • Clinical response (as determined by the adjudication committee) at end of treatment [ Time Frame: 14 days ]
  • Clinical response (as determined by the adjudication committee) at test of cure [ Time Frame: 21 days ]
  • Clinical response (as determined by the adjudication committee) at end of study [ Time Frame: 28 days ]
  • Overall incidence of adverse events [ Time Frame: 60 days ]
  • Plazomicin PK parameters including AUC0-24,Cmax, and Cmin [ Time Frame: 14 days ]
  • Frequency with which the use of TDM leads to a dose adjustment of plazomicin [ Time Frame: 14 days ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: October 23, 2013)
  • Microbiological response at end of treatment [ Time Frame: 14 days ]
  • Microbiological response at test of cure [ Time Frame: 21 days ]
  • Microbiological response at end of study [ Time Frame: 28 days ]
 
Descriptive Information
Brief Title  ICMJE A Study of Plazomicin Compared With Colistin in Patients With Infection Due to Carbapenem-Resistant Enterobacteriaceae (CRE)
Official Title  ICMJE 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)
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).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE
  • Drug: plazomicin
  • Drug: colistin
    Other Name: colistimethate sodium
  • Drug: meropenem
  • Drug: tigecycline
  • Drug: antibiotic of Investigator's choice
Study Arms  ICMJE
  • Experimental: 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.
    Interventions:
    • Drug: plazomicin
    • Drug: meropenem
    • Drug: tigecycline
  • Active Comparator: 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.
    Interventions:
    • Drug: colistin
    • Drug: meropenem
    • Drug: tigecycline
  • Experimental: 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.
    Interventions:
    • Drug: plazomicin
    • Drug: antibiotic of Investigator's choice
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 1, 2016)
69
Original Estimated Enrollment  ICMJE
 (submitted: October 23, 2013)
360
Actual Study Completion Date  ICMJE September 15, 2016
Actual Primary Completion Date August 18, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries Argentina,   Brazil,   Colombia,   France,   Germany,   Greece,   Israel,   Italy,   Mexico,   Spain,   Turkey,   United States
 
Administrative Information
NCT Number  ICMJE NCT01970371
Other Study ID Numbers  ICMJE ACHN-490-007
2013-001997-18 ( EudraCT Number )
U1111-1151-2686 ( Other Identifier: WHO )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Achaogen, Inc.
Study Sponsor  ICMJE Achaogen, Inc.
Collaborators  ICMJE Department of Health and Human Services
Investigators  ICMJE
Study Director: Lynn E Connolly, MD, PhD Achaogen, Inc.
PRS Account Achaogen, Inc.
Verification Date September 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP