Urinary Tract Infections, Pyelonephritis
Conditions
Keywords
Relebactam; MK-7655; Imipenem; Urinary Tract Infections; Pyelonephritis; Urologic Diseases; beta-Lactamase Inhibitors; Anti-Bacterial and Anti-Infective Agent
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.
Interventions
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.
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.
DRUGimipenem/cilastatin 500 mg
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.
DRUGPlacebo to relebactam
Participants randomized to receive imipenem/cilastatin alone will receive a placebo-matching infusion of IV normal saline (0.9%) once every 6 hours.
DRUGCiprofloxacin
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
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Specific AEs With Incidence of >= 4 Participants in One Treatment Group | Up to 14 days following completion of all study therapy (up to 28 days) | 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. |
| 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 | Up to 14 days following completion of all study therapy (up to 28 days) | 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. |
| Percentage of Participants With Any Serious Adverse Event (SAE) | Up to 14 days following completion of all study therapy (up to 28 days) | 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. |
| Percentage of Participants With Any Drug-related AE | Up to 14 days following completion of all study therapy (up to 28 days) | 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. |
| Percentage of Participants With a Drug-related SAE | Up to 42 days following completion of all study therapy (up to 56 days) | 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. |
| Percentage of Participants Who Discontinued IV Study Therapy Due to an AE | Up to 14 days | 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. |
| Percentage of Participants Who Discontinued IV Study Therapy Due to a Drug-related AE | Up to 14 days | 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. |
| Percentage of Participants With at Least 1 Adverse Event (AE) | Up to 14 days following completion of all study therapy (up to 28 days) | 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. |
| Percentage of Participants With a Favorable Microbiological Response at Completion of IV Study Therapy | At time of last IV dose of study drug (up to post-randomization day 14) | 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. |
| 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) | Up to 14 days following completion of all study therapy (up to 28 days) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | 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. |
| 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) | 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 | Up to 9 days following completion of all study IV and oral therapy (up to Day 23) | 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 Late Follow-up | Up to 42 days following completion of all study IV and oral therapy (up to Day 56) | 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 Microbiological Response at Late Follow-up | Up to 42 days following completion of all study IV and oral therapy (up to Day 56) | 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. |
| 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) | 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. |
Participant flow
Recruitment details
Participants were enrolled with complicated urinary tract infection (cUTI) or acute pyelonephritis judged by the investigator to be serious (requiring hospitalization and intravenous (IV) antibiotic therapy); pyuria; and 1 positive urine culture within 48 hours of enrollment.
Participants by arm
| Arm | Count |
|---|---|
| Relebactam 250 mg With Imipenem/Cilastatin 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. | 101 |
| Relebactam 125 mg With Imipenem/Cilastatin 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. | 101 |
| Relebactam Placebo With Imipenem/Cilastatin 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. | 100 |
| Total | 302 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
| Overall Study | Death | 1 | 0 | 0 |
| Overall Study | In a conflict zone | 0 | 0 | 1 |
| Overall Study | Insufficient supply of drug at site | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 1 | 4 | 4 |
| Overall Study | Physician Decision | 1 | 1 | 0 |
| Overall Study | Protocol Violation | 2 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 5 | 1 |
Baseline characteristics
| Characteristic | Relebactam 250 mg With Imipenem/Cilastatin | Relebactam 125 mg With Imipenem/Cilastatin | Relebactam Placebo With Imipenem/Cilastatin | Total |
|---|---|---|---|---|
| Age, Continuous | 57.9 Years STANDARD_DEVIATION 17.3 | 55.9 Years STANDARD_DEVIATION 17.5 | 55.7 Years STANDARD_DEVIATION 19.2 | 56.5 Years STANDARD_DEVIATION 18 |
| Sex: Female, Male Female | 51 Participants | 60 Participants | 42 Participants | 153 Participants |
| Sex: Female, Male Male | 50 Participants | 41 Participants | 58 Participants | 149 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 99 | 0 / 99 | 0 / 100 |
| other Total, other adverse events | 11 / 99 | 9 / 99 | 7 / 100 |
| serious Total, serious adverse events | 5 / 99 | 2 / 99 | 3 / 100 |
Outcome results
Primary
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.
Time frame: Up to 14 days
Population: All randomized participants who received ≥1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Relebactam 250 mg With Imipenem/Cilastatin | Percentage of Participants Who Discontinued IV Study Therapy Due to a Drug-related AE | 2.0 Percentage of participants |
| Relebactam 125 mg With Imipenem/Cilastatin | Percentage of Participants Who Discontinued IV Study Therapy Due to a Drug-related AE | 1.0 Percentage of participants |
| Relebactam Placebo With Imipenem/Cilastatin | Percentage of Participants Who Discontinued IV Study Therapy Due to a Drug-related AE | 1.0 Percentage of participants |
Comparison: Percent Diff in Participants with Discons Due to DR AEs95% CI: [-3.6, 6.2]
Comparison: Percent Diff in Participants with Discons Due to DR AEs95% CI: [-4.5, 4.6]
Primary
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
Population: All randomized participants who received ≥1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Relebactam 250 mg With Imipenem/Cilastatin | Percentage of Participants Who Discontinued IV Study Therapy Due to an AE | 3.0 Percentage of participants |
| Relebactam 125 mg With Imipenem/Cilastatin | Percentage of Participants Who Discontinued IV Study Therapy Due to an AE | 1.0 Percentage of participants |
| Relebactam Placebo With Imipenem/Cilastatin | Percentage of Participants Who Discontinued IV Study Therapy Due to an AE | 2.0 Percentage of participants |
Comparison: Percent Diff in Participants with Discons Due to AEs95% CI: [-4.4, 6.8]
Comparison: Percent Diff in Participants with Discons Due to AEs95% CI: [-6.1, 3.7]
Primary
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)
Population: All randomized participants who received ≥1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Relebactam 250 mg With Imipenem/Cilastatin | Percentage of Participants With a Drug-related SAE | 1.0 Percentage of participants |
| Relebactam 125 mg With Imipenem/Cilastatin | Percentage of Participants With a Drug-related SAE | 0 Percentage of participants |
| Relebactam Placebo With Imipenem/Cilastatin | Percentage of Participants With a Drug-related SAE | 1.0 Percentage of participants |
Comparison: Percent Diff in Participants with DR SAEs95% CI: [-4.5, 4.6]
Comparison: Percent Diff in Participants with DR SAEs95% CI: [-5.5, 2.8]
Primary
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)
Population: All participants in the ME population with non-missing/non-indeterminate response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Relebactam 250 mg With Imipenem/Cilastatin | Percentage of Participants With a Favorable Microbiological Response at Completion of IV Study Therapy | 95.5 Percentage of Participants |
| Relebactam 125 mg With Imipenem/Cilastatin | Percentage of Participants With a Favorable Microbiological Response at Completion of IV Study Therapy | 98.6 Percentage of Participants |
| Relebactam Placebo With Imipenem/Cilastatin | Percentage of Participants With a Favorable Microbiological Response at Completion of IV Study Therapy | 98.7 Percentage of Participants |
Comparison: Percent Difference (Diff) in Favorable MRp-value: 0.00595% CI: [-11.2, 3.2]Miettinen and Nurminen
Comparison: Percent Diff in Favorable MRp-value: <0.00195% CI: [-6.4, 5.9]Miettinen and Nurminen
Primary
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)
Population: All randomized participants who received ≥ 1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Relebactam 250 mg With Imipenem/Cilastatin | 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) | 1.0 Percentage of participants |
| Relebactam 125 mg With Imipenem/Cilastatin | 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) | 1.0 Percentage of participants |
| Relebactam Placebo With Imipenem/Cilastatin | 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) | 0 Percentage of participants |
Comparison: Percent Diff in Participants with Event of Clinical Interest (ECI) #1p-value: 0.31595% CI: [-2.7, 5.5]Miettinen and Nurminen
Comparison: Percent Diff in Participants with ECI #1p-value: 0.31595% CI: [-2.7, 5.5]Miettinen and Nurminen
Primary
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.
Time frame: Up to 14 days following completion of all study therapy (up to 28 days)
Population: All randomized participants who received ≥1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Relebactam 250 mg With Imipenem/Cilastatin | Percentage of Participants With Any Drug-related AE | 10.1 Percentage of participants |
| Relebactam 125 mg With Imipenem/Cilastatin | Percentage of Participants With Any Drug-related AE | 9.1 Percentage of participants |
| Relebactam Placebo With Imipenem/Cilastatin | Percentage of Participants With Any Drug-related AE | 9.0 Percentage of participants |
Comparison: Percent Diff in Participants with DR AEs95% CI: [-7.5, 9.8]
Comparison: Percent Diff in Participants with DR AEs95% CI: [-8.4, 8.6]
Primary
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)
Population: All randomized participants who received ≥1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Relebactam 250 mg With Imipenem/Cilastatin | Percentage of Participants With Any Serious Adverse Event (SAE) | 3.0 Percentage of participants |
| Relebactam 125 mg With Imipenem/Cilastatin | Percentage of Participants With Any Serious Adverse Event (SAE) | 1.0 Percentage of participants |
| Relebactam Placebo With Imipenem/Cilastatin | Percentage of Participants With Any Serious Adverse Event (SAE) | 3.0 Percentage of participants |
Comparison: Percent Diff in Participants with SAEs95% CI: [-5.8, 5.9]
Comparison: Percent Diff in Participants with SAEs95% CI: [-7.6, 2.8]
Primary
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)
Population: All randomized participants who received ≥1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Relebactam 250 mg With Imipenem/Cilastatin | Percentage of Participants With at Least 1 Adverse Event (AE) | 28.3 Percentage of participants |
| Relebactam 125 mg With Imipenem/Cilastatin | Percentage of Participants With at Least 1 Adverse Event (AE) | 29.3 Percentage of participants |
| Relebactam Placebo With Imipenem/Cilastatin | Percentage of Participants With at Least 1 Adverse Event (AE) | 30.0 Percentage of participants |
Comparison: Percent Diff in Participants with AEs95% CI: [-14.3, 10.9]
Comparison: Percent Diff in Participants with AEs95% CI: [-13.4, 12]
Primary
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)
Population: All randomized participants who received ≥ 1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Relebactam 250 mg With Imipenem/Cilastatin | 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 | 0 Percentage of participants |
| Relebactam 125 mg With Imipenem/Cilastatin | 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 | 0 Percentage of participants |
| Relebactam Placebo With Imipenem/Cilastatin | 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 | 0 Percentage of participants |
Comparison: Percent Diff in Participants with ECI #2p-value: >0.99995% CI: [-3.7, 3.8]Miettinen and Nurminen
Comparison: Percent Diff Participants with ECI #2p-value: >0.99995% CI: [-3.7, 3.8]Miettinen and Nurminen
Primary
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.
Time frame: Up to 14 days following completion of all study therapy (up to 28 days)
Population: All randomized participants who received ≥1 dose of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Relebactam 250 mg With Imipenem/Cilastatin | Percentage of Participants With Specific AEs With Incidence of >= 4 Participants in One Treatment Group | White blood cells urine positive | 1.0 Percentage of participants |
| Relebactam 250 mg With Imipenem/Cilastatin | Percentage of Participants With Specific AEs With Incidence of >= 4 Participants in One Treatment Group | Bacteriuria | 1.0 Percentage of participants |
| Relebactam 250 mg With Imipenem/Cilastatin | Percentage of Participants With Specific AEs With Incidence of >= 4 Participants in One Treatment Group | Diarrhoea | 5.1 Percentage of participants |
| Relebactam 250 mg With Imipenem/Cilastatin | Percentage of Participants With Specific AEs With Incidence of >= 4 Participants in One Treatment Group | Nausea | 4.0 Percentage of participants |
| Relebactam 250 mg With Imipenem/Cilastatin | Percentage of Participants With Specific AEs With Incidence of >= 4 Participants in One Treatment Group | Headache | 7.1 Percentage of participants |
| Relebactam 125 mg With Imipenem/Cilastatin | Percentage of Participants With Specific AEs With Incidence of >= 4 Participants in One Treatment Group | Bacteriuria | 2.0 Percentage of participants |
| Relebactam 125 mg With Imipenem/Cilastatin | Percentage of Participants With Specific AEs With Incidence of >= 4 Participants in One Treatment Group | Diarrhoea | 2.0 Percentage of participants |
| Relebactam 125 mg With Imipenem/Cilastatin | Percentage of Participants With Specific AEs With Incidence of >= 4 Participants in One Treatment Group | Nausea | 6.1 Percentage of participants |
| Relebactam 125 mg With Imipenem/Cilastatin | Percentage of Participants With Specific AEs With Incidence of >= 4 Participants in One Treatment Group | White blood cells urine positive | 1.0 Percentage of participants |
| Relebactam 125 mg With Imipenem/Cilastatin | Percentage of Participants With Specific AEs With Incidence of >= 4 Participants in One Treatment Group | Headache | 3.0 Percentage of participants |
| Relebactam Placebo With Imipenem/Cilastatin | Percentage of Participants With Specific AEs With Incidence of >= 4 Participants in One Treatment Group | Headache | 4.0 Percentage of participants |
| Relebactam Placebo With Imipenem/Cilastatin | Percentage of Participants With Specific AEs With Incidence of >= 4 Participants in One Treatment Group | White blood cells urine positive | 4.0 Percentage of participants |
| Relebactam Placebo With Imipenem/Cilastatin | Percentage of Participants With Specific AEs With Incidence of >= 4 Participants in One Treatment Group | Diarrhoea | 4.0 Percentage of participants |
| Relebactam Placebo With Imipenem/Cilastatin | Percentage of Participants With Specific AEs With Incidence of >= 4 Participants in One Treatment Group | Bacteriuria | 4.0 Percentage of participants |
| Relebactam Placebo With Imipenem/Cilastatin | Percentage of Participants With Specific AEs With Incidence of >= 4 Participants in One Treatment Group | Nausea | 4.0 Percentage of participants |
Comparison: Percent Diff in Participants with AEs with Rate ≥4: Diarrhoea95% CI: [-5.5, 7.8]
Comparison: Percent Diff in Participants with AEs with Rate ≥4: Diarrhoea95% CI: [-8.1, 3.6]
Comparison: Percent Diff in Participants with AEs with Rate ≥4: Nausea95% CI: [-6.4, 6.5]
Comparison: Percent Diff in Participants with AEs with Rate ≥4: Nausea95% CI: [-4.6, 9.2]
Comparison: Percent Diff in Participants with AEs with Rate ≥4: Bacteriuria95% CI: [-9, 1.9]
Comparison: Percent Diff in Participants with AEs with Rate ≥4: Bacteriuria95% CI: [-8.1, 3.6]
Comparison: Percent Diff in Participants with AEs with Rate ≥4: White blood cells urine positive95% CI: [-9, 1.9]
Comparison: Percent Diff in Participants with AEs with Rate ≥4: White blood cells urine positive95% CI: [-9, 1.9]
Comparison: Percent Diff in Participants with AEs with Rate ≥4: Headache95% CI: [-3.7, 10.4]
Comparison: Percent Diff in Participants with AEs with Rate ≥4: Headache95% CI: [-7.2, 5.1]
Secondary
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.
Time frame: At time of last IV dose of study drug (up to postrandomization day 14)
Population: All participants in the ME population with non-missing/nonindeterminate response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Relebactam 250 mg With Imipenem/Cilastatin | Percentage of Participants With a Favorable Clinical Response at Completion of IV Study Therapy | 97.1 Percentage of participants |
| Relebactam 125 mg With Imipenem/Cilastatin | Percentage of Participants With a Favorable Clinical Response at Completion of IV Study Therapy | 98.7 Percentage of participants |
| Relebactam Placebo With Imipenem/Cilastatin | Percentage of Participants With a Favorable Clinical Response at Completion of IV Study Therapy | 98.8 Percentage of participants |
Secondary
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.
Time frame: Up to 9 days following completion of all study IV and oral therapy (up to Day 23)
Population: All participants in the ME population with non-missing/non-indeterminate response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Relebactam 250 mg With Imipenem/Cilastatin | Percentage of Participants With a Favorable Clinical Response at Early Follow-up | 89.1 Percentage of Participants |
| Relebactam 125 mg With Imipenem/Cilastatin | Percentage of Participants With a Favorable Clinical Response at Early Follow-up | 91.8 Percentage of Participants |
| Relebactam Placebo With Imipenem/Cilastatin | Percentage of Participants With a Favorable Clinical Response at Early Follow-up | 93.4 Percentage of Participants |
Secondary
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.
Time frame: Up to 42 days following completion of all study IV and oral therapy (up to Day 56)
Population: All participants in the ME population with non-missing/non-indeterminate response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Relebactam 250 mg With Imipenem/Cilastatin | Percentage of Participants With a Favorable Clinical Response at Late Follow-up | 88.7 Percentage of participants |
| Relebactam 125 mg With Imipenem/Cilastatin | Percentage of Participants With a Favorable Clinical Response at Late Follow-up | 87.3 Percentage of participants |
| Relebactam Placebo With Imipenem/Cilastatin | Percentage of Participants With a Favorable Clinical Response at Late Follow-up | 88.2 Percentage of participants |
Secondary
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)
Population: All participants in the ME population with imipenem-resistant gram-negative infections at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Relebactam 250 mg With Imipenem/Cilastatin | Percentage of Participants With a Favorable Microbiological Response at Completion of IV Study Therapy Who Had Imipenem-resistant, Gram-negative cUTI Infections. | 100.0 Percentage of participants |
| Relebactam 125 mg With Imipenem/Cilastatin | Percentage of Participants With a Favorable Microbiological Response at Completion of IV Study Therapy Who Had Imipenem-resistant, Gram-negative cUTI Infections. | 100.0 Percentage of participants |
| Relebactam Placebo With Imipenem/Cilastatin | Percentage of Participants With a Favorable Microbiological Response at Completion of IV Study Therapy Who Had Imipenem-resistant, Gram-negative cUTI Infections. | 100.0 Percentage of participants |
Secondary
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)
Population: All participants in the ME population with non-missing/non-indeterminate response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Relebactam 250 mg With Imipenem/Cilastatin | Percentage of Participants With a Favorable Microbiological Response at Early Follow-up | 61.5 Percentage of participants |
| Relebactam 125 mg With Imipenem/Cilastatin | Percentage of Participants With a Favorable Microbiological Response at Early Follow-up | 68.1 Percentage of participants |
| Relebactam Placebo With Imipenem/Cilastatin | Percentage of Participants With a Favorable Microbiological Response at Early Follow-up | 70.4 Percentage of participants |
Secondary
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)
Population: All participants in the ME population with non-missing/non-indeterminate response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Relebactam 250 mg With Imipenem/Cilastatin | Percentage of Participants With a Favorable Microbiological Response at Late Follow-up | 68.3 Percentage of participants |
| Relebactam 125 mg With Imipenem/Cilastatin | Percentage of Participants With a Favorable Microbiological Response at Late Follow-up | 65.2 Percentage of participants |
| Relebactam Placebo With Imipenem/Cilastatin | Percentage of Participants With a Favorable Microbiological Response at Late Follow-up | 62.5 Percentage of participants |