Safety, Tolerability, and Efficacy of MK-7655 (Relebactam) + Imipenem/Cilastatin Versus Imipenem/Cilastatin Alone for Treating Complicated Urinary Tract Infection (cUTI) (MK-7655-003)

Merck Sharp & Dohme (MSD)

Status and phase: Completed; Phase 2

Conditions: Urinary Tract Infections; Pyelonephritis

Treatments: Drug: Ciprofloxacin; Drug: Relebactam 125 mg; Drug: Placebo to relebactam; Drug: imipenem/cilastatin 500 mg; Drug: Relebactam 250 mg

Study type: Interventional

Funder types: Industry

Identifiers

NCT01505634

2011-005707-32 (EudraCT Number)

MK-7655-003 (Other Identifier)

7655-003

Details and patient eligibility

About

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.

Enrollment: 302 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

---

302 participants in 3 patient groups, including a placebo group

Relebactam 250 mg with imipenem/cilastatin

Experimental group

Description:

Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days.

Treatment:

Drug: imipenem/cilastatin 500 mg

Drug: Relebactam 250 mg

Drug: Ciprofloxacin

Relebactam 125 mg with imipenem/cilastatin

Experimental group

Description:

Relebactam 125 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days.

Treatment:

Drug: imipenem/cilastatin 500 mg

Drug: Ciprofloxacin

Drug: Relebactam 125 mg

Relebactam placebo with imipenem/cilastatin

Placebo Comparator group

Description:

Matching placebo for relebactam (0.9% normal saline) IV co-administered with 500 mg dose of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days.

Treatment:

Drug: imipenem/cilastatin 500 mg

Drug: Ciprofloxacin

Drug: Placebo to relebactam