Back to resultsA Study of Plazomicin Compared With Meropenem for the Treatment of Complicated Urinary Tract Infection (cUTI) Including Acute Pyelonephritis (AP) (EPIC)
Primary Purpose
Complicated Urinary Tract Infection, Acute Pyelonephritis
Status
Completed
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
plazomicin
meropenem
levofloxacin (oral)
Sponsored by
About this trial
This is an interventional treatment trial for Complicated Urinary Tract Infection focused on measuring cUTI, AP, ACHN-490, anti-infective, anti-bacterial, antibiotic, anti-microbial, UTI, bacterial infection, Gram-negative
Eligibility Criteria
Key Inclusion Criteria:
- Pyuria
- Have a pretreatment baseline urine culture obtained within 36 hours before the start of administration of the first dose of study drug
- Clinical signs and/or symptoms of acute pyelonephritis or complicated urinary tract infection
- Normal renal function or moderate renal impairment
Key Exclusion Criteria:
- Confirmed fungal urinary tract infection at the time of randomization
- Known urinary tract infection or colonization with Gram-positive pathogens
- Current cUTI or AP is known to be caused by a pathogen resistant to meropenem
- Female participants of childbearing potential if they are known to be pregnant or have a positive pregnancy test at screening, breastfeeding, or unable or unwilling to use a highly effective method of birth control during the study and for at least 30 days following the last dose of study medication
- Any rapidly progressing disease or immediately life-threatening illness
- Documented presence of immunodeficiency or an immunocompromised condition
- Documented or known history of otologic surgery or disease including use of hearing aid, head injury leading to otologic damage, Ménière's disease, tumor of the head, neck, or auditory system, perilymphatic fistula, or autoimmune disease of the inner ear, or family history of hearing loss (excluding age-related hearing loss [onset after age of 65 years])
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Plazomicin
Meropenem
Arm Description
Patients received 15 milligrams per kilogram (mg/kg) plazomicin as an intravenous (IV) infusion once daily followed by matching placebo infusions 8 and 16 hours later. After a minimum of 4 days of IV plazomicin, patients could switch to 250 or 500 mg oral levofloxacin for a total duration of 7 to 10 days (IV plus oral).
Patients received 1.0 g meropenem as an IV infusion every 8 hours (q8h). After a minimum of 4 days of IV meropenem, patients could switch to 250 or 500 mg oral levofloxacin for a total duration of 7 to 10 days (IV plus oral).
Outcomes
Primary Outcome Measures
Percentage of Patients With Composite of Microbiological Eradication and Clinical Cure in the Microbiological Modified ITT (mMITT) Population at Day 5
Microbiological eradication was defined as a urine culture that showed the pathogen found at baseline at ≥10^5 colony forming units per milliliter (CFU/mL) was reduced to <10^4 CFU/mL. Clinical Cure at Day 5: marked improvement evidenced by complete resolution or return to premorbid levels or reduction in severity of all core baseline symptoms with worsening of none, and no new symptoms developed. Failure: Lack of improvement in core baseline symptoms of cUTI or development of new core symptoms of cUTI; adverse event (AE) requiring the discontinuation of study drug and the patient required alternative non-study antibiotic therapy for the current cUTI. Indeterminate: Insufficient data are available to allow an evaluation of clinical outcome for any reason.
Percentage of Patients With Composite of Microbiological Eradication and Clinical Cure in the mMITT Population at Test of Cure (TOC)
Microbiological eradication was defined as a urine culture that showed the pathogen found at baseline at ≥10^5 CFU/mL was reduced to <10^4 CFU/mL. Clinical Cure at TOC Visit: the complete resolution or return to premorbid levels of core symptoms of cUTI and no new symptoms develop, and no use of non-study antibiotic therapy for the current cUTI. Failure: Persistence of one or more core symptom of infection or reappearance of or development of new core symptoms that require alternative non-study antibiotic therapy for the current cUTI. Indeterminate: Insufficient data are available to allow an evaluation of clinical outcome for any reason.
Secondary Outcome Measures
Percentage of Patients With Composite of Microbiological Eradication and Clinical Cure in the ME Population at Day 5
Microbiological eradication: urine culture showed the pathogen found at baseline at ≥10^5 CFU/mL was reduced to <10^4 CFU/mL. Clinical Cure Day 5: Marked improvement defined as complete resolution or return to premorbid levels or reduction in severity of all core baseline symptoms with worsening of none, and no new symptoms develop. Failure Day 5: Lack of improvement in core baseline symptoms of cUTI or development of new core symptoms of cUTI; AE requiring the discontinuation of study drug and the patient required alternative non-study antibiotic therapy for the current cUTI.
Percentage of Patients With Composite of Microbiological Eradication and Clinical Cure in the ME Population at TOC
Microbiological eradication: urine culture showed the pathogen found at baseline at ≥10^5 CFU/mL was reduced to <10^4 CFU/mL. Clinical Cure TOC: Complete resolution or return to premorbid levels of core symptoms of cUTI and no new symptoms develop, and no use of non-study antibiotic therapy for the current cUTI. Failure TOC: Persistence of one or more core symptom of infection or reappearance of or development of new core symptoms that require alternative non-study antibiotic therapy for the current cUTI.
Percentage of Patients With Treatment-Emergent Adverse Events (TEAEs)
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.
Plasma Pharmacokinetics (PK): Area Under the Curve From 0 to 24 Hours (AUC 0-24h)
PK blood samples were collected on Day 3 (plus or minus 1 day) of study drug administration for the determination of plazomicin concentrations in plazomicin-treated patients.
Plasma PK: Maximum Observed Plasma Drug Concentration (Cmax)
PK blood samples were collected on Day 3 (plus or minus 1 day) of study drug administration for the determination of plazomicin concentrations in plazomicin-treated patients.
Plasma PK: Minimum Observed Plasma Drug Concentration (Cmin)
PK blood samples were collected on Day 3 (plus or minus 1 day) of study drug administration for the determination of plazomicin concentrations in plazomicin-treated patients.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02486627
Brief Title
A Study of Plazomicin Compared With Meropenem for the Treatment of Complicated Urinary Tract Infection (cUTI) Including Acute Pyelonephritis (AP)
Acronym
EPIC
Official Title
A Phase 3, Randomized, Multicenter, Double-Blind Study to Evaluate the Efficacy and Safety of Plazomicin Compared With Meropenem Followed by Optional Oral Therapy for the Treatment of Complicated Urinary Tract Infection (cUTI), Including Acute Pyelonephritis (AP), in Adults
Study Type
Interventional
2. Study Status
Record Verification Date
July 2018
Overall Recruitment Status
Completed
Study Start Date
January 11, 2016 (Actual)
Primary Completion Date
September 22, 2016 (Actual)
Study Completion Date
September 22, 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Achaogen, Inc.
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This was a randomized, multicenter, multinational, double-blind study comparing the efficacy and safety of plazomicin compared with meropenem followed by optional oral (PO) therapy in the treatment of cUTI, including AP, in adults.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Complicated Urinary Tract Infection, Acute Pyelonephritis
Keywords
cUTI, AP, ACHN-490, anti-infective, anti-bacterial, antibiotic, anti-microbial, UTI, bacterial infection, Gram-negative
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
609 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Plazomicin
Arm Type
Experimental
Arm Description
Patients received 15 milligrams per kilogram (mg/kg) plazomicin as an intravenous (IV) infusion once daily followed by matching placebo infusions 8 and 16 hours later. After a minimum of 4 days of IV plazomicin, patients could switch to 250 or 500 mg oral levofloxacin for a total duration of 7 to 10 days (IV plus oral).
Arm Title
Meropenem
Arm Type
Active Comparator
Arm Description
Patients received 1.0 g meropenem as an IV infusion every 8 hours (q8h). After a minimum of 4 days of IV meropenem, patients could switch to 250 or 500 mg oral levofloxacin for a total duration of 7 to 10 days (IV plus oral).
Intervention Type
Drug
Intervention Name(s)
plazomicin
Intervention Type
Drug
Intervention Name(s)
meropenem
Intervention Type
Drug
Intervention Name(s)
levofloxacin (oral)
Primary Outcome Measure Information:
Title
Percentage of Patients With Composite of Microbiological Eradication and Clinical Cure in the Microbiological Modified ITT (mMITT) Population at Day 5
Description
Microbiological eradication was defined as a urine culture that showed the pathogen found at baseline at ≥10^5 colony forming units per milliliter (CFU/mL) was reduced to <10^4 CFU/mL. Clinical Cure at Day 5: marked improvement evidenced by complete resolution or return to premorbid levels or reduction in severity of all core baseline symptoms with worsening of none, and no new symptoms developed. Failure: Lack of improvement in core baseline symptoms of cUTI or development of new core symptoms of cUTI; adverse event (AE) requiring the discontinuation of study drug and the patient required alternative non-study antibiotic therapy for the current cUTI. Indeterminate: Insufficient data are available to allow an evaluation of clinical outcome for any reason.
Time Frame
Day 5
Title
Percentage of Patients With Composite of Microbiological Eradication and Clinical Cure in the mMITT Population at Test of Cure (TOC)
Description
Microbiological eradication was defined as a urine culture that showed the pathogen found at baseline at ≥10^5 CFU/mL was reduced to <10^4 CFU/mL. Clinical Cure at TOC Visit: the complete resolution or return to premorbid levels of core symptoms of cUTI and no new symptoms develop, and no use of non-study antibiotic therapy for the current cUTI. Failure: Persistence of one or more core symptom of infection or reappearance of or development of new core symptoms that require alternative non-study antibiotic therapy for the current cUTI. Indeterminate: Insufficient data are available to allow an evaluation of clinical outcome for any reason.
Time Frame
Day 17 TOC Visit
Secondary Outcome Measure Information:
Title
Percentage of Patients With Composite of Microbiological Eradication and Clinical Cure in the ME Population at Day 5
Description
Microbiological eradication: urine culture showed the pathogen found at baseline at ≥10^5 CFU/mL was reduced to <10^4 CFU/mL. Clinical Cure Day 5: Marked improvement defined as complete resolution or return to premorbid levels or reduction in severity of all core baseline symptoms with worsening of none, and no new symptoms develop. Failure Day 5: Lack of improvement in core baseline symptoms of cUTI or development of new core symptoms of cUTI; AE requiring the discontinuation of study drug and the patient required alternative non-study antibiotic therapy for the current cUTI.
Time Frame
Day 5
Title
Percentage of Patients With Composite of Microbiological Eradication and Clinical Cure in the ME Population at TOC
Description
Microbiological eradication: urine culture showed the pathogen found at baseline at ≥10^5 CFU/mL was reduced to <10^4 CFU/mL. Clinical Cure TOC: Complete resolution or return to premorbid levels of core symptoms of cUTI and no new symptoms develop, and no use of non-study antibiotic therapy for the current cUTI. Failure TOC: Persistence of one or more core symptom of infection or reappearance of or development of new core symptoms that require alternative non-study antibiotic therapy for the current cUTI.
Time Frame
Day 17 TOC Visit
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.
Time Frame
Up to Day 32
Title
Plasma Pharmacokinetics (PK): Area Under the Curve From 0 to 24 Hours (AUC 0-24h)
Description
PK blood samples were collected on Day 3 (plus or minus 1 day) of study drug administration for the determination of plazomicin concentrations in plazomicin-treated patients.
Time Frame
Day 3
Title
Plasma PK: Maximum Observed Plasma Drug Concentration (Cmax)
Description
PK blood samples were collected on Day 3 (plus or minus 1 day) of study drug administration for the determination of plazomicin concentrations in plazomicin-treated patients.
Time Frame
Day 3
Title
Plasma PK: Minimum Observed Plasma Drug Concentration (Cmin)
Description
PK blood samples were collected on Day 3 (plus or minus 1 day) of study drug administration for the determination of plazomicin concentrations in plazomicin-treated patients.
Time Frame
Day 3
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Key Inclusion Criteria:
Pyuria
Have a pretreatment baseline urine culture obtained within 36 hours before the start of administration of the first dose of study drug
Clinical signs and/or symptoms of acute pyelonephritis or complicated urinary tract infection
Normal renal function or moderate renal impairment
Key Exclusion Criteria:
Confirmed fungal urinary tract infection at the time of randomization
Known urinary tract infection or colonization with Gram-positive pathogens
Current cUTI or AP is known to be caused by a pathogen resistant to meropenem
Female participants of childbearing potential if they are known to be pregnant or have a positive pregnancy test at screening, breastfeeding, or unable or unwilling to use a highly effective method of birth control during the study and for at least 30 days following the last dose of study medication
Any rapidly progressing disease or immediately life-threatening illness
Documented presence of immunodeficiency or an immunocompromised condition
Documented or known history of otologic surgery or disease including use of hearing aid, head injury leading to otologic damage, Ménière's disease, tumor of the head, neck, or auditory system, perilymphatic fistula, or autoimmune disease of the inner ear, or family history of hearing loss (excluding age-related hearing loss [onset after age of 65 years])
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lynn E Connolly, MD, PhD
Organizational Affiliation
Achaogen, Inc.
Official's Role
Study Director
12. IPD Sharing Statement
Citations:
PubMed Identifier
30786187
Citation
Wagenlehner FME, Cloutier DJ, Komirenko AS, Cebrik DS, Krause KM, Keepers TR, Connolly LE, Miller LG, Friedland I, Dwyer JP; EPIC Study Group. Once-Daily Plazomicin for Complicated Urinary Tract Infections. N Engl J Med. 2019 Feb 21;380(8):729-740. doi: 10.1056/NEJMoa1801467.
Results Reference
derived
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A Study of Plazomicin Compared With Meropenem for the Treatment of Complicated Urinary Tract Infection (cUTI) Including Acute Pyelonephritis (AP)
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