Clinical trial NCT01505634: Safety, Tolerability, and Efficacy of MK-7655 (Relebactam) + Imipenem/Cilastatin Versus Imipenem/Cilastatin Alone for Treating Complicated Urinary Tract Infection (cUTI) (MK-7655-003)
Official title: A Phase II, Randomized, Active Comparator-Controlled Clinical Trial to Study the Safety, Tolerability, and Efficacy of MK-7655 + Imipenem/Cilastatin Versus Imipenem/Cilastatin Alone in Patients With Complicated Urinary Tract Infection (cUTI)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Urinary Tract Infections
Pyelonephritis
Keywords: Relebactam; MK-7655; Imipenem; Urinary Tract Infections; Pyelonephritis; Urologic Diseases; beta-Lactamase Inhibitors; Anti-Bacterial and Anti-Infective Agent
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2012-01-06
Enrollment: 302
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the efficacy, safety and tolerability of adding 125 mg or 250 mg doses of MK-7655 (relebactam) to imipenem/cilastatin in adults 18 years or older with complicated urinary tract infection (cUTI). The primary hypothesis is that the relebactam + imipenem/cilastatin treatment regimen is non-inferior to imipenem/cilastatin with respect to the proportion of participants with a favorable microbiological response at completion of intravenous (IV) study therapy.


Eligibility criteria: Inclusion Criteria:

- Clinically suspected and/or bacteriologically documented cUTI or acute

pyelonephritis judged by the investigator to be serious (requiring hospitalization and treatment with IV antibiotic therapy)

- Pyuria, determined by a midstream clean-catch (MSCC) or catheterized

(indwelling or straight catheter) urine specimen with greater than or equal to 10 white blood cells (WBCs) per high-power field (hpf) on standard examination of urine sediment or greater than or equal to 10 WBCs/mm3 in unspun urine

- One positive urine culture within 48 hours of enrollment

Exclusion Criteria:

- Complete obstruction of any portion of the urinary tract (requiring a

permanent indwelling urinary catheter or instrumentation), a known ileal loop, or intractable vesico-ureteral reflux

* A temporary indwelling urinary catheter is in place and cannot be removed at study entry.
* Perinephric or intrarenal abscess or known or suspected prostatitis
* Uncomplicated UTI
* Any history of recent accidental trauma to the pelvis or urinary tract
* Any amount of effective antibiotic therapy after obtaining the urine culture for admission to this study and prior to the administration of the first dose of IV study therapy
* An infection which has been treated with greater than 24 hours of systemic antibiotic therapy known to be effective against the presumed or documented etiologic pathogen(s) within the 72-hour period immediately prior to consideration for entry into the study
* History of serious allergy, hypersensitivity (e.g., anaphylaxis), or any

serious reaction to carbapenem antibiotics, any cephalosporins, penicillins, or other beta (β)-lactam agents

* History of serious allergy, hypersensitivity (e.g., anaphylaxis), or any serious reaction to other beta-lactam inhibitors (e.g., tazobactam, sulbactam, clavulanic acid)
* History of a seizure disorder
* Currently being treated with valproic acid or has received treatment with

valproic acid in the 2 weeks prior to screening.

* Rapidly progressive or terminal illness unlikely to survive the approximately 6 to 8 week study period
* Pregnant or expecting to conceive, breast feeding, or plans to breast feed

during the study

- A response to all study therapy (IV study therapy or subsequent oral

ciprofloxacin) within the timeframe of treatment specified in this protocol is

considered unlikely.

- Concurrent infection that would interfere with evaluation of response to

the study antibiotics

- Need for concomitant systemic antimicrobial agents in addition to those

designated in the various study treatment groups (use of vancomycin, daptomycin, or linezolid is allowed for certain infections)

* cUTI due to a confirmed fungal pathogen
* Currently receiving immunosuppressive therapy, including use of high-dose

corticosteroids

* Prior recipient of a renal transplantation
* Laboratory abnormalities as specified in protocol
* History of any other illness that, in the opinion of the investigator, might

confound the results of the study or pose additional risk in administering the study drug

- Currently participating in, or has participated in, any other clinical study

involving the administration of investigational or experimental medication (not

licensed by regulatory agencies) at the time of presentation or during the previous 30 days prior to screening or is anticipated to participate in such a clinical study during the course of this trial

- Estimated or actual creatinine clearance of \<5 mL/minute, or is currently undergoing hemodialysis

Primary outcomes:
measure: Percentage of Participants With a Favorable Microbiological Response at Completion of IV Study Therapy
timeFrame: At time of last IV dose of study drug (up to post-randomization day 14)
measure: Percentage of Participants With an Elevated Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) Laboratory Value That Was Greater Than or Equal to 5 Times the Upper Limit of Normal (ULN)
timeFrame: Up to 14 days following completion of all study therapy (up to 28 days)
measure: Percentage of Participants With Elevated AST or ALT Laboratory Values ≥ 3 Times the ULN, as Well as Elevated Total Bilirubin ≥ 2 Times the ULN, and Alkaline Phosphatase Values That Were < 2 Times the ULN
timeFrame: Up to 14 days following completion of all study therapy (up to 28 days)
measure: Percentage of Participants With at Least 1 Adverse Event (AE)
timeFrame: Up to 14 days following completion of all study therapy (up to 28 days)
measure: Percentage of Participants With Any Serious Adverse Event (SAE)
timeFrame: Up to 14 days following completion of all study therapy (up to 28 days)
measure: Percentage of Participants With Any Drug-related AE
timeFrame: Up to 14 days following completion of all study therapy (up to 28 days)
measure: Percentage of Participants With a Drug-related SAE
timeFrame: Up to 42 days following completion of all study therapy (up to 56 days)
measure: Percentage of Participants Who Discontinued IV Study Therapy Due to an AE
timeFrame: Up to 14 days
measure: Percentage of Participants Who Discontinued IV Study Therapy Due to a Drug-related AE
timeFrame: Up to 14 days
measure: Percentage of Participants With Specific AEs With Incidence of >= 4 Participants in One Treatment Group
timeFrame: Up to 14 days following completion of all study therapy (up to 28 days)
Secondary outcomes:
measure: Percentage of Participants With a Favorable Microbiological Response at Completion of IV Study Therapy Who Had Imipenem-resistant, Gram-negative cUTI Infections.
timeFrame: At time of last IV dose of study drug (up to post-randomization day 14)
measure: Percentage of Participants With a Favorable Microbiological Response at Early Follow-up
timeFrame: Up to 9 days following completion of all study IV and oral therapy (up to Day 23)
measure: Percentage of Participants With a Favorable Clinical Response at Completion of IV Study Therapy
timeFrame: At time of last IV dose of study drug (up to postrandomization day 14)
measure: Percentage of Participants With a Favorable Clinical Response at Early Follow-up
timeFrame: Up to 9 days following completion of all study IV and oral therapy (up to Day 23)
measure: Percentage of Participants With a Favorable Clinical Response at Late Follow-up
timeFrame: Up to 42 days following completion of all study IV and oral therapy (up to Day 56)
measure: Percentage of Participants With a Favorable Microbiological Response at Late Follow-up
timeFrame: Up to 42 days following completion of all study IV and oral therapy (up to Day 56)
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Sims M, Mariyanovski V, McLeroth P, Akers W, Lee YC, Brown ML, Du J, Pedley A, Kartsonis NA, Paschke A. Prospective, randomized, double-blind, Phase 2 dose-ranging study comparing efficacy and safety of imipenem/cilastatin plus relebactam with imipenem/cilastatin alone in patients with complicated urinary tract infections. J Antimicrob Chemother. 2017 Sep 1;72(9):2616-2626. doi: 10.1093/jac/dkx139.