A Study of Plazomicin Compared With Meropenem for the Treatment of Complicated Urinary Tract Infection (cUTI) Including Acute Pyelonephritis (AP) (EPIC)

• ClinicalTrials.gov Identifier: NCT02486627
• Recruitment Status: Completed
• First Posted: July 1, 2015
• Results First Posted: August 23, 2018
• Last Update Posted: August 23, 2018
• Sponsor: Achaogen, Inc.
• Information provided by (Responsible Party): Achaogen, Inc.

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.

Condition or disease	Intervention/treatment	Phase
Complicated Urinary Tract Infection; Acute Pyelonephritis	Drug: plazomicin; Drug: meropenem; Drug: levofloxacin (oral)	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 609 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: January 11, 2016
• Actual Primary Completion Date: September 22, 2016
• Actual Study Completion Date: September 22, 2016

Arms and Interventions

Arm	Intervention/treatment
Experimental: Plazomicin; 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).	Drug: plazomicin; Drug: levofloxacin (oral)
Active Comparator: Meropenem; 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).	Drug: meropenem; Drug: levofloxacin (oral)

Outcome Measures

Primary Outcome Measures :

1. Percentage of Patients With Composite of Microbiological Eradication and Clinical Cure in the Microbiological Modified ITT (mMITT) Population at Day 5 [ Time Frame: 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.
2. Percentage of Patients With Composite of Microbiological Eradication and Clinical Cure in the mMITT Population at Test of Cure (TOC) [ Time Frame: Day 17 TOC Visit ]
   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 :

1. Percentage of Patients With Composite of Microbiological Eradication and Clinical Cure in the ME Population at Day 5 [ Time Frame: 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.
2. Percentage of Patients With Composite of Microbiological Eradication and Clinical Cure in the ME Population at TOC [ Time Frame: Day 17 TOC Visit ]
   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.
3. Percentage of Patients With Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Up to Day 32 ]
   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.
4. Plasma Pharmacokinetics (PK): Area Under the Curve From 0 to 24 Hours (AUC 0-24h) [ Time Frame: Day 3 ]
   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.
5. Plasma PK: Maximum Observed Plasma Drug Concentration (Cmax) [ Time Frame: Day 3 ]
   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.
6. Plasma PK: Minimum Observed Plasma Drug Concentration (Cmin) [ Time Frame: Day 3 ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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])

Contacts and Locations

Sponsors and Collaborators

Achaogen, Inc.

Investigators

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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Achaogen, Inc.
• ClinicalTrials.gov Identifier: NCT02486627
• Other Study ID Numbers: ACHN-490-009; 2015-001588-37 ( EudraCT Number ); U1111-1171-1554 ( Other Identifier: WHO )
• First Posted: July 1, 2015
• Results First Posted: August 23, 2018
• Last Update Posted: August 23, 2018
• Last Verified: July 2018

Keywords provided by Achaogen, Inc.:

cUTI; AP; ACHN-490; anti-infective; anti-bacterial; antibiotic; anti-microbial; UTI; bacterial infection; Gram-negative

Additional relevant MeSH terms:

Infection; Communicable Diseases; Urinary Tract Infections; Pyelonephritis; Urologic Diseases; Nephritis, Interstitial; Nephritis; Kidney Diseases; Pyelitis; Levofloxacin; Ofloxacin; Meropenem; Anti-Infective Agents, Urinary; Anti-Infective Agents; Renal Agents; Anti-Bacterial Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 Enzyme Inhibitors