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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Urinary Tract Infections, Pyelonephritis

Intervention / Treatment
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* Drug: Relebactam 250 mg
* Drug: Relebactam 125 mg
* Drug: imipenem/cilastatin 500 mg
* Drug: Placebo to relebactam
* Drug: Ciprofloxacin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Relebactam 250 mg with imipenem/cilastatin<br>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<br>* 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.<br>* Other names: MK-7655;Drug: imipenem/cilastatin 500 mg<br>* 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.<br>* Other names: PRIMAXIN®, TIENAM®;Drug: Ciprofloxacin<br>* 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<br>|
| Experimental: Relebactam 125 mg with imipenem/cilastatin<br>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<br>* 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.<br>* Other names: MK-7655;Drug: imipenem/cilastatin 500 mg<br>* 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.<br>* Other names: PRIMAXIN®, TIENAM®;Drug: Ciprofloxacin<br>* 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<br>|
| Placebo Comparator: Relebactam placebo with imipenem/cilastatin<br>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<br>* 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.<br>* Other names: PRIMAXIN®, TIENAM®;Drug: Placebo to relebactam<br>* Participants randomized to receive imipenem/cilastatin alone will receive a placebo-matching infusion of IV normal saline (0.9%) once every 6 hours.<br>Drug: Ciprofloxacin<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 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 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Favorable Clinical Response at Late Follow-up | Clinical response was assessed as favorable (cured or improved) or unfavorable (failure) relative to baseline. Response determination was based on physical findings including fever (or history of fever), chills or rigors (accompanied by fever), flank pain, costovertebral angle tenderness, dysuria, urinary urgency, urinary frequency, suprapubic or pelvic pain, nausea, or vomiting. Clinical response was assessed in the 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. | Up to 42 days following completion of all study IV and oral therapy (up to Day 56) | 
| Percentage of Participants With a Favorable Microbiological Response at Completion of IV Study Therapy Who Had Imipenem-resistant, Gram-negative cUTI Infections. | Microbiological response 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 imipenem-resistant gram-negative or anaerobic infections at baseline. 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 a Favorable Microbiological Response at Early Follow-up | Microbiological response was assessed based on results of bacterial cultures obtained up to 9 days following completion of all study medication (IV and oral) 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 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. | 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 | Clinical response was assessed as favorable (cured or improved) or unfavorable (failure) relative to baseline. Response determination was based on physical findings including fever (or history of fever), chills or rigors (accompanied by fever), flank pain, costovertebral angle tenderness, dysuria, urinary urgency, urinary frequency, suprapubic or pelvic pain, nausea, or vomiting. Clinical response was assessed in the 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. | 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 | Clinical response was assessed as favorable (cured or improved) or unfavorable (failure) relative to baseline. Response determination was based on physical findings including fever (or history of fever), chills or rigors (accompanied by fever), flank pain, costovertebral angle tenderness, dysuria, urinary urgency, urinary frequency, suprapubic or pelvic pain, nausea, or vomiting. Clinical response was assessed in the 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. | Up to 9 days following completion of all study IV and oral therapy (up to Day 23) | 
| Percentage of Participants With a Favorable Microbiological Response at Late Follow-up | Microbiological response was assessed based on results of bacterial cultures obtained up to 42 days following completion of all study medication (IV and oral) 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 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. | Up to 42 days following completion of all study IV and oral therapy (up to Day 56) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relebactam; MK-7655; Imipenem; Urinary Tract Infections; Pyelonephritis; Urologic Diseases; beta-Lactamase Inhibitors; Anti-Bacterial and Anti-Infective Agent