Safety, Tolerability, and Efficacy of MK-7655 (Relebactam... | NCT01505634

NCT01505634

ID	Type	Description	Link
2011-005707-32	EudraCT Number
MK-7655-003	Other Identifier	Merck Protocol Number

Status Module

Sponsor/Collaborators Module

Oversight Module

Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Relebactam 250 mg with imipenem/cilastatin	Experimental	Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days.	Drug: Relebactam 250 mg Drug: imipenem/cilastatin 500 mg Drug: Ciprofloxacin
Relebactam 125 mg with imipenem/cilastatin	Experimental	Relebactam 125 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days.	Drug: Relebactam 125 mg Drug: imipenem/cilastatin 500 mg Drug: Ciprofloxacin
Relebactam placebo with imipenem/cilastatin	Placebo Comparator	Matching placebo for relebactam (0.9% normal saline) IV co-administered with 500 mg dose of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days.	Drug: imipenem/cilastatin 500 mg Drug: Placebo to relebactam

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Relebactam 250 mg	Drug	Participants randomized to receive relebactam 250 mg will be administered a 250 mg dose of relebactam IV in a blinded fashion once every 6 hours with each dose infused over a 30-minute interval.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Percentage of Participants With a Favorable Microbiological Response at Completion of IV Study Therapy	Microbiological response (MR) was assessed based on results of bacterial cultures obtained at completion of IV study medication relative to cultures obtained at baseline. A favorable microbiological response was defined as eradication of all pathogens identified at baseline. Microbiological response was assessed separately for each participant and pathogen identified in the Microbiologically Evaluable (ME) population that included participants with a urine culture confirmed to be positive for at least 1 gram-negative and/or anaerobic pathogen(s) commonly isolated in UTI. The overall microbiological response was determined as "favorable" if all pathogens isolated from a participant at baseline demonstrated a "favorable" response (eradication) at the time point evaluated.	At time of last IV dose of study drug (up to post-randomization day 14)
Percentage of Participants With an Elevated Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) Laboratory Value That Was Greater Than or Equal to 5 Times the Upper Limit of Normal (ULN)	All randomized participants who received ≥1 dose of study treatment had AST and ALT levels measured up to 14 days following completion of all study medication. Participants who had 2 confirmed elevations of either AST or ALT that were 5 times ULN or greater were recorded.	Up to 14 days following completion of all study therapy (up to 28 days)
Percentage of Participants With Elevated AST or ALT Laboratory Values ≥ 3 Times the ULN, as Well as Elevated Total Bilirubin ≥ 2 Times the ULN, and Alkaline Phosphatase Values That Were < 2 Times the ULN	All randomized participants who received ≥1 dose of study treatment had AST, ALT, total bilirubin, and Alkaline Phosphatase (ALP) levels measured up to 14 days following completion of all study medication. Participants who had elevations of AST or ALT that were ≥3 times ULN, total bilirubin measurements that were ≥2 times ULN and, at the same time, an ALP measurement of < 2X ULN were recorded.	Up to 14 days following completion of all study therapy (up to 28 days)

Secondary Outcomes

Measure	Description	Time Frame
Percentage of Participants With a Favorable Microbiological Response at Completion of IV Study Therapy Who Had Imipenem-resistant, Gram-negative cUTI Infections.	Microbiological response was assessed based on results of bacterial cultures obtained at completion of IV study medication relative to cultures obtained at baseline. A favorable microbiological response was defined as eradication of all pathogens identified at baseline. Microbiological response was assessed separately for each participant and pathogen identified in the Microbiologically Evaluable (ME) population that included participants with a urine culture confirmed to be positive for imipenem-resistant gram-negative or anaerobic infections at baseline. The overall microbiological response was determined as "favorable" if all pathogens isolated from a participant at baseline demonstrated a "favorable" response (eradication) at the time point evaluated.

Eligibility Module

Eligibility Criteria

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/Locations Module

Name	Affiliation	Role
Medical Director	Merck Sharp & Dohme LLC	Study Director

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
28575389	Result	Sims M, Mariyanovski V, McLeroth P, Akers W, Lee YC, Brown ML, Du J, Pedley A, Kartsonis NA, Paschke A. Prospective, randomized, double-blind, Phase 2 dose-ranging study comparing efficacy and safety of imipenem/cilastatin plus relebactam with imipenem/cilastatin alone in patients with complicated urinary tract infections. J Antimicrob Chemother. 2017 Sep 1;72(9):2616-2626. doi: 10.1093/jac/dkx139.

IPD Sharing Statement Module

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	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.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

No data available

No data is available for this block.

Document Section

No data available

No data is available for this block.

Derived Section

Miscellaneous Info Module

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

Intervention Browse Module

Masking Info

Relebactam 250 mg with imipenem/cilastatin

Type of Units Analyzed

Arm/Group Information

ID	Title	Description
BG000	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.
BG001	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.
BG002	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.
BG003	Total	Total of all reporting groups

Units	Counts
Participants	BG000101 BG001101 BG002100 BG003302

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

Years

Title

Denominators

Categories

Title	Measurements
	OG00095.5(87.5 to 99.1) OG00198.6(92.4 to 100.0) OG00298.7(92.8 to 100.0)

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG002	Percent Difference (Diff) in Favorable MR	Miettinen and Nurminen		0.005		Percent Difference	-3.1			2-Sided	95	-11.2	3.2			Relebactam minus Placebo		Non-Inferiority	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%.

Primary

Percentage of Participants With an Elevated Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) Laboratory Value That Was Greater Than or Equal to 5 Times the Upper Limit of Normal (ULN)

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

All randomized participants who received ≥ 1 dose of study treatment.

Posted

Number

Percentage of participants

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

ID	Title	Description
OG000	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.
OG001	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.

Primary

Percentage of Participants With Elevated AST or ALT Laboratory Values ≥ 3 Times the ULN, as Well as Elevated Total Bilirubin ≥ 2 Times the ULN, and Alkaline Phosphatase Values That Were < 2 Times the ULN

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

All randomized participants who received ≥ 1 dose of study treatment.

Posted

Number

Percentage of participants

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

ID	Title	Description
OG000	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.
OG001	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.

Primary

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

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

All randomized participants who received ≥1 dose of study treatment.

Posted

Number

Percentage of participants

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

ID	Title	Description
OG000	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.
OG001	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.

Primary

Percentage of Participants With Any Serious Adverse Event (SAE)

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

All randomized participants who received ≥1 dose of study treatment.

Posted

Number

Percentage of participants

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

ID	Title	Description
OG000	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.
OG001	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.

Primary

Percentage of Participants With Any Drug-related AE

All randomized participants who received ≥1 dose of study treatment.

Posted

Number

Percentage of participants

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

ID	Title	Description
OG000	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.
OG001	Relebactam 125 mg With Imipenem/Cilastatin

Primary

Percentage of Participants With a Drug-related SAE

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

All randomized participants who received ≥1 dose of study treatment.

Posted

Number

Percentage of participants

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

ID	Title	Description
OG000	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.
OG001	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.

Primary

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

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

All randomized participants who received ≥1 dose of study treatment.

Posted

Number

Percentage of participants

Up to 14 days

ID	Title	Description
OG000	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.
OG001	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.

Primary

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

All randomized participants who received ≥1 dose of study treatment.

Posted

Number

Percentage of participants

Up to 14 days

ID	Title	Description
OG000	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.
OG001	Relebactam 125 mg With Imipenem/Cilastatin

Primary

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

All randomized participants who received ≥1 dose of study treatment.

Posted

Number

Percentage of participants

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

ID	Title	Description
OG000	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.
OG001	Relebactam 125 mg With Imipenem/Cilastatin

Secondary

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

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

All participants in the ME population with imipenem-resistant gram-negative infections at baseline.

Posted

Number

95% Confidence Interval

Percentage of participants

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

ID	Title	Description
OG000	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.

Secondary

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

Microbiological response was assessed based on results of bacterial cultures obtained up to 9 days following completion of all study medication (IV and oral) relative to cultures obtained at baseline. A favorable microbiological response was defined as eradication of all pathogens identified at baseline. Microbiological response was assessed separately for each participant and pathogen identified in the ME population that included participants with a urine culture confirmed to be positive for at least 1 gram-negative and/or anaerobic pathogen(s) commonly isolated in UTI. The overall microbiological response was determined as "favorable" if all pathogens isolated from a participant at baseline demonstrated a "favorable" response (eradication) at the time point evaluated.

All participants in the ME population with non-missing/non-indeterminate response.

Posted

Number

95% Confidence Interval

Percentage of participants

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

ID	Title	Description
OG000	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.
OG001

Secondary

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

Clinical response was assessed as favorable (cured or improved) or unfavorable (failure) relative to baseline. Response determination was based on physical findings including fever (or history of fever), chills or rigors (accompanied by fever), flank pain, costovertebral angle tenderness, dysuria, urinary urgency, urinary frequency, suprapubic or pelvic pain, nausea, or vomiting. Clinical response was assessed in the ME population that included participants with a urine culture confirmed to be positive for at least 1 gram-negative and/or anaerobic pathogen(s) commonly isolated in UTI.

All participants in the ME population with non-missing/nonindeterminate response.

Posted

Number

95% Confidence Interval

Percentage of participants

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

ID	Title	Description
OG000	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.
OG001	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.

Secondary

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

All participants in the ME population with non-missing/non-indeterminate response.

Posted

Number

95% Confidence Interval

Percentage of Participants

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

ID	Title	Description
OG000	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.
OG001	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.

Secondary

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

All participants in the ME population with non-missing/non-indeterminate response.

Posted

Number

95% Confidence Interval

Percentage of participants

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

ID	Title	Description
OG000	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.
OG001	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.

Secondary

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

Microbiological response was assessed based on results of bacterial cultures obtained up to 42 days following completion of all study medication (IV and oral) relative to cultures obtained at baseline. A favorable microbiological response was defined as eradication of all pathogens identified at baseline. Microbiological response was assessed separately for each participant and pathogen identified in the ME population that included participants with a urine culture confirmed to be positive for at least 1 gram-negative and/or anaerobic pathogen(s) commonly isolated in UTI. The overall microbiological response was determined as "favorable" if all pathogens isolated from a participant at baseline demonstrated a "favorable" response (eradication) at the time point evaluated.

All participants in the ME population with non-missing/non-indeterminate response.

Posted

Number

95% Confidence Interval

Percentage of participants

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

ID	Title	Description
OG000	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.
OG001

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	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.	2	99	5	99	11	99
EG001	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.	0	99	2	99	9	99
EG002	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.	0	100	3	100	7	100

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Cardiac arrest	Cardiac disorders	MedDRA 18.0	Systematic Assessment	EG0001 events1 affected99 at risk EG0010 events0 affected99 at risk EG0020 events0 affected100 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0001 events1 affected99 at risk EG0010 events0 affected99 at risk EG0021 events1 affected100 at risk
Duodenal ulcer	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0001 events1 affected99 at risk EG0010 events0 affected99 at risk EG0020 events0 affected100 at risk
Duodenal ulcer perforation	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0001 events1 affected99 at risk EG0010 events0 affected99 at risk EG0020 events0 affected100 at risk
Intestinal obstruction	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0000 events0 affected99 at risk EG0010 events0 affected99 at risk EG0021 events1 affected100 at risk
Glomerulonephritis rapidly progressive	Renal and urinary disorders	MedDRA 18.0	Systematic Assessment	EG0000 events0 affected99 at risk EG0010 events0 affected99 at risk EG0021 events1 affected100 at risk
Peritonitis	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0001 events1 affected99 at risk EG0010 events0 affected99 at risk EG0020 events0 affected100 at risk
Pyelonephritis acute	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0001 events1 affected99 at risk EG0010 events0 affected99 at risk EG0020 events0 affected100 at risk
Urosepsis	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0000 events0 affected99 at risk EG0011 events1 affected99 at risk EG0020 events0 affected100 at risk
Postoperative wound complication	Injury, poisoning and procedural complications	MedDRA 18.0	Systematic Assessment	EG0000 events0 affected99 at risk EG0011 events1 affected99 at risk EG0020 events0 affected100 at risk
Renal cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 18.0	Systematic Assessment	EG0001 events1 affected99 at risk EG0010 events0 affected99 at risk EG0020 events0 affected100 at risk
Renal neoplasm	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 18.0	Systematic Assessment	EG0001 events1 affected99 at risk EG0010 events0 affected99 at risk EG0020 events0 affected100 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Headache	Nervous system disorders	MedDRA 18.0	Systematic Assessment		EG0007 events7 affected99 at risk EG0013 events3 affected99 at risk EG0024 events4 affected100 at risk
Nausea	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment		EG0004 events4 affected99 at risk EG0016 events6 affected99 at risk EG0025 events4 affected100 at risk

ID	Term
D014552	Urinary Tract Infections
D011704	Pyelonephritis
D014570	Urologic Diseases

Ancestor Terms

ID	Term
D007239	Infections
D052776	Female Urogenital Diseases
D005261	Female Urogenital Diseases and Pregnancy Complications
D000091642	Urogenital Diseases
D052801	Male Urogenital Diseases
D009395	Nephritis, Interstitial
D009393	Nephritis
D007674	Kidney Diseases
D011702	Pyelitis

ID	Term
C568736	relebactam
D015378	Imipenem
D015377	Cilastatin
D000077728	Cilastatin, Imipenem Drug Combination
D002939	Ciprofloxacin

Ancestor Terms

ID	Term
D013845	Thienamycins
D015780	Carbapenems
D047090	beta-Lactams
D007769	Lactams
D000577	Amides
D009930	Organic Chemicals
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring
D006571	Heterocyclic Compounds
D003521	Cyclopropanes
D003516	Cycloparaffins
D006840	Hydrocarbons, Alicyclic
D006844	Hydrocarbons, Cyclic
D006838	Hydrocarbons
D005229	Fatty Acids, Monounsaturated
D005231	Fatty Acids, Unsaturated
D005227	Fatty Acids
D008055	Lipids
D004338	Drug Combinations
D004364	Pharmaceutical Preparations
D024841	Fluoroquinolones
D042462	4-Quinolones
D015363	Quinolones
D011804	Quinolines

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.