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 LLC302 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

302

Conditions

Urinary Tract Infections Pyelonephritis

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

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

Percentage of Participants With Any Drug-related AE

Time frame: 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.

Time frame: 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.

Time frame: Up to 14 days

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

Time frame: Up to 14 days

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

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

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

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

Time frame: 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

Time frame: 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 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.

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