A Study of Plazomicin Compared With Levofloxacin for the Treatment of Complicated Urinary Tract Infection (cUTI) and Acute Pyelonephritis (AP)

A Double-blind, Randomized, Comparator-controlled Study to Assess the Safety, Efficacy, and Pharmacokinetics of ACHN-490 Injection Administered IV in Patients With Complicated Urinary Tract Infections or Acute Pyelonephritis

This was a multi-center, multi-national, double-blind, randomized, comparator-controlled study of plazomicin administered intravenously compared with levofloxacin, a standard approved intravenous therapy for complicated urinary tract infection (cUTI) and acute pyelonephritis (AP).

Study Overview

• Status: Completed
• Conditions: Acute Pyelonephritis; Complicated Urinary Tract Infection
• Intervention / Treatment: Drug: placebo; Drug: plazomicin; Drug: levofloxacin

• Study Type: Interventional
• Enrollment (Actual): 145
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Documented or suspected cUTI/AP with clinical signs and symptoms
• Normal kidney function defined as creatinine clearance (CLcr) of ≥60mL/min using Cockcroft-Gault formula

Key Exclusion Criteria:

• Acute bacterial prostatis, orchitis, epididymitis, or chronic bacterial prostatis
• Gross heanaturia requiring intervention other than study drug
• Urinary tract surgery within 7 days of randomization or during the study period
• A known nonrenal source of infection diagnosed within 7 days of randomization
• A corrected QT interval > 440 msec
• History of hearing loss with onset before the age of 40 years, sensorineural hearing loss, or family history of hearing loss
• Pregnant or breastfeeding women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: plazomicin (10 mg/kg); Patients received two intravenous (IV) infusions daily for 5 consecutive days: 10 milligrams per kilogram (mg/kg) plazomicin followed by placebo.	Drug: placebo; Drug: plazomicin
Experimental: plazomicin (15 mg/kg); Patients received two IV infusions daily for 5 consecutive days: 15 mg/kg plazomicin followed by placebo.	Drug: placebo; Drug: plazomicin
Active Comparator: levofloxacin; Patients received two IV infusions daily for 5 consecutive days: placebo followed by 750 milligrams (mg) levofloxacin.	Drug: placebo; Drug: levofloxacin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients Who Attained Microbiological Eradication (MBE) at the Test of Cure (TOC) Visit in the Microbiological Intent to Treat (MITT) Population	MBE was defined as documented eradication of all isolated pathogens. This was based on a urine culture, taken at the TOC visit that showed that all pathogens isolated at baseline at ≥10^5 colony forming unit(s) per milliliter (CFU/mL) were reduced to <10^4 CFU/mL.	Day 1 to TOC (Day 12)
Percentage of Patients Who Attained MBE at the TOC Visit in the Microbiologically Evaluable (ME) Population	MBE was defined as documented eradication of all isolated pathogens. This was based on a urine culture, taken at the TOC visit that showed that all pathogens isolated at baseline at ≥10^5 CFU/mL were reduced to <10^4 CFU/mL.	Day 1 to TOC (Day 12)
Percentage of Patients With Treatment-Emergent Adverse Events (TEAE)	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.	Day 1 to the end of study (Day 40)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients Who Attained Clinical Cure Based on Investigator and Sponsor Assessments at TOC Visit in the Intent-to-treat (ITT) Population	Investigator's assessment criteria defined Clinical Cure as resolution of baseline clinical signs and symptoms of infection through the TOC visit. The sponsor's assessment criteria was programmatically based on the investigator's assessment of participant clinical outcome, the number of days and doses of drug received and whether an antibiotic was administered.	Day 1 to TOC (Day 12)
Percentage of Patients Who Attained Clinical Cure Based on Investigator and Sponsor Assessments at the TOC Visit in the CE Population	Investigator's assessment criteria defined Clinical Cure as a resolution of baseline clinical signs and symptoms of infection through the TOC visit. The sponsor's assessment criteria was programmatically based on the investigator's assessment of participant clinical outcome, the number of days and doses of drug received and whether an antibiotic was administered.	Day 1 to TOC (Day 12)
Percentage of Patients Who Attained Clinical Cure Based on Investigator and Sponsor Assessments at the End of Treatment (EOT) Visit in the CE Population	Investigator's assessment criteria defined Clinical Cure as a resolution of baseline clinical signs and symptoms of infection through the EOT visit. The Sponsor's assessment criteria was programmatically based on the investigator's assessment of participant clinical outcome, the number of days and doses of drug received and whether an antibiotic was administered.	Day 1 to EOT (Day 5)
Percentage of Patients Who Attained MBE at the EOT Visit in the ME Population	MBE was defined as documented eradication of all isolated pathogens. This was based on a urine culture, taken at the EOT visit that showed that all pathogens isolated at baseline at ≥10^5 CFU/mL were reduced to <10^4 CFU/mL.	Day 1 to EOT (Day 5)
Percentage of Patients Who Attained MBE at the EOT Visit in the MITT Population	MBE was defined as documented eradication of all isolated pathogens. This was based on a urine culture, taken at the EOT visit that showed that all pathogens isolated at baseline at ≥10^5 CFU/mL were reduced to <10^4 CFU/mL.	Day 1 to EOT (Day 5)
Percentage of Patients Who Attained MBE at the TOC Visit in the ME Population by Baseline Pathogen	MBE was defined as documented eradication of all isolated pathogens. This was based on a urine culture, taken at the TOC visit that showed that all pathogens isolated at baseline at ≥10^5 CFU/mL were reduced to <10^4 CFU/mL.	Day 1 to TOC (Day 12)
Percentage of Patients Who Attained MBE at the TOC Visit in the ME Population Stratified by Infection Category	MBE was defined as documented eradication of all isolated pathogens. This was based on a urine culture, taken at the TOC visit that showed that all pathogens isolated at baseline at ≥10^5 CFU/mL were reduced to <10^4 CFU/mL.	Day 1 to TOC (Day 12)
Percentage of Patients Who Attained MBE at the TOC Visit in the ME Population by Country/Region	MBE was defined as documented eradication of all isolated pathogens. This was based on a urine culture, taken at the TOC visit that showed that all pathogens isolated at baseline at ≥10^5 CFU/mL were reduced to <10^4 CFU/mL.	Day 1 to TOC (Day 12)
Time (Days) to Resolution of Signs and Symptoms of cUTI and AP in the MITT Population	Resolution of clinical signs and symptoms is defined as absence of all signs and symptoms present at baseline.	Day 1 to End of Study (Day 40)
Time (Days) to Clinical Cure Based on Investigator's and Sponsor's Assessments in the MITT Population	Investigator's assessment criteria defined Clinical Cure as a resolution of baseline clinical signs and symptoms of infection through the TOC visit. The Sponsor's assessment criteria was programmatically based on the investigator's assessment of participant clinical outcome, the number of days and doses of drug received and whether an antibiotic was administered.	Day 1 to End of Study (Day 40)
Time (Days) to Defervescense in the MITT Population	Defervescence is defined as the absence of fever <37.7 degrees Celsius and is assessed in patients who were afebrile at baseline.	Day 1 to End of Study (Day 40)
Percentage of Patients Experiencing a Clinical Relapse or Microbiological Recurrence in the ME Population	Patients who had a clinical relapse (defined as the return of clinical signs and symptoms requiring antibiotic therapy) or microbiological recurrence (defined as eradication of the original pathogen[s] at the TOC visit but regrowth at the level >10^5 CFU/mL by the LTFU [long term follow up] visit).	Day 1 to LTFU (Day 40)
Percentage of Patients With a Superinfection or New Infection in the ME Population	Superinfections are defined as a pathogen other than the one at baseline found in urine at ≥10^5 CFU/mL any time after the first infusion through EOT. New infections are defined as a pathogen other than the one at baseline found in urine at ≥10^5 CFU/mL any time after EOT.	Day 1 to to End of Study (Day 40)

Collaborators and Investigators

• Sponsor: Achaogen, Inc.
• Investigators: Study Director: Medical Director, Achaogen, Inc.

Publications and helpful links

General Publications

• Connolly LE, Riddle V, Cebrik D, Armstrong ES, Miller LG. A Multicenter, Randomized, Double-Blind, Phase 2 Study of the Efficacy and Safety of Plazomicin Compared with Levofloxacin in the Treatment of Complicated Urinary Tract Infection and Acute Pyelonephritis. Antimicrob Agents Chemother. 2018 Mar 27;62(4):e01989-17. doi: 10.1128/AAC.01989-17. Print 2018 Apr.

Study record dates

Study Major Dates

• Study Start (Actual): July 13, 2010
• Primary Completion (Actual): April 3, 2012
• Study Completion (Actual): April 3, 2012

Study Registration Dates

• First Submitted: March 12, 2010
• First Submitted That Met QC Criteria: March 30, 2010
• First Posted (Estimate): March 31, 2010

Study Record Updates

• Last Update Posted (Actual): August 22, 2018
• Last Update Submitted That Met QC Criteria: August 20, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: AP; cUTI; UTI; urinary tract infection; ACHN-490; pyelonephritis
• Additional Relevant MeSH Terms: Pathologic Processes; Kidney Diseases; Urologic Diseases; Disease Attributes; Nephritis; Nephritis, Interstitial; Pyelitis; Infections; Communicable Diseases; Urinary Tract Infections; Pyelonephritis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Anti-Infective Agents, Urinary; Renal Agents; Levofloxacin; Ofloxacin
• Other Study ID Numbers: ACHN-490-002