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

• Sponsor: Achaogen, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01970371
• Collaborator: Department of Health and Human Services (U.S. Fed)
• Enrollment: 69
• Arms: 3
• Actual Duration (Months): 24

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
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	Drug: plazomicin; Drug: colistin; Drug: meropenem; Drug: tigecycline; Drug: antibiotic of Investigator's choice	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 69 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: Sep 16, 2014
• Actual Primary Completion Date: Aug 18, 2016
• Actual Study Completion Date: Sep 15, 2016

Arms and Interventions

Arm	Intervention/Treatment
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.	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.	Drug: colistin; Other Names: colistimethate sodium ; 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.	Drug: plazomicin; Drug: antibiotic of Investigator's choice

Outcome Measures

Primary Outcome Measures

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 [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).

Secondary Outcome Measures

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

2. 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)]

   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.

3. Time to Death Through Day 28 in the mMITT Population in Cohort 1 [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.

4. Percentage of Patients With ACM at Day 14 in the mMITT Population in Cohort 1 [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.

5. Percentage of Patients With Dose Adjustment Due to Therapeutic Drug Management (TDM) [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.

6. Percentage of Patients With Treatment-Emergent Adverse Events (TEAEs) [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.

7. Plasma Pharmacokinetics (PK): Area Under the Curve From 0 to 24 Hours (AUC 0-24h) [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.

8. Plasma Pharmacokinetics (PK): Maximum Observed Plasma Drug Concentration (Cmax) [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.

9. Plasma Pharmacokinetics (PK): Minimum Observed Plasma Drug Concentration (Cmin) [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Achaogen, Inc.
• Department of Health and Human Services

Investigators

• Study Director: Lynn E Connolly, MD, PhD, Achaogen, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Achaogen, Inc.
• ClinicalTrials.gov Identifier: NCT01970371
• Other Study ID Numbers: ACHN-490-007; 2013-001997-18; U1111-1151-2686
• First Posted: Oct 28, 2013
• Last Update Posted: Oct 16, 2018
• Last Verified: Sep 1, 2018

• Keywords provided by Achaogen, Inc.: Gram-negative; bacterial infection; antibacterial; antimicrobial; CRE; CPE; BSI; pneumonia; HABP; VABP; AP; cUTI; UTI
• Additional relevant MeSH terms: Infections; Communicable Diseases; Pneumonia; Urinary Tract Infections; Sepsis; Pneumonia, Bacterial; Pyelonephritis; Anti-Bacterial Agents; Meropenem; Colistin; Tigecycline

Study Results

Participant Flow

Arm/Group Title	Plazomicin in Combination With Meropenem or Tigecycline	Colistin in Combination With Meropenem or Tigecycline	Plazomicin in Combination With Adjunctive Antibiotic
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

Baseline Characteristics

Arm/Group Title	Plazomicin in Combination With Meropenem or Tigecycline	Colistin in Combination With Meropenem or Tigecycline	Plazomicin in Combination With Adjunctive Antibiotic	Total
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 Participants	18	21	30	69
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.94 (13.94)	63.29 (18.25)	62.8 (18.15)	63.51 (16.97)
Sex: Female, Male (Count of 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 (Count of Participants)
White	16 88.9%	17 81%	29 96.7%	62 89.9%
Black or African American	1 5.6%	1 4.8%	0 0%	2 2.9%
Asian	1 5.6%	0 0%	0 0%	1 1.4%
Multiple	0 0%	1 4.8%	0 0%	1 1.4%
Other Unspecified	0 0%	2 9.5%	1 3.3%	3 4.3%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	5 27.8%	3 14.3%	0 0%	8 11.6%
Not Hispanic or Latino	13 72.2%	18 85.7%	29 96.7%	60 87%
Not Reported	0 0%	0 0%	1 3.3%	1 1.4%

Outcome Measures

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
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.

Outcome Measure Data

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
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.
Measure Participants	17	20
Number [percentage of patients]	23.5	50

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Plazomicin in Combination With Meropenem or Tigecycline, Colistin in Combination With Meropenem or Tigecycline
	Comments
	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
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference Estimate
	Estimated Value	26.5
	Confidence Interval	(2-Sided) 90%; -0.7 to 51.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

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

Outcome Measure Data

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
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.
Measure Participants	17	20
Number [percentage of patients]	11.8	40

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Plazomicin in Combination With Meropenem or Tigecycline, Colistin in Combination With Meropenem or Tigecycline
	Comments
	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
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference Estimate
	Estimated Value	28.2
	Confidence Interval	(2-Sided) 90%; 0.7 to 52.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
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)

Outcome Measure Data

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
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.
Measure Participants	17	20
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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Plazomicin in Combination With Meropenem or Tigecycline, Colistin in Combination With Meropenem or Tigecycline
	Comments
	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
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference Estimate
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 90%; -26.9 to 26.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

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

Outcome Measure Data

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
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.
Measure Participants	17	20
% 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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Plazomicin in Combination With Meropenem or Tigecycline, Colistin in Combination With Meropenem or Tigecycline
	Comments
	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
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	3.97
	Confidence Interval	(2-Sided) 90%; 1.08 to 14.61
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

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

Outcome Measure Data

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
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.
Measure Participants	17	20
Number [percentage of patients]	5.9	20

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Plazomicin in Combination With Meropenem or Tigecycline, Colistin in Combination With Meropenem or Tigecycline
	Comments
	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
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference Estimate
	Estimated Value	14.1
	Confidence Interval	(2-Sided) 90%; -13 to 40.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

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

Outcome Measure Data

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
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.
Measure Participants	18	30
Number [percentage of patients]	77.8	86.7

7. Secondary Outcome

Title	Percentage of Patients With Treatment-Emergent Adverse Events (TEAEs)
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

Outcome Measure Data

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
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.
Measure Participants	18	21	30
Number [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)
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

Outcome Measure Data

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
Arm/Group Description	All patients who received plazomicin throughout the study.
Measure Participants	48
Geometric Mean (Geometric Coefficient of Variation) [mg*h/L (millgrams times hours per liter)]	235 (42)

9. Secondary Outcome

Title	Plasma Pharmacokinetics (PK): Maximum Observed Plasma Drug Concentration (Cmax)
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

Outcome Measure Data

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
Arm/Group Description	All patients who received plazomicin throughout the study.
Measure Participants	48
Geometric Mean (Geometric Coefficient of Variation) [mg/L]	37.1 (39.3)

10. Secondary Outcome

Title	Plasma Pharmacokinetics (PK): Minimum Observed Plasma Drug Concentration (Cmin)
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

Outcome Measure Data

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
Arm/Group Description	All patients who received plazomicin throughout the study.
Measure Participants	48
Geometric Mean (Geometric Coefficient of Variation) [mg/L]	2.1 (99.4)

Adverse Events

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
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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/18 (44.4%)		13/21 (61.9%)		12/30 (40%)
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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/18 (50%)		17/21 (81%)		20/30 (66.7%)
Cardiac disorders
Acute myocardial infarction	0/18 (0%)		0/21 (0%)		1/30 (3.3%)
Cardiac Arrest	1/18 (5.6%)		2/21 (9.5%)		4/30 (13.3%)
Cardio-respiratory arrest	1/18 (5.6%)		0/21 (0%)		0/30 (0%)
Gastrointestinal disorders
Gastrointestinal haemorrhage	0/18 (0%)		0/21 (0%)		1/30 (3.3%)
Intra-abdominal haemorrhage	0/18 (0%)		1/21 (4.8%)		0/30 (0%)
General disorders
Multiple organ dysfunction syndrome	0/18 (0%)		1/21 (4.8%)		2/30 (6.7%)
Hepatobiliary disorders
Drug-induced liver injury	0/18 (0%)		0/21 (0%)		1/30 (3.3%)
Infections and infestations
Endocarditis	1/18 (5.6%)		0/21 (0%)		0/30 (0%)
Hepatitis infectious	1/18 (5.6%)		0/21 (0%)		0/30 (0%)
Infection	1/18 (5.6%)		0/21 (0%)		0/30 (0%)
Lung infection	1/18 (5.6%)		0/21 (0%)		0/30 (0%)
Pneumonia	1/18 (5.6%)		1/21 (4.8%)		1/30 (3.3%)
Pneumonia necrotising	0/18 (0%)		0/21 (0%)		1/30 (3.3%)
Pseudomonal bacteraemia	0/18 (0%)		0/21 (0%)		1/30 (3.3%)
Sepsis	0/18 (0%)		3/21 (14.3%)		0/30 (0%)
Septic shock	4/18 (22.2%)		5/21 (23.8%)		5/30 (16.7%)
Urinary tract infection	0/18 (0%)		0/21 (0%)		4/30 (13.3%)
Injury, poisoning and procedural complications
Pneumonitis chemical	1/18 (5.6%)		0/21 (0%)		0/30 (0%)
Investigations
Blood creatinine increased	0/18 (0%)		2/21 (9.5%)		0/30 (0%)
Metabolism and nutrition disorders
Hyperosmolar state	0/18 (0%)		1/21 (4.8%)		0/30 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer	0/18 (0%)		1/21 (4.8%)		0/30 (0%)
Non-Hodgkin's lymphoma	0/18 (0%)		1/21 (4.8%)		0/30 (0%)
Nervous system disorders
Cerebral ischaemia	0/18 (0%)		1/21 (4.8%)		0/30 (0%)
Cerebrovascular accident	0/18 (0%)		0/21 (0%)		1/30 (3.3%)
Renal and urinary disorders
Acute kidney injury	2/18 (11.1%)		3/21 (14.3%)		1/30 (3.3%)
Renal failure	0/18 (0%)		1/21 (4.8%)		0/30 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumonia aspiration	0/18 (0%)		1/21 (4.8%)		1/30 (3.3%)
Pneumothorax	0/18 (0%)		1/21 (4.8%)		0/30 (0%)
Pulmonary embolism	0/18 (0%)		1/21 (4.8%)		0/30 (0%)
Vascular disorders
Deep vein thrombosis	1/18 (5.6%)		1/21 (4.8%)		0/30 (0%)
Haemodynamic instability	0/18 (0%)		0/21 (0%)		1/30 (3.3%)
Orthostatic hypotension	1/18 (5.6%)		0/21 (0%)		0/30 (0%)
Other (Not Including 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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/18 (72.2%)		20/21 (95.2%)		22/30 (73.3%)
Blood and lymphatic system disorders
Anaemia	4/18 (22.2%)		2/21 (9.5%)		1/30 (3.3%)
Leukocytosis	1/18 (5.6%)		0/21 (0%)		0/30 (0%)
Thrombocytopenia	2/18 (11.1%)		2/21 (9.5%)		2/30 (6.7%)
Cardiac disorders
Atrial fibrillation	2/18 (11.1%)		1/21 (4.8%)		2/30 (6.7%)
Extrasystoles	1/18 (5.6%)		0/21 (0%)		0/30 (0%)
Gastrointestinal disorders
Constipation	1/18 (5.6%)		0/21 (0%)		1/30 (3.3%)
Diarrhoea	2/18 (11.1%)		2/21 (9.5%)		3/30 (10%)
Nausea	0/18 (0%)		1/21 (4.8%)		3/30 (10%)
Vomiting	1/18 (5.6%)		2/21 (9.5%)		2/30 (6.7%)
General disorders
Pyrexia	2/18 (11.1%)		0/21 (0%)		0/30 (0%)
Hepatobiliary disorders
Jaundice	1/18 (5.6%)		0/21 (0%)		0/30 (0%)
Infections and infestations
Bacteraemia	1/18 (5.6%)		0/21 (0%)		0/30 (0%)
Fungal sepsis	1/18 (5.6%)		0/21 (0%)		0/30 (0%)
Oral fungal infection	1/18 (5.6%)		0/21 (0%)		0/30 (0%)
Lower respiratory tract infection	1/18 (5.6%)		0/21 (0%)		1/30 (3.3%)
Pneumonia	1/18 (5.6%)		2/21 (9.5%)		0/30 (0%)
Sepsis	1/18 (5.6%)		1/21 (4.8%)		1/30 (3.3%)
Skin infection	1/18 (5.6%)		0/21 (0%)		0/30 (0%)
Stoma site abscess	1/18 (5.6%)		0/21 (0%)		0/30 (0%)
Systemic candida	1/18 (5.6%)		0/21 (0%)		0/30 (0%)
Tinea cruris	1/18 (5.6%)		0/21 (0%)		0/30 (0%)
Tracheobronchitis	1/18 (5.6%)		1/21 (4.8%)		0/30 (0%)
Investigations
Blood bilirubin increased	0/18 (0%)		0/21 (0%)		2/30 (6.7%)
Blood creatinine increased	1/18 (5.6%)		2/21 (9.5%)		1/30 (3.3%)
Blood fibrinogen decreased	1/18 (5.6%)		0/21 (0%)		0/30 (0%)
International normalised ratio increased	0/18 (0%)		1/21 (4.8%)		2/30 (6.7%)
Metabolism and nutrition disorders
Dehydration	1/18 (5.6%)		0/21 (0%)		0/30 (0%)
Hypernatraemia	1/18 (5.6%)		1/21 (4.8%)		2/30 (6.7%)
Hypoalbuminaemia	0/18 (0%)		2/21 (9.5%)		2/30 (6.7%)
Hypocalcaemia	0/18 (0%)		0/21 (0%)		2/30 (6.7%)
Hypomagnesaemia	1/18 (5.6%)		1/21 (4.8%)		0/30 (0%)
Hypokalaemia	1/18 (5.6%)		1/21 (4.8%)		2/30 (6.7%)
Hyponatraemia	1/18 (5.6%)		1/21 (4.8%)		2/30 (6.7%)
Hypophosphataemia	0/18 (0%)		1/21 (4.8%)		2/30 (6.7%)
Psychiatric disorders
Delirium	0/18 (0%)		2/21 (9.5%)		3/30 (10%)
Depression	1/18 (5.6%)		0/21 (0%)		1/30 (3.3%)
Renal and urinary disorders
Acute kidney injury	2/18 (11.1%)		4/21 (19%)		5/30 (16.7%)
Renal impairment	1/18 (5.6%)		1/21 (4.8%)		1/30 (3.3%)
Haematuria	1/18 (5.6%)		0/21 (0%)		0/30 (0%)
Respiratory, thoracic and mediastinal disorders
Bronchospasm	0/18 (0%)		2/21 (9.5%)		0/30 (0%)
Pleural effusion	1/18 (5.6%)		1/21 (4.8%)		1/30 (3.3%)
Pneumothorax	1/18 (5.6%)		0/21 (0%)		0/30 (0%)
Skin and subcutaneous tissue disorders
Dermatitis allergic	1/18 (5.6%)		0/21 (0%)		0/30 (0%)
Penile ulceration	1/18 (5.6%)		0/21 (0%)		0/30 (0%)
Pruritus generalised	1/18 (5.6%)		0/21 (0%)		0/30 (0%)
Vascular disorders
Hypotension	1/18 (5.6%)		0/21 (0%)		3/30 (10%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.