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

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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Complicated Urinary Tract Infection, Acute Pyelonephritis

Intervention / Treatment
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* Drug: levofloxacin
* Drug: plazomicin
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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urinary tract infection, UTI, cUTI, pyelonephritis, AP, ACHN-490