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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.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
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
Interventions Drug: plazomicin
Drug: colistin
Drug: meropenem
Drug: tigecycline
Drug: antibiotic of Investigator's choice
Enrollment 69
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Plazomicin in Combination With Meropenem or Tigecycline Colistin in Combination With Meropenem or Tigecycline Plazomicin in Combination With Adjunctive Antibiotic
Hide Arm/Group Description 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. 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. Cohort 2: Patients received 15 mg/kg as a 30 minute IV infusion once daily. Bloodstream infection (BSI), hospital acquired bacterial pneumonia (HABP), or ventilator associated bacterial pneumonia (VABP) patients received plazomicin and any supplemental antibiotic therapy, according to Investigator's choice, for 7 to 14 days. Complicated urinary tract infection (cUTI) or acute pyelonephritis (AP) patients received plazomicin monotherapy only for 4 to 7 days with an option to switch to oral therapy on or after Day 5.
Period Title: Overall Study
Started 18 21 30
Completed 10 8 17
Not Completed 8 13 13
Reason Not Completed
Death             8             13             12
Lost to Follow-up             0             0             1
Arm/Group Title Plazomicin in Combination With Meropenem or Tigecycline Colistin in Combination With Meropenem or Tigecycline Plazomicin in Combination With Adjunctive Antibiotic Total
Hide Arm/Group Description Cohort 1: Patients received 15 mg/kg plazomicin therapy (plus meropenem or tigecycline) as a 30-minute IV infusion once daily for 7 to 14 days. 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 q8h or q12h for 7 to 14 days. 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. Total of all reporting groups
Overall Number of Baseline Participants 18 21 30 69
Hide Baseline Analysis Population Description
The intent-to-treat (ITT) population includes all randomized patients in Cohort 1 and all enrolled patients in Cohort 2.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 18 participants 21 participants 30 participants 69 participants
64.94  (13.94) 63.29  (18.25) 62.8  (18.15) 63.51  (16.97)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants 21 participants 30 participants 69 participants
Female
6
  33.3%
11
  52.4%
7
  23.3%
24
  34.8%
Male
12
  66.7%
10
  47.6%
23
  76.7%
45
  65.2%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants 21 participants 30 participants 69 participants
White
16
  88.9%
17
  81.0%
29
  96.7%
62
  89.9%
Black or African American
1
   5.6%
1
   4.8%
0
   0.0%
2
   2.9%
Asian
1
   5.6%
0
   0.0%
0
   0.0%
1
   1.4%
Multiple
0
   0.0%
1
   4.8%
0
   0.0%
1
   1.4%
Other Unspecified
0
   0.0%
2
   9.5%
1
   3.3%
3
   4.3%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants 21 participants 30 participants 69 participants
Hispanic or Latino
5
  27.8%
3
  14.3%
0
   0.0%
8
  11.6%
Not Hispanic or Latino
13
  72.2%
18
  85.7%
29
  96.7%
60
  87.0%
Not Reported
0
   0.0%
0
   0.0%
1
   3.3%
1
   1.4%
1.Primary Outcome
Title 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
Hide Description

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).

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.
Hide Outcome Measure Data
Hide Analysis Population Description
The mMITT population was a subset of the MITT population and included all patients who received ≥1 dose of study drug and had a CRE pathogen. CRE=meropenem minimum inhibitory concentration (MIC) of ≥4 micrograms per milliliter (μg/mL) or meropenem MIC=2 μg/mL and disk diffusion results (≤19 millimetres [mm]) indicating meropenem resistance.
Arm/Group Title Plazomicin in Combination With Meropenem or Tigecycline Colistin in Combination With Meropenem or Tigecycline
Hide Arm/Group Description:
Cohort 1: Patients received 15 mg/kg plazomicin therapy (plus meropenem or tigecycline) as a 30-minute IV infusion once daily for 7 to 14 days.
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 q8h or q12h for 7 to 14 days.
Overall Number of Participants Analyzed 17 20
Measure Type: Number
Unit of Measure: percentage of patients
23.5 50
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Plazomicin in Combination With Meropenem or Tigecycline, Colistin in Combination With Meropenem or Tigecycline
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The 2-sided 90% confidence interval (CI) for the difference between groups in Cohort 1 (colistin minus plazomicin) is based on the unconditional exact method.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method 1-sided Fisher's exact test
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference Estimate
Estimated Value 26.5
Confidence Interval (2-Sided) 90%
-0.7 to 51.2
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Percentage of Patients With ACM at Day 28 in the mMITT Population in Cohort 1
Hide Description

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.

Time Frame Up to Day 28
Hide Outcome Measure Data
Hide Analysis Population Description
The mMITT population was a subset of MITT population and included all patients who received at least 1 dose of study drug and had a CRE pathogen. CRE=meropenem MIC of ≥4 μg/mL or meropenem MIC=2 μg/mL and disk diffusion results (≤19 mm) indicating meropenem resistance.
Arm/Group Title Plazomicin in Combination With Meropenem or Tigecycline Colistin in Combination With Meropenem or Tigecycline
Hide Arm/Group Description:
Cohort 1: Patients received 15 mg/kg plazomicin therapy (plus meropenem or tigecycline) as a 30-minute IV infusion once daily for 7 to 14 days.
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 q8h or q12h for 7 to 14 days.
Overall Number of Participants Analyzed 17 20
Measure Type: Number
Unit of Measure: percentage of patients
11.8 40
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Plazomicin in Combination With Meropenem or Tigecycline, Colistin in Combination With Meropenem or Tigecycline
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The 2-sided 90% confidence interval (CI) for the difference between groups in Cohort 1 (colistin minus plazomicin) is based on the unconditional exact method.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method 1-sided Fisher's exact test
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference Estimate
Estimated Value 28.2
Confidence Interval (2-Sided) 90%
0.7 to 52.5
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Percentage of Patients With Adjudicated Clinical Cure at the Test of Cure (TOC) Visit in the mMITT Population in Cohort 1
Hide Description

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 Frame Up to TOC (Day 23)
Hide Outcome Measure Data
Hide Analysis Population Description
The mMITT population was a subset of MITT population and included all patients who received at least 1 dose of study drug and had a CRE pathogen. CRE=meropenem MIC of ≥4 μg/mL or meropenem MIC=2 μ/mL and disk diffusion results (≤19 mm) indicating meropenem resistance.
Arm/Group Title Plazomicin in Combination With Meropenem or Tigecycline Colistin in Combination With Meropenem or Tigecycline
Hide Arm/Group Description:
Cohort 1: Patients received 15 mg/kg plazomicin therapy (plus meropenem or tigecycline) as a 30-minute IV infusion once daily for 7 to 14 days.
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 q8h or q12h for 7 to 14 days.
Overall Number of Participants Analyzed 17 20
Measure Type: Number
Unit of Measure: percentage of patients
EOT Visit: Clinical Cure 64.7 45
EOT Visit: Clinical Failure 35.3 55
TOC Visit: Clinical Cure 35.3 35
TOC Visit: Clinical Failure 58.8 65
TOC Visit: Indeterminate Response 5.9 0
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Plazomicin in Combination With Meropenem or Tigecycline, Colistin in Combination With Meropenem or Tigecycline
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The 2-sided 90% confidence interval (CI) for the difference in clinical cure percentage at the TOC visit between groups in Cohort 1 (colistin minus plazomicin) is based on the unconditional exact method.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method 1-sided Fisher's exact test
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference Estimate
Estimated Value -0.3
Confidence Interval (2-Sided) 90%
-26.9 to 26.8
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Time to Death Through Day 28 in the mMITT Population in Cohort 1
Hide Description

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.

Time Frame Up to Day 28
Hide Outcome Measure Data
Hide Analysis Population Description
The mMITT population included all patients who received at least 1 dose of study drug and had a CRE pathogen. CRE=meropenem MIC of ≥4 μg/mL or meropenem MIC=2 μg/mL and disk diffusion results (≤19 mm) indicating meropenem resistance.
Arm/Group Title Plazomicin in Combination With Meropenem or Tigecycline Colistin in Combination With Meropenem or Tigecycline
Hide Arm/Group Description:
Cohort 1: Patients received 15 mg/kg plazomicin therapy (plus meropenem or tigecycline) as a 30-minute IV infusion once daily for 7 to 14 days.
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 q8h or q12h for 7 to 14 days.
Overall Number of Participants Analyzed 17 20
Measure Type: Number
Unit of Measure: percentage of patients
% of patients who died by Day 28 11.8 40.0
% of patients censored at 28 days 88.2 60.0
% of patients censored at <28 days 0.0 0.0
Kaplan-Meier estmate of ACM at Day 28 11.8 40
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Plazomicin in Combination With Meropenem or Tigecycline, Colistin in Combination With Meropenem or Tigecycline
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The 2-sided 90% confidence interval (CI) for the unadjusted hazard ratio between groups in Cohort 1 (colistin:plazomicin) is based on a Cox proportional hazards regression model.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method 1-sided logrank test
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 3.97
Confidence Interval (2-Sided) 90%
1.08 to 14.61
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Percentage of Patients With ACM at Day 14 in the mMITT Population in Cohort 1
Hide Description

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.

Time Frame Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
The mMITT population was a subset of MITT population and included all patients who received ≥1 dose of study drug and had a CRE pathogen. CRE=meropenem MIC of ≥4 μg/mL or meropenem MIC=2 μg/mL and disk diffusion results (≤19 mm) indicating meropenem resistance.
Arm/Group Title Plazomicin in Combination With Meropenem or Tigecycline Colistin in Combination With Meropenem or Tigecycline
Hide Arm/Group Description:
Cohort 1: Patients received 15 mg/kg plazomicin therapy (plus meropenem or tigecycline) as a 30-minute IV infusion once daily for 7 to 14 days.
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 q8h or q12h for 7 to 14 days.
Overall Number of Participants Analyzed 17 20
Measure Type: Number
Unit of Measure: percentage of patients
5.9 20
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Plazomicin in Combination With Meropenem or Tigecycline, Colistin in Combination With Meropenem or Tigecycline
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The two-sided 90% confidence interval for the difference between groups in Cohort 1 (colistin minus plazomicin) is based on the unconditional exact method.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method 1-sided Fisher's exact test
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference Estimate
Estimated Value 14.1
Confidence Interval (2-Sided) 90%
-13 to 40.3
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Percentage of Patients With Dose Adjustment Due to Therapeutic Drug Management (TDM)
Hide Description

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.

Time Frame Up to Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
The safety population included all randomized patients who received any amount of study drug.
Arm/Group Title Plazomicin in Combination With Meropenem or Tigecycline Plazomicin in Combination With Adjunctive Antibiotic
Hide Arm/Group Description:
Cohort 1: Patients received 15 mg/kg plazomicin therapy (plus meropenem or tigecycline) as a 30-minute IV infusion once daily for 7 to 14 days.
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.
Overall Number of Participants Analyzed 18 30
Measure Type: Number
Unit of Measure: percentage of patients
77.8 86.7
7.Secondary Outcome
Title Percentage of Patients With Treatment-Emergent Adverse Events (TEAEs)
Hide Description 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.
Time Frame Up to Day 67
Hide Outcome Measure Data
Hide Analysis Population Description
The safety population included all randomized patients who received any amount of study drug.
Arm/Group Title Plazomicin in Combination With Meropenem or Tigecycline Colistin in Combination With Meropenem or Tigecycline Plazomicin in Combination With Adjunctive Antibiotic
Hide Arm/Group Description:
Cohort 1: Patients received 15 mg/kg plazomicin therapy (plus meropenem or tigecycline) as a 30-minute IV infusion once daily for 7 to 14 days.
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 q8h or q12h for 7 to 14 days.
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.
Overall Number of Participants Analyzed 18 21 30
Measure Type: Number
Unit of Measure: percentage of patients
88.9 100 86.7
8.Secondary Outcome
Title Plasma Pharmacokinetics (PK): Area Under the Curve From 0 to 24 Hours (AUC 0–24h)
Hide Description 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.
Time Frame 48 hours
Hide Outcome Measure Data
Hide Analysis Population Description
PK population included all patients who had received at least 1 dose of plazomicin and had at least 1 quantifiable plazomicin plasma concentration available for analysis.
Arm/Group Title Plazomicin
Hide Arm/Group Description:
All patients who received plazomicin throughout the study.
Overall Number of Participants Analyzed 48
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: mg*h/L (millgrams times hours per liter)
235
(42%)
9.Secondary Outcome
Title Plasma Pharmacokinetics (PK): Maximum Observed Plasma Drug Concentration (Cmax)
Hide Description 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.
Time Frame 48 hours
Hide Outcome Measure Data
Hide Analysis Population Description
PK population included all patients who had received at least 1 dose of plazomicin and had at least 1 quantifiable plazomicin plasma concentration available for analysis.
Arm/Group Title Plazomicin
Hide Arm/Group Description:
All patients who received plazomicin throughout the study.
Overall Number of Participants Analyzed 48
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: mg/L
37.1
(39.3%)
10.Secondary Outcome
Title Plasma Pharmacokinetics (PK): Minimum Observed Plasma Drug Concentration (Cmin)
Hide Description 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.
Time Frame 48 hours
Hide Outcome Measure Data
Hide Analysis Population Description
PK population included all patients who had received at least 1 dose of plazomicin and had at least 1 quantifiable plazomicin plasma concentration available for analysis.
Arm/Group Title Plazomicin
Hide Arm/Group Description:
All patients who received plazomicin throughout the study.
Overall Number of Participants Analyzed 48
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: mg/L
2.1
(99.4%)
Time Frame Up to Day 67
Adverse Event Reporting Description The safety population included all randomized patients who received any amount of IV study drug. Because of the small sample size enrolled and the requirement to report AEs occurring in ≥5% of patients, all AEs are reported here, including those occurring in only a single patient.
 
Arm/Group Title Plazomicin in Combination With Meropenem or Tigecycline Colistin in Combination With Meropenem or Tigecycline Plazomicin in Combination With Adjunctive Antibiotic
Hide Arm/Group Description Cohort 1: Patients received 15 mg/kg plazomicin therapy (plus meropenem or tigecycline) as a 30-minute IV infusion once daily for 7 to 14 days. 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 q8h or q12h for 7 to 14 days. 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.
All-Cause Mortality
Plazomicin in Combination With Meropenem or Tigecycline Colistin in Combination With Meropenem or Tigecycline Plazomicin in Combination With Adjunctive Antibiotic
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   8/18 (44.44%)   13/21 (61.90%)   12/30 (40.00%) 
Show Serious Adverse Events Hide Serious Adverse Events
Plazomicin in Combination With Meropenem or Tigecycline Colistin in Combination With Meropenem or Tigecycline Plazomicin in Combination With Adjunctive Antibiotic
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   9/18 (50.00%)   17/21 (80.95%)   20/30 (66.67%) 
Cardiac disorders       
Acute myocardial infarction  1  0/18 (0.00%)  0/21 (0.00%)  1/30 (3.33%) 
Cardiac Arrest  1  1/18 (5.56%)  2/21 (9.52%)  4/30 (13.33%) 
Cardio-respiratory arrest  1  1/18 (5.56%)  0/21 (0.00%)  0/30 (0.00%) 
Gastrointestinal disorders       
Gastrointestinal haemorrhage  1  0/18 (0.00%)  0/21 (0.00%)  1/30 (3.33%) 
Intra-abdominal haemorrhage  1  0/18 (0.00%)  1/21 (4.76%)  0/30 (0.00%) 
General disorders       
Multiple organ dysfunction syndrome  1  0/18 (0.00%)  1/21 (4.76%)  2/30 (6.67%) 
Hepatobiliary disorders       
Drug-induced liver injury  1  0/18 (0.00%)  0/21 (0.00%)  1/30 (3.33%) 
Infections and infestations       
Endocarditis  1  1/18 (5.56%)  0/21 (0.00%)  0/30 (0.00%) 
Hepatitis infectious  1  1/18 (5.56%)  0/21 (0.00%)  0/30 (0.00%) 
Infection  1  1/18 (5.56%)  0/21 (0.00%)  0/30 (0.00%) 
Lung infection  1  1/18 (5.56%)  0/21 (0.00%)  0/30 (0.00%) 
Pneumonia  1  1/18 (5.56%)  1/21 (4.76%)  1/30 (3.33%) 
Pneumonia necrotising  1  0/18 (0.00%)  0/21 (0.00%)  1/30 (3.33%) 
Pseudomonal bacteraemia  1  0/18 (0.00%)  0/21 (0.00%)  1/30 (3.33%) 
Sepsis  1  0/18 (0.00%)  3/21 (14.29%)  0/30 (0.00%) 
Septic shock  1  4/18 (22.22%)  5/21 (23.81%)  5/30 (16.67%) 
Urinary tract infection  1  0/18 (0.00%)  0/21 (0.00%)  4/30 (13.33%) 
Injury, poisoning and procedural complications       
Pneumonitis chemical  1  1/18 (5.56%)  0/21 (0.00%)  0/30 (0.00%) 
Investigations       
Blood creatinine increased  1  0/18 (0.00%)  2/21 (9.52%)  0/30 (0.00%) 
Metabolism and nutrition disorders       
Hyperosmolar state  1  0/18 (0.00%)  1/21 (4.76%)  0/30 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Bladder cancer  1  0/18 (0.00%)  1/21 (4.76%)  0/30 (0.00%) 
Non-Hodgkin's lymphoma  1  0/18 (0.00%)  1/21 (4.76%)  0/30 (0.00%) 
Nervous system disorders       
Cerebral ischaemia  1  0/18 (0.00%)  1/21 (4.76%)  0/30 (0.00%) 
Cerebrovascular accident  1  0/18 (0.00%)  0/21 (0.00%)  1/30 (3.33%) 
Renal and urinary disorders       
Acute kidney injury  1  2/18 (11.11%)  3/21 (14.29%)  1/30 (3.33%) 
Renal failure  1  0/18 (0.00%)  1/21 (4.76%)  0/30 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Pneumonia aspiration  1  0/18 (0.00%)  1/21 (4.76%)  1/30 (3.33%) 
Pneumothorax  1  0/18 (0.00%)  1/21 (4.76%)  0/30 (0.00%) 
Pulmonary embolism  1  0/18 (0.00%)  1/21 (4.76%)  0/30 (0.00%) 
Vascular disorders       
Deep vein thrombosis  1  1/18 (5.56%)  1/21 (4.76%)  0/30 (0.00%) 
Haemodynamic instability  1  0/18 (0.00%)  0/21 (0.00%)  1/30 (3.33%) 
Orthostatic hypotension  1  1/18 (5.56%)  0/21 (0.00%)  0/30 (0.00%) 
1
Term from vocabulary, MedDRA (19.0)
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Plazomicin in Combination With Meropenem or Tigecycline Colistin in Combination With Meropenem or Tigecycline Plazomicin in Combination With Adjunctive Antibiotic
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   13/18 (72.22%)   20/21 (95.24%)   22/30 (73.33%) 
Blood and lymphatic system disorders       
Anaemia  1  4/18 (22.22%)  2/21 (9.52%)  1/30 (3.33%) 
Leukocytosis  1  1/18 (5.56%)  0/21 (0.00%)  0/30 (0.00%) 
Thrombocytopenia  1  2/18 (11.11%)  2/21 (9.52%)  2/30 (6.67%) 
Cardiac disorders       
Atrial fibrillation  1  2/18 (11.11%)  1/21 (4.76%)  2/30 (6.67%) 
Extrasystoles  1  1/18 (5.56%)  0/21 (0.00%)  0/30 (0.00%) 
Gastrointestinal disorders       
Constipation  1  1/18 (5.56%)  0/21 (0.00%)  1/30 (3.33%) 
Diarrhoea  1  2/18 (11.11%)  2/21 (9.52%)  3/30 (10.00%) 
Nausea  1  0/18 (0.00%)  1/21 (4.76%)  3/30 (10.00%) 
Vomiting  1  1/18 (5.56%)  2/21 (9.52%)  2/30 (6.67%) 
General disorders       
Pyrexia  1  2/18 (11.11%)  0/21 (0.00%)  0/30 (0.00%) 
Hepatobiliary disorders       
Jaundice  1  1/18 (5.56%)  0/21 (0.00%)  0/30 (0.00%) 
Infections and infestations       
Bacteraemia  1  1/18 (5.56%)  0/21 (0.00%)  0/30 (0.00%) 
Fungal sepsis  1  1/18 (5.56%)  0/21 (0.00%)  0/30 (0.00%) 
Oral fungal infection  1  1/18 (5.56%)  0/21 (0.00%)  0/30 (0.00%) 
Lower respiratory tract infection  1  1/18 (5.56%)  0/21 (0.00%)  1/30 (3.33%) 
Pneumonia  1  1/18 (5.56%)  2/21 (9.52%)  0/30 (0.00%) 
Sepsis  1  1/18 (5.56%)  1/21 (4.76%)  1/30 (3.33%) 
Skin infection  1  1/18 (5.56%)  0/21 (0.00%)  0/30 (0.00%) 
Stoma site abscess  1  1/18 (5.56%)  0/21 (0.00%)  0/30 (0.00%) 
Systemic candida  1  1/18 (5.56%)  0/21 (0.00%)  0/30 (0.00%) 
Tinea cruris  1  1/18 (5.56%)  0/21 (0.00%)  0/30 (0.00%) 
Tracheobronchitis  1  1/18 (5.56%)  1/21 (4.76%)  0/30 (0.00%) 
Investigations       
Blood bilirubin increased  1  0/18 (0.00%)  0/21 (0.00%)  2/30 (6.67%) 
Blood creatinine increased  1  1/18 (5.56%)  2/21 (9.52%)  1/30 (3.33%) 
Blood fibrinogen decreased  1  1/18 (5.56%)  0/21 (0.00%)  0/30 (0.00%) 
International normalised ratio increased  1  0/18 (0.00%)  1/21 (4.76%)  2/30 (6.67%) 
Metabolism and nutrition disorders       
Dehydration  1  1/18 (5.56%)  0/21 (0.00%)  0/30 (0.00%) 
Hypernatraemia  1  1/18 (5.56%)  1/21 (4.76%)  2/30 (6.67%) 
Hypoalbuminaemia  1  0/18 (0.00%)  2/21 (9.52%)  2/30 (6.67%) 
Hypocalcaemia  1  0/18 (0.00%)  0/21 (0.00%)  2/30 (6.67%) 
Hypomagnesaemia  1  1/18 (5.56%)  1/21 (4.76%)  0/30 (0.00%) 
Hypokalaemia  1  1/18 (5.56%)  1/21 (4.76%)  2/30 (6.67%) 
Hyponatraemia  1  1/18 (5.56%)  1/21 (4.76%)  2/30 (6.67%) 
Hypophosphataemia  1  0/18 (0.00%)  1/21 (4.76%)  2/30 (6.67%) 
Psychiatric disorders       
Delirium  1  0/18 (0.00%)  2/21 (9.52%)  3/30 (10.00%) 
Depression  1  1/18 (5.56%)  0/21 (0.00%)  1/30 (3.33%) 
Renal and urinary disorders       
Acute kidney injury  1  2/18 (11.11%)  4/21 (19.05%)  5/30 (16.67%) 
Renal impairment  1  1/18 (5.56%)  1/21 (4.76%)  1/30 (3.33%) 
Haematuria  1  1/18 (5.56%)  0/21 (0.00%)  0/30 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Bronchospasm  1  0/18 (0.00%)  2/21 (9.52%)  0/30 (0.00%) 
Pleural effusion  1  1/18 (5.56%)  1/21 (4.76%)  1/30 (3.33%) 
Pneumothorax  1  1/18 (5.56%)  0/21 (0.00%)  0/30 (0.00%) 
Skin and subcutaneous tissue disorders       
Dermatitis allergic  1  1/18 (5.56%)  0/21 (0.00%)  0/30 (0.00%) 
Penile ulceration  1  1/18 (5.56%)  0/21 (0.00%)  0/30 (0.00%) 
Pruritus generalised  1  1/18 (5.56%)  0/21 (0.00%)  0/30 (0.00%) 
Vascular disorders       
Hypotension  1  1/18 (5.56%)  0/21 (0.00%)  3/30 (10.00%) 
1
Term from vocabulary, MedDRA (19.0)
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The Investigator may publish/present the study results provided all of the following: (i) the primary publication has been published; or, if no such publication has occurred, at least 18m have passed since the completion of the study; (ii) Achaogen is allowed at least 60d to review; (iii) confidential information is deleted as requested; (iv) comments and proposed revisions are considered; and (v) during the 60d review, if requested, the Investigator shall delay the publication or presentation.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Clinical Trials Registration Group
Organization: Achaogen, Inc.
EMail: clinical-trials@achaogen.com
Layout table for additonal information
Responsible Party: Achaogen, Inc.
ClinicalTrials.gov Identifier: NCT01970371     History of Changes
Other Study ID Numbers: ACHN-490-007
2013-001997-18 ( EudraCT Number )
U1111-1151-2686 ( Other Identifier: WHO )
First Submitted: October 23, 2013
First Posted: October 28, 2013
Results First Submitted: July 24, 2018
Results First Posted: October 16, 2018
Last Update Posted: October 16, 2018