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

NCT01505634 | Completed Phase 2 Results

• 3 other identifiers: 7655-0032011-005707-32MK-7655-003
• Study Type: interventional
• Target: 302
• Locations: 0 countries
• Sites: N/A

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.

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

Outcome Measures

Primary Outcomes (10)

• Percentage of Participants With a Favorable Microbiological Response at Completion of IV Study Therapy

  Microbiological response (MR) was assessed based on results of bacterial cultures obtained at completion of IV study medication relative to cultures obtained at baseline. A favorable microbiological response was defined as eradication of all pathogens identified at baseline. Microbiological response was assessed separately for each participant and pathogen identified in the Microbiologically Evaluable (ME) population that included participants with a urine culture confirmed to be positive for at least 1 gram-negative and/or anaerobic pathogen(s) commonly isolated in UTI. The overall microbiological response was determined as "favorable" if all pathogens isolated from a participant at baseline demonstrated a "favorable" response (eradication) at the time point evaluated.

  At time of last IV dose of study drug (up to post-randomization day 14)

• 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)

  All randomized participants who received ≥1 dose of study treatment had AST and ALT levels measured up to 14 days following completion of all study medication. Participants who had 2 confirmed elevations of either AST or ALT that were 5 times ULN or greater were recorded.

  Up to 14 days following completion of all study therapy (up to 28 days)

• 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

  All randomized participants who received ≥1 dose of study treatment had AST, ALT, total bilirubin, and Alkaline Phosphatase (ALP) levels measured up to 14 days following completion of all study medication. Participants who had elevations of AST or ALT that were ≥3 times ULN, total bilirubin measurements that were ≥2 times ULN and, at the same time, an ALP measurement of \< 2X ULN were recorded.

  Up to 14 days following completion of all study therapy (up to 28 days)

• Percentage of Participants With at Least 1 Adverse Event (AE)

  An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE.

  Up to 14 days following completion of all study therapy (up to 28 days)

• Percentage of Participants With Any Serious Adverse Event (SAE)

  A SAE was an AE that resulted in death, was life threatening, resulted in persistent or significant disability/incapacity, resulted in or prolonged an existing inpatient hospitalization, was a congenital anomaly/birth defect, was a cancer, was associated with an overdose, was another important medical event.

  Up to 14 days following completion of all study therapy (up to 28 days)

• Percentage of Participants With Any Drug-related AE

  An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE. A drug-related (DR) AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product that the investigator determined to be possibly, probably, or definitely related to the treatment.

  Up to 14 days following completion of all study therapy (up to 28 days)

• Percentage of Participants With a Drug-related SAE

  A serious, drug-related (DR) AE was an AE that resulted in death, was life threatening, resulted in persistent or significant disability/incapacity, resulted in or prolonged an existing inpatient hospitalization, was a congenital anomaly/birth defect, was a cancer, was associated with an overdose, was another important medical event. The SAE was determined to be possibly, probably, or definitely related to the treatment by the investigator.

  Up to 42 days following completion of all study therapy (up to 56 days)

• Percentage of Participants Who Discontinued IV Study Therapy Due to an AE

  An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a pre-existing condition temporally associated with the use of the product was also an AE.

  Up to 14 days

• Percentage of Participants Who Discontinued IV Study Therapy Due to a Drug-related AE

  An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE. A drug-related AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product that the investigator determined to be possibly, probably, or definitely related to the treatment.

  Up to 14 days

• Percentage of Participants With Specific AEs With Incidence of >= 4 Participants in One Treatment Group

  An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE. Analysis includes specific adverse events with an incidence of ≥4 participants in one treatment group or system organ class.

  Up to 14 days following completion of all study therapy (up to 28 days)

Secondary Outcomes (6)

• Percentage of Participants With a Favorable Microbiological Response at Completion of IV Study Therapy Who Had Imipenem-resistant, Gram-negative cUTI Infections.

  At time of last IV dose of study drug (up to post-randomization day 14)

• Percentage of Participants With a Favorable Microbiological Response at Early Follow-up

  Up to 9 days following completion of all study IV and oral therapy (up to Day 23)

• Percentage of Participants With a Favorable Clinical Response at Completion of IV Study Therapy

  At time of last IV dose of study drug (up to postrandomization day 14)

• Percentage of Participants With a Favorable Clinical Response at Early Follow-up

  Up to 9 days following completion of all study IV and oral therapy (up to Day 23)

• Percentage of Participants With a Favorable Clinical Response at Late Follow-up

  Up to 42 days following completion of all study IV and oral therapy (up to Day 56)

Study Arms (3)

Relebactam 250 mg with imipenem/cilastatin

EXPERIMENTAL

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.

Drug: Relebactam 250 mg; Drug: imipenem/cilastatin 500 mg; Drug: Ciprofloxacin

Relebactam 125 mg with imipenem/cilastatin

EXPERIMENTAL

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.

Drug: Relebactam 125 mg; Drug: imipenem/cilastatin 500 mg; Drug: Ciprofloxacin

Relebactam placebo with imipenem/cilastatin

PLACEBO COMPARATOR

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.

Drug: imipenem/cilastatin 500 mg; Drug: Placebo to relebactam; Drug: Ciprofloxacin

Interventions

Relebactam 250 mg DRUG

Participants randomized to receive relebactam 250 mg will be administered a 250 mg dose of relebactam IV in a blinded fashion once every 6 hours with each dose infused over a 30-minute interval.

Also known as: MK-7655

Relebactam 250 mg with imipenem/cilastatin

Relebactam 125 mg DRUG

Participants randomized to receive relebactam 125 mg will be administered a 125 mg dose of relebactam IV in a blinded-treatment fashion once every 6 hours with each dose infused over a 30-minute interval.

Also known as: MK-7655

Relebactam 125 mg with imipenem/cilastatin

imipenem/cilastatin 500 mg DRUG

A 500 mg dose of imipenem/cilastatin will be administered IV in an open-label fashion once every 6 hours with each dose infused over a 30-minute interval.

Also known as: PRIMAXIN®, TIENAM®

Relebactam 125 mg with imipenem/cilastatin; Relebactam 250 mg with imipenem/cilastatin; Relebactam placebo with imipenem/cilastatin

Placebo to relebactam DRUG

Participants randomized to receive imipenem/cilastatin alone will receive a placebo-matching infusion of IV normal saline (0.9%) once every 6 hours.

Relebactam placebo with imipenem/cilastatin

Ciprofloxacin DRUG

After at least 96 hours of IV treatment, participants may be switched, at the discretion of the investigator, to 500 mg ciprofloxacin, administered orally, twice daily

Relebactam 125 mg with imipenem/cilastatin; Relebactam 250 mg with imipenem/cilastatin; Relebactam placebo with imipenem/cilastatin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \- 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

You may not qualify if:

• \- 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

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (1)

• 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.

  PMID: 28575389 RESULT

MeSH Terms

Conditions

Urinary Tract Infections; Pyelonephritis; Urologic Diseases

Interventions

relebactam; Imipenem; Cilastatin; Cilastatin, Imipenem Drug Combination; Ciprofloxacin

Condition Hierarchy (Ancestors)

Infections; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Nephritis, Interstitial; Nephritis; Kidney Diseases; Pyelitis

Intervention Hierarchy (Ancestors)

Thienamycins; Carbapenems; beta-Lactams; Lactams; Amides; Organic Chemicals; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Cyclopropanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Fatty Acids; Lipids; Drug Combinations; Pharmaceutical Preparations; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 4, 2012
• First Posted: January 6, 2012
• Study Start: May 16, 2012
• Primary Completion: July 28, 2015
• Study Completion: July 28, 2015
• Last Updated: May 24, 2019
• Results First Posted: May 24, 2019

Record last verified: 2019-04

Data Sharing

• IPD Sharing: Will share