Safety, Tolerability, and Efficacy of MK-7655 (Relebactam) + Imipenem/Cilastatin Versus Imipenem/Cilastatin Alone for Treating Complicated Urinary Tract Infection (cUTI) (MK-7655-003)
Sponsor
Merck Sharp & Dohme LLC (Industry)
Overall Status
Completed
CT.gov ID
NCT01505634
Collaborator
(none)
302
3
38.4
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
302 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
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)
Actual Study Start Date
:
May 16, 2012
Actual Primary Completion Date
:
Jul 28, 2015
Actual Study Completion Date
:
Jul 28, 2015
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: 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. |
Drug: Relebactam 250 mg
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.
Other Names:
Drug: imipenem/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.
Other Names:
Drug: Ciprofloxacin
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
|
| Experimental: 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. |
Drug: Relebactam 125 mg
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.
Other Names:
Drug: imipenem/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.
Other Names:
Drug: Ciprofloxacin
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
|
| Placebo Comparator: 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. |
Drug: imipenem/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.
Other Names:
Drug: Placebo 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.
Drug: Ciprofloxacin
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
|
Outcome Measures
Primary Outcome Measures
- 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.
- 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 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 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 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.
Secondary Outcome Measures
- 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.
- 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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts 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
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Merck Sharp & Dohme LLC
Investigators
- Study Director: Medical Director, Merck Sharp & Dohme LLC
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier:
NCT01505634
Other Study ID Numbers:
- 7655-003
- 2011-005707-32
- MK-7655-003
First Posted:
Jan 6, 2012
Last Update Posted:
May 24, 2019
Last Verified:
Apr 1, 2019
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Keywords provided by Merck Sharp & Dohme LLC
Additional relevant MeSH terms:
Study Results
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. |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Relebactam 250 mg With Imipenem/Cilastatin | Relebactam 125 mg With Imipenem/Cilastatin | Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|---|
| Arm/Group Description | Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | 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. | 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. |
| Period Title: Overall Study | |||
| STARTED | 101 | 101 | 100 |
| Treated | 99 | 99 | 100 |
| COMPLETED | 92 | 91 | 94 |
| NOT COMPLETED | 9 | 10 | 6 |
Baseline Characteristics
| Arm/Group Title | Relebactam 250 mg With Imipenem/Cilastatin | Relebactam 125 mg With Imipenem/Cilastatin | Relebactam Placebo With Imipenem/Cilastatin | Total |
|---|---|---|---|---|
| Arm/Group Description | Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | 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. | 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. | Total of all reporting groups |
| Overall Participants | 101 | 101 | 100 | 302 |
| Age (Years) [Mean (Standard Deviation) ] | ||||
| Mean (Standard Deviation) [Years] |
57.9
(17.3)
|
55.9
(17.5)
|
55.7
(19.2)
|
56.5
(18.0)
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
51
50.5%
|
60
59.4%
|
42
42%
|
153
50.7%
|
| Male |
50
49.5%
|
41
40.6%
|
58
58%
|
149
49.3%
|
Outcome Measures
| Title | Percentage of Participants With a Favorable Microbiological Response at Completion of IV Study Therapy |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants in the ME population with non-missing/non-indeterminate response. |
| Arm/Group Title | Relebactam 250 mg With Imipenem/Cilastatin | Relebactam 125 mg With Imipenem/Cilastatin | Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|---|
| Arm/Group Description | Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | 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. | 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. |
| Measure Participants | 67 | 71 | 75 |
| Number (95% Confidence Interval) [Percentage of Participants] |
95.5
94.6%
|
98.6
97.6%
|
98.7
98.7%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 250 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Difference (Diff) in Favorable MR | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | Non-inferiority for the relebactam 250 mg + imipenem/cilastatin group versus the Placebo for relebactam + imipenem/cilastatin group was demonstrated if the lower bound of the 95% CI was not lower than the pre-specified non-inferiority margin of -15%. | |
| Statistical Test of Hypothesis | p-Value | 0.005 |
| Comments | ||
| Method | Miettinen and Nurminen | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | -3.1 | |
| Confidence Interval |
(2-Sided) 95% -11.2 to 3.2 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 125 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff in Favorable MR | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | Non-inferiority for the relebactam 125 mg + imipenem/cilastatin group versus the Placebo for relebactam + imipenem/cilastatin group was demonstrated if the lower bound of the 95% CI was not lower than the pre-specified non-inferiority margin of -15%. | |
| Statistical Test of Hypothesis | p-Value | < 0.001 |
| Comments | ||
| Method | Miettinen and Nurminen | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | -0.1 | |
| Confidence Interval |
(2-Sided) 95% -6.4 to 5.9 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
| Title | 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) |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received ≥ 1 dose of study treatment. |
| Arm/Group Title | Relebactam 250 mg With Imipenem/Cilastatin | Relebactam 125 mg With Imipenem/Cilastatin | Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|---|
| Arm/Group Description | Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | 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. | 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. |
| Measure Participants | 99 | 99 | 100 |
| Number [Percentage of participants] |
1.0
1%
|
1.0
1%
|
0
0%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 250 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff in Participants with Event of Clinical Interest (ECI) #1 | |
| Type of Statistical Test | Other | |
| Comments | ECI #1 is a confirmed elevated AST or ALT ≥5X ULN. Inferential testing for statistical significance with p-values and 95% confidence intervals was performed to provide a comparison between the relebactam 250 mg + imipenem/cilastatin group versus the Placebo for relebactam + imipenem/cilastatin group. | |
| Statistical Test of Hypothesis | p-Value | 0.315 |
| Comments | ||
| Method | Miettinen and Nurminen | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | 1.0 | |
| Confidence Interval |
(2-Sided) 95% -2.7 to 5.5 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 125 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff in Participants with ECI #1 | |
| Type of Statistical Test | Other | |
| Comments | ECI #1 is a confirmed elevated AST or ALT ≥5X ULN. Inferential testing for statistical significance with p-values and 95% confidence intervals was performed to provide a comparison between the relebactam 125 mg + imipenem/cilastatin group versus the Placebo for relebactam + imipenem/cilastatin group. | |
| Statistical Test of Hypothesis | p-Value | 0.315 |
| Comments | ||
| Method | Miettinen and Nurminen | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | 1.0 | |
| Confidence Interval |
(2-Sided) 95% -2.7 to 5.5 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
| Title | 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 |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received ≥ 1 dose of study treatment. |
| Arm/Group Title | Relebactam 250 mg With Imipenem/Cilastatin | Relebactam 125 mg With Imipenem/Cilastatin | Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|---|
| Arm/Group Description | Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | 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. | 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. |
| Measure Participants | 99 | 99 | 100 |
| Number [Percentage of participants] |
0
0%
|
0
0%
|
0
0%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 250 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff Participants with ECI #2 | |
| Type of Statistical Test | Other | |
| Comments | Event of Clinical Interest (ECI) #2 is elevated AST or ALT ≥3X ULN, elevated total bilirubin ≥2X ULN, and with an ALP <2X ULN. Inferential testing for statistical significance with p-values and 95% confidence intervals was performed to provide a comparison between the relebactam 250 mg + imipenem/cilastatin group versus the Placebo for relebactam + imipenem/cilastatin group. | |
| Statistical Test of Hypothesis | p-Value | > 0.999 |
| Comments | No participants met the criteria for ECI #2. | |
| Method | Miettinen and Nurminen | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | 0.0 | |
| Confidence Interval |
(2-Sided) 95% -3.7 to 3.8 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 125 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff in Participants with ECI #2 | |
| Type of Statistical Test | Other | |
| Comments | Event of Clinical Interest (ECI) #2 is elevated AST or ALT ≥3X ULN, elevated total bilirubin ≥2X ULN, and with an ALP <2X ULN. Inferential testing for statistical significance with p-values and 95% confidence intervals was performed to provide a comparison between the relebactam 125 mg + imipenem/cilastatin group versus the Placebo for relebactam + imipenem/cilastatin group. | |
| Statistical Test of Hypothesis | p-Value | > 0.999 |
| Comments | No participants met the criteria for ECI #2. | |
| Method | Miettinen and Nurminen | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | 0.0 | |
| Confidence Interval |
(2-Sided) 95% -3.7 to 3.8 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
| Title | Percentage of Participants With at Least 1 Adverse Event (AE) |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received ≥1 dose of study treatment. |
| Arm/Group Title | Relebactam 250 mg With Imipenem/Cilastatin | Relebactam 125 mg With Imipenem/Cilastatin | Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|---|
| Arm/Group Description | Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | 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. | 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. |
| Measure Participants | 99 | 99 | 100 |
| Number [Percentage of participants] |
28.3
28%
|
29.3
29%
|
30.0
30%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 250 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff in Participants with AEs | |
| Type of Statistical Test | Other | |
| Comments | Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | -1.7 | |
| Confidence Interval |
() 95% -14.3 to 10.9 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 125 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff in Participants with AEs | |
| Type of Statistical Test | Other | |
| Comments | Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | -0.7 | |
| Confidence Interval |
(2-Sided) 95% -13.4 to 12.0 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
| Title | Percentage of Participants With Any Serious Adverse Event (SAE) |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received ≥1 dose of study treatment. |
| Arm/Group Title | Relebactam 250 mg With Imipenem/Cilastatin | Relebactam 125 mg With Imipenem/Cilastatin | Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|---|
| Arm/Group Description | Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | 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. | 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. |
| Measure Participants | 99 | 99 | 100 |
| Number [Percentage of participants] |
3.0
3%
|
1.0
1%
|
3.0
3%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 250 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff in Participants with SAEs | |
| Type of Statistical Test | Other | |
| Comments | Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | 0.0 | |
| Confidence Interval |
(2-Sided) 95% -5.8 to 5.9 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 125 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff in Participants with SAEs | |
| Type of Statistical Test | Other | |
| Comments | Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | -2.0 | |
| Confidence Interval |
(2-Sided) 95% -7.6 to 2.8 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
| Title | Percentage of Participants With Any Drug-related AE |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received ≥1 dose of study treatment. |
| Arm/Group Title | Relebactam 250 mg With Imipenem/Cilastatin | Relebactam 125 mg With Imipenem/Cilastatin | Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|---|
| Arm/Group Description | Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | 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. | 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. |
| Measure Participants | 99 | 99 | 100 |
| Number [Percentage of participants] |
10.1
10%
|
9.1
9%
|
9.0
9%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 250 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff in Participants with DR AEs | |
| Type of Statistical Test | Other | |
| Comments | Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | 1.1 | |
| Confidence Interval |
(2-Sided) 95% -7.5 to 9.8 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 125 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff in Participants with DR AEs | |
| Type of Statistical Test | Other | |
| Comments | Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | 0.1 | |
| Confidence Interval |
(2-Sided) 95% -8.4 to 8.6 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
| Title | Percentage of Participants With a Drug-related SAE |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received ≥1 dose of study treatment. |
| Arm/Group Title | Relebactam 250 mg With Imipenem/Cilastatin | Relebactam 125 mg With Imipenem/Cilastatin | Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|---|
| Arm/Group Description | Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | 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. | 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. |
| Measure Participants | 99 | 99 | 100 |
| Number [Percentage of participants] |
1.0
1%
|
0
0%
|
1.0
1%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 250 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff in Participants with DR SAEs | |
| Type of Statistical Test | Other | |
| Comments | Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | 0.0 | |
| Confidence Interval |
(2-Sided) 95% -4.5 to 4.6 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 125 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff in Participants with DR SAEs | |
| Type of Statistical Test | Other | |
| Comments | Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | -1.0 | |
| Confidence Interval |
(2-Sided) 95% -5.5 to 2.8 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
| Title | Percentage of Participants Who Discontinued IV Study Therapy Due to an AE |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received ≥1 dose of study treatment. |
| Arm/Group Title | Relebactam 250 mg With Imipenem/Cilastatin | Relebactam 125 mg With Imipenem/Cilastatin | Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|---|
| Arm/Group Description | Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | 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. | 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. |
| Measure Participants | 99 | 99 | 100 |
| Number [Percentage of participants] |
3.0
3%
|
1.0
1%
|
2.0
2%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 250 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff in Participants with Discons Due to AEs | |
| Type of Statistical Test | Other | |
| Comments | Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | 1.0 | |
| Confidence Interval |
(2-Sided) 95% -4.4 to 6.8 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 125 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff in Participants with Discons Due to AEs | |
| Type of Statistical Test | Other | |
| Comments | Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | -1.0 | |
| Confidence Interval |
(2-Sided) 95% -6.1 to 3.7 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
| Title | Percentage of Participants Who Discontinued IV Study Therapy Due to a Drug-related AE |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received ≥1 dose of study treatment. |
| Arm/Group Title | Relebactam 250 mg With Imipenem/Cilastatin | Relebactam 125 mg With Imipenem/Cilastatin | Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|---|
| Arm/Group Description | Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | 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. | 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. |
| Measure Participants | 99 | 99 | 100 |
| Number [Percentage of participants] |
2.0
2%
|
1.0
1%
|
1.0
1%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 250 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff in Participants with Discons Due to DR AEs | |
| Type of Statistical Test | Other | |
| Comments | Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | 1.0 | |
| Confidence Interval |
(2-Sided) 95% -3.6 to 6.2 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 125 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff in Participants with Discons Due to DR AEs | |
| Type of Statistical Test | Other | |
| Comments | Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | 0.0 | |
| Confidence Interval |
(2-Sided) 95% -4.5 to 4.6 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
| Title | Percentage of Participants With Specific AEs With Incidence of >= 4 Participants in One Treatment Group |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received ≥1 dose of study treatment. |
| Arm/Group Title | Relebactam 250 mg With Imipenem/Cilastatin | Relebactam 125 mg With Imipenem/Cilastatin | Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|---|
| Arm/Group Description | Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | 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. | 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. |
| Measure Participants | 99 | 99 | 100 |
| Diarrhoea |
5.1
5%
|
2.0
2%
|
4.0
4%
|
| Nausea |
4.0
4%
|
6.1
6%
|
4.0
4%
|
| Bacteriuria |
1.0
1%
|
2.0
2%
|
4.0
4%
|
| White blood cells urine positive |
1.0
1%
|
1.0
1%
|
4.0
4%
|
| Headache |
7.1
7%
|
3.0
3%
|
4.0
4%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 250 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff in Participants with AEs with Rate ≥4: Diarrhoea | |
| Type of Statistical Test | Other | |
| Comments | Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | 1.1 | |
| Confidence Interval |
(2-Sided) 95% -5.5 to 7.8 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 125 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff in Participants with AEs with Rate ≥4: Diarrhoea | |
| Type of Statistical Test | Other | |
| Comments | Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | -2.0 | |
| Confidence Interval |
(2-Sided) 95% -8.1 to 3.6 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 250 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff in Participants with AEs with Rate ≥4: Nausea | |
| Type of Statistical Test | Other | |
| Comments | Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | 0.0 | |
| Confidence Interval |
(2-Sided) 95% -6.4 to 6.5 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 125 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff in Participants with AEs with Rate ≥4: Nausea | |
| Type of Statistical Test | Other | |
| Comments | Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | 2.1 | |
| Confidence Interval |
(2-Sided) 95% -4.6 to 9.2 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 250 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff in Participants with AEs with Rate ≥4: Bacteriuria | |
| Type of Statistical Test | Other | |
| Comments | Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | -3.0 | |
| Confidence Interval |
(2-Sided) 95% -9.0 to 1.9 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
Statistical Analysis 6
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 125 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff in Participants with AEs with Rate ≥4: Bacteriuria | |
| Type of Statistical Test | Other | |
| Comments | Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | -2.0 | |
| Confidence Interval |
(2-Sided) 95% -8.1 to 3.6 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
Statistical Analysis 7
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 250 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff in Participants with AEs with Rate ≥4: White blood cells urine positive | |
| Type of Statistical Test | Other | |
| Comments | Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | -3.0 | |
| Confidence Interval |
(2-Sided) 95% -9.0 to 1.9 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
Statistical Analysis 8
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 125 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff in Participants with AEs with Rate ≥4: White blood cells urine positive | |
| Type of Statistical Test | Other | |
| Comments | Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | -3.0 | |
| Confidence Interval |
(2-Sided) 95% -9.0 to 1.9 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
Statistical Analysis 9
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 250 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff in Participants with AEs with Rate ≥4: Headache | |
| Type of Statistical Test | Other | |
| Comments | Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | 3.1 | |
| Confidence Interval |
(2-Sided) 95% -3.7 to 10.4 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
Statistical Analysis 10
| Statistical Analysis Overview | Comparison Group Selection | Relebactam 125 mg With Imipenem/Cilastatin, Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|
| Comments | Percent Diff in Participants with AEs with Rate ≥4: Headache | |
| Type of Statistical Test | Other | |
| Comments | Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent Difference |
| Estimated Value | -1.0 | |
| Confidence Interval |
(2-Sided) 95% -7.2 to 5.1 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relebactam minus Placebo | |
| Title | Percentage of Participants With a Favorable Microbiological Response at Completion of IV Study Therapy Who Had Imipenem-resistant, Gram-negative cUTI Infections. |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants in the ME population with imipenem-resistant gram-negative infections at baseline. |
| Arm/Group Title | Relebactam 250 mg With Imipenem/Cilastatin | Relebactam 125 mg With Imipenem/Cilastatin | Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|---|
| Arm/Group Description | Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | 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. | 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. |
| Measure Participants | 10 | 7 | 6 |
| Number (95% Confidence Interval) [Percentage of participants] |
100.0
99%
|
100.0
99%
|
100.0
100%
|
| Title | Percentage of Participants With a Favorable Microbiological Response at Early Follow-up |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants in the ME population with non-missing/non-indeterminate response. |
| Arm/Group Title | Relebactam 250 mg With Imipenem/Cilastatin | Relebactam 125 mg With Imipenem/Cilastatin | Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|---|
| Arm/Group Description | Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | 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. | 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. |
| Measure Participants | 65 | 72 | 71 |
| Number (95% Confidence Interval) [Percentage of participants] |
61.5
60.9%
|
68.1
67.4%
|
70.4
70.4%
|
| Title | Percentage of Participants With a Favorable Clinical Response at Completion of IV Study Therapy |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants in the ME population with non-missing/nonindeterminate response. |
| Arm/Group Title | Relebactam 250 mg With Imipenem/Cilastatin | Relebactam 125 mg With Imipenem/Cilastatin | Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|---|
| Arm/Group Description | Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | 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. | 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. |
| Measure Participants | 69 | 78 | 80 |
| Number (95% Confidence Interval) [Percentage of participants] |
97.1
96.1%
|
98.7
97.7%
|
98.8
98.8%
|
| Title | Percentage of Participants With a Favorable Clinical Response at Early Follow-up |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants in the ME population with non-missing/non-indeterminate response. |
| Arm/Group Title | Relebactam 250 mg With Imipenem/Cilastatin | Relebactam 125 mg With Imipenem/Cilastatin | Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|---|
| Arm/Group Description | Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | 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. | 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. |
| Measure Participants | 64 | 73 | 76 |
| Number (95% Confidence Interval) [Percentage of Participants] |
89.1
88.2%
|
91.8
90.9%
|
93.4
93.4%
|
| Title | Percentage of Participants With a Favorable Clinical Response at Late Follow-up |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants in the ME population with non-missing/non-indeterminate response. |
| Arm/Group Title | Relebactam 250 mg With Imipenem/Cilastatin | Relebactam 125 mg With Imipenem/Cilastatin | Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|---|
| Arm/Group Description | Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | 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. | 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. |
| Measure Participants | 62 | 71 | 76 |
| Number (95% Confidence Interval) [Percentage of participants] |
88.7
87.8%
|
87.3
86.4%
|
88.2
88.2%
|
| Title | Percentage of Participants With a Favorable Microbiological Response at Late Follow-up |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants in the ME population with non-missing/non-indeterminate response. |
| Arm/Group Title | Relebactam 250 mg With Imipenem/Cilastatin | Relebactam 125 mg With Imipenem/Cilastatin | Relebactam Placebo With Imipenem/Cilastatin |
|---|---|---|---|
| Arm/Group Description | Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | 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. | 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. |
| Measure Participants | 63 | 69 | 72 |
| Number (95% Confidence Interval) [Percentage of participants] |
68.3
67.6%
|
65.2
64.6%
|
62.5
62.5%
|
Adverse Events
| Time Frame | Up to 42 days following completion of all study therapy for drug-related serious adverse events (up to 56 days); and up to 14 days following completion of all study therapy for all-cause serious and non-serious adverse events (up to 28 days). | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | AEs were reported for the All Participants as Treated Population that included all randomized participants who received ≥ 1 dose of study treatment. All-Cause Mortality included deaths outside the 14 day follow up period. | |||||
| Arm/Group Title | Relebactam 250 mg With Imipenem/Cilastatin | Relebactam 125 mg With Imipenem/Cilastatin | Relebactam Placebo With Imipenem/Cilastatin | |||
| Arm/Group Description | Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | 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. | 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. | |||
All Cause Mortality |
||||||
| Relebactam 250 mg With Imipenem/Cilastatin | Relebactam 125 mg With Imipenem/Cilastatin | Relebactam Placebo With Imipenem/Cilastatin | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 2/99 (2%) | 0/99 (0%) | 0/100 (0%) | |||
Serious Adverse Events |
||||||
| Relebactam 250 mg With Imipenem/Cilastatin | Relebactam 125 mg With Imipenem/Cilastatin | Relebactam Placebo With Imipenem/Cilastatin | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 5/99 (5.1%) | 2/99 (2%) | 3/100 (3%) | |||
| Cardiac disorders | ||||||
| Cardiac arrest | 1/99 (1%) | 1 | 0/99 (0%) | 0 | 0/100 (0%) | 0 |
| Gastrointestinal disorders | ||||||
| Diarrhoea | 1/99 (1%) | 1 | 0/99 (0%) | 0 | 1/100 (1%) | 1 |
| Duodenal ulcer | 1/99 (1%) | 1 | 0/99 (0%) | 0 | 0/100 (0%) | 0 |
| Duodenal ulcer perforation | 1/99 (1%) | 1 | 0/99 (0%) | 0 | 0/100 (0%) | 0 |
| Intestinal obstruction | 0/99 (0%) | 0 | 0/99 (0%) | 0 | 1/100 (1%) | 1 |
| Infections and infestations | ||||||
| Peritonitis | 1/99 (1%) | 1 | 0/99 (0%) | 0 | 0/100 (0%) | 0 |
| Pyelonephritis acute | 1/99 (1%) | 1 | 0/99 (0%) | 0 | 0/100 (0%) | 0 |
| Urosepsis | 0/99 (0%) | 0 | 1/99 (1%) | 1 | 0/100 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||||
| Postoperative wound complication | 0/99 (0%) | 0 | 1/99 (1%) | 1 | 0/100 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Renal cancer | 1/99 (1%) | 1 | 0/99 (0%) | 0 | 0/100 (0%) | 0 |
| Renal neoplasm | 1/99 (1%) | 1 | 0/99 (0%) | 0 | 0/100 (0%) | 0 |
| Renal and urinary disorders | ||||||
| Glomerulonephritis rapidly progressive | 0/99 (0%) | 0 | 0/99 (0%) | 0 | 1/100 (1%) | 1 |
Other (Not Including Serious) Adverse Events |
||||||
| Relebactam 250 mg With Imipenem/Cilastatin | Relebactam 125 mg With Imipenem/Cilastatin | Relebactam Placebo With Imipenem/Cilastatin | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 11/99 (11.1%) | 9/99 (9.1%) | 7/100 (7%) | |||
| Gastrointestinal disorders | ||||||
| Nausea | 4/99 (4%) | 4 | 6/99 (6.1%) | 6 | 4/100 (4%) | 5 |
| Nervous system disorders | ||||||
| Headache | 7/99 (7.1%) | 7 | 3/99 (3%) | 3 | 4/100 (4%) | 4 |
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The SPONSOR must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation. Any information identified by the SPONSOR as confidential must be deleted prior to submission.
Results Point of Contact
| Name/Title | Senior Vice President, Global Clinical Development |
|---|---|
| Organization | Merck Sharp & Dohme Corp. |
| Phone | 1-800-672-6372 |
| ClinicalTrialsDisclosure@merck.com |
Responsible Party:
Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier:
NCT01505634
Other Study ID Numbers:
- 7655-003
- 2011-005707-32
- MK-7655-003
First Posted:
Jan 6, 2012
Last Update Posted:
May 24, 2019
Last Verified:
Apr 1, 2019