RESTORE-IMI 1: Efficacy and Safety of Imipenem+Cilastatin/Relebactam (MK-7655A) Versus Colistimethate Sodium+Imipenem+Cilastatin in Imipenem-Resistant Bacterial Infection (MK-7655A-013)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02452047
• Collaborator: (none)
• Enrollment: 50
• Arms: 3
• Actual Duration (Months): 24.9

Study Details

Study Description

Brief Summary

The study will evaluate the efficacy and safety of imipenem+cilastatin/relebactam (MK-7655A) versus colistimethate sodium+imipenem+cilastatin in the treatment of imipenem-resistant bacterial infections. Infections evaluated in the study will be hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), complicated intra-abdominal infection (cIAI), and complicated urinary tract infection (cUTI).

Condition or Disease	Intervention/Treatment	Phase
Bacterial Infections	Drug: Imipenem+Cilastatin/Relebactam; Drug: Colistimethate sodium (CMS); Drug: Imipenem+Cilastatin; Drug: Placebo to CMS	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase III, Randomized, Double-Blind, Active Comparator-Controlled Clinical Trial to Estimate the Efficacy and Safety of Imipenem/Cilastatin/Relebactam (MK-7655A) Versus Colistimethate Sodium + Imipenem/Cilastatin in Subjects With Imipenem-Resistant Bacterial Infection
• Actual Study Start Date: Aug 21, 2015
• Actual Primary Completion Date: Sep 18, 2017
• Actual Study Completion Date: Sep 18, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group 1: Imipenem+Cilastatin/Relebactam Participants will be stratified by infection type (HABP/VABP, cIAI, and cUTI) and randomized to receive imipenem+cilastatin/relebactam intravenous (IV) infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days for cIAI and cUTI or for 7 to 21 days for HABP or VABP. Treatment durations >21 days may be approved by the Sponsor for participants requiring longer treatment duration.	Drug: Imipenem+Cilastatin/Relebactam; Imipenem+Cilastatin/Relebactam 200/100 mg to 500/250 mg, depending on renal function, IV infusion once every 6 hours; Other Names: MK-7655A ; Drug: Placebo to CMS; Placebo to CMS IV infusion once every 12 hours
Active Comparator: Group 2: Colistimethate sodium + Imipenem+Cilastatin Participants will be stratified by infection type (HABP/VABP, cIAI, and cUTI) and randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days for cIAI and cUTI or for 7 to 21 days for HABP or VABP. Treatment durations >21 days may be approved by the Sponsor for participants requiring longer treatment duration.	Drug: Colistimethate sodium (CMS); Colistimethate base activity 300 mg (~720 mg CMS) IV infusion loading dose, followed by colistimethate base activity 75 mg to 150 mg (~180 to 360 mg CMS), depending on renal function, once every 12 hours; Drug: Imipenem+Cilastatin; Imipenem+cilastatin 200 mg to 500 mg, depending on renal function, IV infusion once every 6 hours
Experimental: Group 3: Imipenem+Cilastatin/Relebactam Participants with documented imipenem-resistant and colistin-resistant bacterial infections may be eligible to receive open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days for cIAI and cUTI or for 7 to 21 days for HABP or VABP. Treatment durations >21 days may be approved by the Sponsor for participants requiring longer treatment duration.	Drug: Imipenem+Cilastatin/Relebactam; Imipenem+Cilastatin/Relebactam 200/100 mg to 500/250 mg, depending on renal function, IV infusion once every 6 hours; Other Names: MK-7655A

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Favorable Overall Response (FOR) [Up to Day 30 (up to 9 days after completing study treatment)]

   The percentage of participants with FOR was determined for Groups 1 and 2. FOR was determined based on clinically relevant outcomes for the primary site of infection as follows: HABP/VABP: survival through Day 28; cIAI: favorable clinical response (all pretherapy symptoms of index infection resolved with no evidence of resurgence, no additional antibiotic therapy required, and no unplanned surgical or percutaneous drainage procedures) at Day 28; cUTI: favorable composite clinical response (all pretherapy symptoms of index infection resolved with no evidence of resurgence, no additional antibiotic therapy required) and microbiological response (urine culture shows sustained eradication of the baseline uropathogen [e.g., ≥10^5 CFU/mL at study entry is reduced to <10^4 CFU/mL]) at Early Follow-up (EFU).

2. Percentage of Participants With ≥1 Adverse Events (AEs) [Up to Day 35 (up to 14 days after completing study treatment)]

   The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 AEs during treatment and 14-day follow-up was determined. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.

3. Percentage of Participants With ≥1 Serious Adverse Events (SAEs) [Up to Day 35 (up to 14 days after completing study treatment)]

   The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 SAEs during treatment and 14-day follow-up was determined. An SAE is any untoward medical occurrence that, at any dose, results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant injury/incapacity; is a congenital anomaly/birth defect; or is an other important medical event. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.

4. Percentage of Participants With ≥1 Drug-Related AEs [Up to Day 35 (up to 14 days after completing study treatment)]

   The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 drug-related AEs during treatment and 14-day follow-up was determined. A drug-related AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, and considered by the investigator to be related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.

5. Percentage of Participants With ≥1 Drug-Related SAEs [Up to Day 35 (up to 14 days after completing study treatment)]

   The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 drug-related SAEs during treatment and 14-day follow-up was determined. A drug-related SAE is any untoward medical occurrence that, at any dose, results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant injury/incapacity; is a congenital anomaly/birth defect; or is an other important medical event, that is considered by the investigator to be related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.

6. Percentage of Participants Discontinuing From Study Therapy Due to ≥1 AEs [Up to Day 21]

   The percentage of participants in Group 1, 2, and 3 discontinuing from study drug due to ≥1 AEs during the treatment period was determined. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.

7. Percentage of Participants Discontinuing From Study Therapy Due to ≥1 Drug-Related AEs [Up to Day 21]

   The percentage of participants in Groups 1, 2, and 3 discontinuing from study drug due to ≥1 drug-related AEs during the treatment period was determined. A drug-related AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, and considered by the investigator to be related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.

8. Analysis of Specific AEs With an Incidence of ≥4 Participants in a Treatment Group [Up to Day 35 (up to 14 days after completing study treatment)]

   The percentage of participants experiencing AEs that occurred in ≥4 participants within either Group 1 or Group 2 was assessed. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol; Group 3 had <4 participants and therefore no data are presented.

9. Percentage of Participants With ≥1 Events of Clinical Interest (ECI) [Up to Day 35 (up to 14 days after completing study treatment)]

   The percentage of participants in Groups 1, 2, and 3 having ECIs within 2 categories was determined. Category 1 ECIs included post-baseline laboratory values of an elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value that is ≥3x upper limit of normal (ULN) and an elevated total bilirubin value that is ≥2x ULN and (at the same time) an alkaline phosphatase value that is ≤2x ULN. Category 2 ECIs included a confirmed elevated AST or ALT value that is ≥5x ULN. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.

Secondary Outcome Measures

1. Percentage of Participants With ≥1 Events of Treatment-Emergent Nephrotoxicity [Up to Day 35 (up to 14 days after completing study treatment)]

   Treatment-emergent nephrotoxity was assessed in Groups 1 and 2 as indicated by the protocol (Group 3 was not included). Nephrotoxicity for participants with normal baseline serum creatinine levels (<1.2 mg/dL) was defined as "doubling of serum creatinine to >1.2 mg/dL or reduction in creatinine clearance (ClCR) of ≥50%". Nephrotoxicity for participants with pre-existing renal dysfunction (baseline serum creatinine level ≥1.2 mg/dL) was defined as "increase in serum creatinine by ≥1 mg/dL or reduction from baseline ClCR of ≥20% or need for renal replacement therapy (RRT)".

2. Percentage of Participants With Favorable Clinical Response (FCR) at Day 28 [Day 28]

   The percentage of participants with FCR at Day 28 was determined for Groups 1 and 2. FCR at Day 28 was defined as "sustained cure" or "cure". Sustained cure (for participants with "cure" response at the prior visit) was defined as "all pretherapy signs and symptoms of index infection resolved with no evidence of resurgence and no additional antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures have been performed". Cure (for participants with "improved" response at EOT visit) was defined as "all pretherapy signs and symptoms of index infection resolved or returned to preinfection status, and no additional IV antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures performed".

3. Percentage of Participants With All-cause Mortality Up to Day 28 [Up to Day 28]

   The percentage of participants with all-cause mortality up to Day 28 was determined for Groups 1 and 2.

4. Percentage of Participants With FCR on Therapy (OTX) [OTX (Day 3)]

   The percentage of participants with a FCR at OTX was determined for Groups 1 and 2. FCR at OTX was defined as "improved". Improved was defined as "all or most pretherapy signs and symptoms of index infection have improved or resolved, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures have been performed.

5. Percentage of Participants With FCR at End of Therapy (EOT) [At EOT (up to Day 21)]

   The percentage of participants with FCR at EOT was determined for Groups 1 and 2. FCR at EOT was defined as "cure" or "improved". Cure was defined as "all pretherapy signs and symptoms of index infection resolved or returned to preinfection status, and no additional IV antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures performed". Improved was defined as "all or most pretherapy signs and symptoms of index infection have improved or resolved, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures have been performed.

6. Percentage of Participants With FCR at EFU [EFU (Between Day 10 and Day 30 [5 to 9 Days after EOT])]

   The percentage of participants with FCR at EFU was determined for Groups 1 and 2. FCR at EFU was defined as "sustained cure" or "cure". Sustained cure (for participants with "cure" response at the prior visit) was defined as "all pretherapy signs and symptoms of index infection resolved with no evidence of resurgence and no additional antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures have been performed". Cure (for participants with "improved" response at EOT visit) was defined as "all pretherapy signs and symptoms of index infection resolved or returned to preinfection status, and no additional IV antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures performed".

7. Percentage of cUTI Participants With Favorable Microbiological Response (FMR) at OTX [OTX (Day 3)]

   The percentage of participants with FMR at OTX was determined for participants with cUTI in Groups 1 and 2. FMR was defined as "urine culture results at OTX showing eradication (i.e., ≥10^5 colony forming units [CFU]/mL at baseline was reduced to <10^4 CFU/mL at OTX) of the uropathogen".

8. Percentage of cUTI Participants With FMR at EOT [At EOT (up to Day 21)]

   The percentage of participants with FMR at EOT was determined for participants with cUTI in Groups 1 and 2. FMR was defined as "urine culture results at EOT showing eradication (i.e., ≥10^5 CFU/mL at baseline was reduced to <10^4 CFU/mL at EOT) or sustained eradication (i.e., ≥10^5 CFU/mL at baseline that was reduced to <10^4 CFU/mL previously remained <10^4 CFU/mL at EOT) of the uropathogen".

9. Percentage of cUTI Participants With FMR at EFU [EFU (Between Day 10 and Day 30 [5 to 9 Days after EOT])]

   The percentage of participants with FMR at EFU was determined for participants with cUTI in Groups 1 and 2. FMR was defined as "urine culture results at EFU showing sustained eradication (i.e., ≥10^5 CFU/mL at baseline that was reduced to <10^4 CFU/mL previously remained <10^4 CFU/mL at EFU) of the uropathogen".

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Hospitalization that requires treatment with IV antibiotic therapy for a new, persistent or progressing bacterial infection involving at least 1 of 3 primary infection types (HABP, VABP, cIAI, or cUTI)

• Positive culture data from the primary infection-site specimen collected within 1 week of study entry. At least one of the suspected causative pathogens from the specimen meets all of the following: 1) identified as a Gram-negative bacterium, 2) culture-confirmed imipenem resistance (and colistin resistance for Group 3 only), 3) culture-confirmed susceptibility to imipenem/relebactam and to colistin (for Groups 1 and 2 only)

• Not of reproductive potential, or of reproductive potential and agrees to avoid becoming pregnant or impregnating a partner by complying with one of the following: 1) practice abstinence, or 2) use of acceptable contraception during heterosexual activity

Exclusion Criteria:

• Concurrent infection (endocarditis, osteomyelitis, meningitis, prosthetic joint infection, disseminated fungal infection, or active pulmonary tuberculosis) that would interfere with evaluation of the response to the study antibiotics

• Received treatment with any form of systemic colistin for >24 hours within 72 hours before initiation of study drug (for Groups 1 and 2 only)

• HABP or VABP caused by an obstructive process

• cUTI which meets any of the following: 1) complete obstruction of any portion of the urinary tract, 2) known ileal loop, 3) intractable vesico-ureteral reflux, 4) presence of an indwelling urinary catheter which cannot be removed at study entry

• History of serious allergy, hypersensitivity, or any serious reaction to listed antibiotics (per-protocol)

• Female who is pregnant or is expecting to conceive (or a male partner of a female who is expecting to conceive), is breastfeeding, or plans to breastfeed before completion of the study

• Anticipated treatment with any of the following during the study: valproic acid or divalproex sodium, or concomitant systemic (e.g. IV, oral or inhaled) antimicrobial agents with known Gram-negative bacterial coverage

• Currently undergoing hemodialysis or peritoneal dialysis

• Participated or anticipates participating in any other clinical study involving administration of investigational medication up to 30 days before screening or during the course of the trial

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)

• Study Protocol and Statistical Analysis Plan - Sep 11, 2017

More Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT02452047
• Other Study ID Numbers: 7655A-013; 2015-000066-62; 163367
• First Posted: May 22, 2015
• Last Update Posted: Oct 19, 2018
• Last Verified: Oct 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Infections; Communicable Diseases; Bacterial Infections; Imipenem; Relebactam; Cilastatin, Imipenem Drug Combination; Cilastatin

Study Results

Participant Flow

Recruitment Details	Adult participants with hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), complicated intra-abdominal infection (cIAI), or complicated urinary tract infection (cUTI) were recruited at 35 study centers in 17 countries.

Arm/Group Title	Group 1: Imipenem+Cilastatin/Relebactam	Group 2: Colistimethate Sodium + Imipenem+Cilastatin	Group 3: Open-Label Imipenem+Cilastatin/Relebactam
Arm/Group Description	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Period Title: Overall Study
STARTED	31	16	3
COMPLETED	27	11	1
NOT COMPLETED	4	5	2

Baseline Characteristics

Arm/Group Title	Group 1: Imipenem+Cilastatin/Relebactam	Group 2: Colistimethate Sodium + Imipenem+Cilastatin	Group 3: Open-Label Imipenem+Cilastatin/Relebactam	Total
Arm/Group Description	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Total of all reporting groups
Overall Participants	31	16	3	50
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	56.1 (16.5)	62.8 (14.9)	50.0 (23.1)	57.9 (16.4)
Sex: Female, Male (Count of Participants)
Female	11 35.5%	6 37.5%	2 66.7%	19 38%
Male	20 64.5%	10 62.5%	1 33.3%	31 62%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 3.2%	0 0%	0 0%	1 2%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	1 6.3%	0 0%	1 2%
White	26 83.9%	15 93.8%	3 100%	44 88%
More than one race	4 12.9%	0 0%	0 0%	4 8%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Favorable Overall Response (FOR)
Description	The percentage of participants with FOR was determined for Groups 1 and 2. FOR was determined based on clinically relevant outcomes for the primary site of infection as follows: HABP/VABP: survival through Day 28; cIAI: favorable clinical response (all pretherapy symptoms of index infection resolved with no evidence of resurgence, no additional antibiotic therapy required, and no unplanned surgical or percutaneous drainage procedures) at Day 28; cUTI: favorable composite clinical response (all pretherapy symptoms of index infection resolved with no evidence of resurgence, no additional antibiotic therapy required) and microbiological response (urine culture shows sustained eradication of the baseline uropathogen [e.g., ≥10^5 CFU/mL at study entry is reduced to <10^4 CFU/mL]) at Early Follow-up (EFU).
Time Frame	Up to Day 30 (up to 9 days after completing study treatment)

Outcome Measure Data

Analysis Population Description

Participants in Groups 1 and 2 who received ≥1 dose of each trial drug within a given IV treatment regimen, and who had a baseline bacterial pathogen that met inclusion criteria, are included. As per protocol, efficacy data from open-label Group 3 was considered exploratory and not included in the comparative analysis.

Arm/Group Title	Group 1: Imipenem+Cilastatin/Relebactam	Group 2: Colistimethate Sodium + Imipenem+Cilastatin	Group 3: Open-Label Imipenem+Cilastatin/Relebactam
Arm/Group Description	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Measure Participants	21	10	0
Number (95% Confidence Interval) [Percentage of Participants]	71.4 230.3%	70.0 437.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: Imipenem+Cilastatin/Relebactam, Group 2: Colistimethate Sodium + Imipenem+Cilastatin
	Comments
	Type of Statistical Test	Other
	Comments	Difference in percentages
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in FOR %
	Estimated Value	-7.3
	Confidence Interval	(2-Sided) 90%; -27.5 to 21.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Stratified Miettinen & Nurminen method by infection type

2. Primary Outcome

Title	Percentage of Participants With ≥1 Adverse Events (AEs)
Description	The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 AEs during treatment and 14-day follow-up was determined. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.
Time Frame	Up to Day 35 (up to 14 days after completing study treatment)

Outcome Measure Data

Analysis Population Description

All participants in Groups 1, 2, and 3 who received ≥1 dose of study drug are included.

Arm/Group Title	Group 1: Imipenem+Cilastatin/Relebactam	Group 2: Colistimethate Sodium + Imipenem+Cilastatin	Group 3: Open-Label Imipenem+Cilastatin/Relebactam
Arm/Group Description	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Measure Participants	31	16	3
Number [Percentage of Participants]	71.0 229%	81.3 508.1%	100.0 3333.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: Imipenem+Cilastatin/Relebactam, Group 2: Colistimethate Sodium + Imipenem+Cilastatin
	Comments
	Type of Statistical Test	Other
	Comments	Difference in percentages
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in AE %
	Estimated Value	-10.3
	Confidence Interval	(2-Sided) 95%; -33.1 to 18.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Miettinen & Nurminen method

3. Primary Outcome

Title	Percentage of Participants With ≥1 Serious Adverse Events (SAEs)
Description	The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 SAEs during treatment and 14-day follow-up was determined. An SAE is any untoward medical occurrence that, at any dose, results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant injury/incapacity; is a congenital anomaly/birth defect; or is an other important medical event. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.
Time Frame	Up to Day 35 (up to 14 days after completing study treatment)

Outcome Measure Data

Analysis Population Description

All participants in Groups 1, 2, and 3 who received ≥1 dose of study drug are included.

Arm/Group Title	Group 1: Imipenem+Cilastatin/Relebactam	Group 2: Colistimethate Sodium + Imipenem+Cilastatin	Group 3: Open-Label Imipenem+Cilastatin/Relebactam
Arm/Group Description	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Measure Participants	31	16	3
Number [Percentage of Participants]	9.7 31.3%	31.3 195.6%	100.0 3333.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: Imipenem+Cilastatin/Relebactam, Group 2: Colistimethate Sodium + Imipenem+Cilastatin
	Comments
	Type of Statistical Test	Other
	Comments	Difference in percentages
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in SAE %
	Estimated Value	-21.6
	Confidence Interval	(2-Sided) 95%; -47.8 to 1.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Miettinen & Nurminen method

4. Primary Outcome

Title	Percentage of Participants With ≥1 Drug-Related AEs
Description	The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 drug-related AEs during treatment and 14-day follow-up was determined. A drug-related AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, and considered by the investigator to be related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.
Time Frame	Up to Day 35 (up to 14 days after completing study treatment)

Outcome Measure Data

Analysis Population Description

All participants in Groups 1, 2, and 3 who received ≥1 dose of study drug are included.

Arm/Group Title	Group 1: Imipenem+Cilastatin/Relebactam	Group 2: Colistimethate Sodium + Imipenem+Cilastatin	Group 3: Open-Label Imipenem+Cilastatin/Relebactam
Arm/Group Description	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Measure Participants	31	16	3
Number [Percentage of Participants]	16.1 51.9%	31.3 195.6%	33.3 1110%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: Imipenem+Cilastatin/Relebactam, Group 2: Colistimethate Sodium + Imipenem+Cilastatin
	Comments
	Type of Statistical Test	Other
	Comments	Difference in percentages
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in drug-related AE %
	Estimated Value	-15.1
	Confidence Interval	(2-Sided) 95%; -42.3 to 9.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Miettinen & Nurminen method

5. Primary Outcome

Title	Percentage of Participants With ≥1 Drug-Related SAEs
Description	The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 drug-related SAEs during treatment and 14-day follow-up was determined. A drug-related SAE is any untoward medical occurrence that, at any dose, results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant injury/incapacity; is a congenital anomaly/birth defect; or is an other important medical event, that is considered by the investigator to be related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.
Time Frame	Up to Day 35 (up to 14 days after completing study treatment)

Outcome Measure Data

Analysis Population Description

All participants in Groups 1, 2, and 3 who received ≥1 dose of study drug are included.

Arm/Group Title	Group 1: Imipenem+Cilastatin/Relebactam	Group 2: Colistimethate Sodium + Imipenem+Cilastatin	Group 3: Open-Label Imipenem+Cilastatin/Relebactam
Arm/Group Description	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Measure Participants	31	16	3
Number [Percentage of Participants]	0.0 0%	0.0 0%	33.3 1110%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: Imipenem+Cilastatin/Relebactam, Group 2: Colistimethate Sodium + Imipenem+Cilastatin
	Comments
	Type of Statistical Test	Other
	Comments	Difference in percentages
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in drug-related SAE %
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -19.7 to 11.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Miettinen & Nurminen method

6. Primary Outcome

Title	Percentage of Participants Discontinuing From Study Therapy Due to ≥1 AEs
Description	The percentage of participants in Group 1, 2, and 3 discontinuing from study drug due to ≥1 AEs during the treatment period was determined. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.
Time Frame	Up to Day 21

Outcome Measure Data

Analysis Population Description

All participants in Groups 1, 2, and 3 who received ≥1 dose of study drug are included.

Arm/Group Title	Group 1: Imipenem+Cilastatin/Relebactam	Group 2: Colistimethate Sodium + Imipenem+Cilastatin	Group 3: Open-Label Imipenem+Cilastatin/Relebactam
Arm/Group Description	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Measure Participants	31	16	3
Number [Percentage of Participants]	0.0 0%	18.8 117.5%	33.3 1110%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: Imipenem+Cilastatin/Relebactam, Group 2: Colistimethate Sodium + Imipenem+Cilastatin
	Comments
	Type of Statistical Test	Other
	Comments	Difference in percentages
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in discontinuation %
	Estimated Value	-18.8
	Confidence Interval	(2-Sided) 95%; -43.3 to -6.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Miettinen & Nurminen method

7. Primary Outcome

Title	Percentage of Participants Discontinuing From Study Therapy Due to ≥1 Drug-Related AEs
Description	The percentage of participants in Groups 1, 2, and 3 discontinuing from study drug due to ≥1 drug-related AEs during the treatment period was determined. A drug-related AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, and considered by the investigator to be related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.
Time Frame	Up to Day 21

Outcome Measure Data

Analysis Population Description

All participants in Groups 1, 2, and 3 who received ≥1 dose of study drug are included.

Arm/Group Title	Group 1: Imipenem+Cilastatin/Relebactam	Group 2: Colistimethate Sodium + Imipenem+Cilastatin	Group 3: Open-Label Imipenem+Cilastatin/Relebactam
Arm/Group Description	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Measure Participants	31	16	3
Number [Percentage of Participants]	0.0 0%	12.5 78.1%	33.3 1110%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: Imipenem+Cilastatin/Relebactam, Group 2: Colistimethate Sodium + Imipenem+Cilastatin
	Comments
	Type of Statistical Test	Other
	Comments	Difference in percentages
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in drug-related discon %
	Estimated Value	-12.5
	Confidence Interval	(2-Sided) 95%; -36.3 to -0.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Miettinen & Nurminen method

8. Primary Outcome

Title	Analysis of Specific AEs With an Incidence of ≥4 Participants in a Treatment Group
Description	The percentage of participants experiencing AEs that occurred in ≥4 participants within either Group 1 or Group 2 was assessed. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol; Group 3 had <4 participants and therefore no data are presented.
Time Frame	Up to Day 35 (up to 14 days after completing study treatment)

Outcome Measure Data

Analysis Population Description

All participants in Groups 1 and 2 who received ≥1 dose of study drug are included. Group 3 data is not shown for this measure because there are only 3 participants.

Arm/Group Title	Group 1: Imipenem+Cilastatin/Relebactam	Group 2: Colistimethate Sodium + Imipenem+Cilastatin	Group 3: Open-Label Imipenem+Cilastatin/Relebactam
Arm/Group Description	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Measure Participants	31	16	0
Pyrexia	12.9 41.6%	12.5 78.1%
Blood creatinine increased	0.0 0%	25.0 156.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: Imipenem+Cilastatin/Relebactam, Group 2: Colistimethate Sodium + Imipenem+Cilastatin
	Comments
	Type of Statistical Test	Other
	Comments	Difference in percentages
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in pyrexia %
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 95%; -25.2 to 19.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Miettinen & Nurminen method

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Group 1: Imipenem+Cilastatin/Relebactam, Group 2: Colistimethate Sodium + Imipenem+Cilastatin
	Comments
	Type of Statistical Test	Other
	Comments	Difference in percentages
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference blood creatinine inc %
	Estimated Value	-25.0
	Confidence Interval	(2-Sided) 95%; -49.8 to -10.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Miettinen & Nurminen method

9. Primary Outcome

Title	Percentage of Participants With ≥1 Events of Clinical Interest (ECI)
Description	The percentage of participants in Groups 1, 2, and 3 having ECIs within 2 categories was determined. Category 1 ECIs included post-baseline laboratory values of an elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value that is ≥3x upper limit of normal (ULN) and an elevated total bilirubin value that is ≥2x ULN and (at the same time) an alkaline phosphatase value that is ≤2x ULN. Category 2 ECIs included a confirmed elevated AST or ALT value that is ≥5x ULN. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.
Time Frame	Up to Day 35 (up to 14 days after completing study treatment)

Outcome Measure Data

Analysis Population Description

All participants in Groups 1, 2, and 3 who received ≥1 dose of study drug are included.

Arm/Group Title	Group 1: Imipenem+Cilastatin/Relebactam	Group 2: Colistimethate Sodium + Imipenem+Cilastatin	Group 3: Open-Label Imipenem+Cilastatin/Relebactam
Arm/Group Description	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Measure Participants	31	16	3
Category 1 ECI	0.0 0%	12.5 78.1%
Category 2 ECI	0.0 0%	12.5 78.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: Imipenem+Cilastatin/Relebactam, Group 2: Colistimethate Sodium + Imipenem+Cilastatin
	Comments
	Type of Statistical Test	Other
	Comments	Difference in Category 1 ECI %
Statistical Test of Hypothesis	p-Value	0.047
	Comments
	Method	Miettinen and Nurminen method
	Comments
Method of Estimation	Estimation Parameter	Difference in Category 1 ECI %
	Estimated Value	-12.5
	Confidence Interval	(2-Sided) 95%; -36.3 to -0.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Group 1: Imipenem+Cilastatin/Relebactam, Group 2: Colistimethate Sodium + Imipenem+Cilastatin
	Comments
	Type of Statistical Test	Other
	Comments	Difference in Category 2 ECI %
Statistical Test of Hypothesis	p-Value	0.047
	Comments
	Method	Miettinen and Nurminen method
	Comments
Method of Estimation	Estimation Parameter	Difference in Category 2 ECI %
	Estimated Value	-12.5
	Confidence Interval	() 95%; -36.3 to -0.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Percentage of Participants With ≥1 Events of Treatment-Emergent Nephrotoxicity
Description	Treatment-emergent nephrotoxity was assessed in Groups 1 and 2 as indicated by the protocol (Group 3 was not included). Nephrotoxicity for participants with normal baseline serum creatinine levels (<1.2 mg/dL) was defined as "doubling of serum creatinine to >1.2 mg/dL or reduction in creatinine clearance (ClCR) of ≥50%". Nephrotoxicity for participants with pre-existing renal dysfunction (baseline serum creatinine level ≥1.2 mg/dL) was defined as "increase in serum creatinine by ≥1 mg/dL or reduction from baseline ClCR of ≥20% or need for renal replacement therapy (RRT)".
Time Frame	Up to Day 35 (up to 14 days after completing study treatment)

Outcome Measure Data

Analysis Population Description

All participants in Groups 1 and 2 who received ≥1 dose of study drug are included. Per protocol, Group 3 was not included in the nephrotoxicity analysis.

Arm/Group Title	Group 1: Imipenem+Cilastatin/Relebactam	Group 2: Colistimethate Sodium + Imipenem+Cilastatin	Group 3: Open-Label Imipenem+Cilastatin/Relebactam
Arm/Group Description	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Measure Participants	31	16	0
Number (95% Confidence Interval) [Percentage of Participants]	10.3 33.2%	56.3 351.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: Imipenem+Cilastatin/Relebactam, Group 2: Colistimethate Sodium + Imipenem+Cilastatin
	Comments
	Type of Statistical Test	Other
	Comments	Difference in percentages
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Difference in nephrotoxicity %
	Estimated Value	-45.9
	Confidence Interval	() 95%; -69.1 to -18.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Miettinen & Nurminen method

11. Secondary Outcome

Title	Percentage of Participants With Favorable Clinical Response (FCR) at Day 28
Description	The percentage of participants with FCR at Day 28 was determined for Groups 1 and 2. FCR at Day 28 was defined as "sustained cure" or "cure". Sustained cure (for participants with "cure" response at the prior visit) was defined as "all pretherapy signs and symptoms of index infection resolved with no evidence of resurgence and no additional antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures have been performed". Cure (for participants with "improved" response at EOT visit) was defined as "all pretherapy signs and symptoms of index infection resolved or returned to preinfection status, and no additional IV antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures performed".
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

Participants in Groups 1 and 2 who received ≥1 dose of each trial drug within a given IV treatment regimen, and who had a baseline bacterial pathogen that met inclusion criteria, are included. As per protocol, efficacy data from open-label Group 3 was considered exploratory and not included in the comparative analysis.

Arm/Group Title	Group 1: Imipenem+Cilastatin/Relebactam	Group 2: Colistimethate Sodium + Imipenem+Cilastatin	Group 3: Open-Label Imipenem+Cilastatin/Relebactam
Arm/Group Description	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Measure Participants	21	10	0
Number (95% Confidence Interval) [Percentage of Participants]	71.4 230.3%	40.0 250%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: Imipenem+Cilastatin/Relebactam, Group 2: Colistimethate Sodium + Imipenem+Cilastatin
	Comments
	Type of Statistical Test	Other
	Comments	Difference in Day 28 FCR %
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Day 28 FCR %
	Estimated Value	26.3
	Confidence Interval	(2-Sided) 90%; 1.3 to 51.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Miettinen and Nurminen method stratified by infection-site stratum

12. Secondary Outcome

Title	Percentage of Participants With All-cause Mortality Up to Day 28
Description	The percentage of participants with all-cause mortality up to Day 28 was determined for Groups 1 and 2.
Time Frame	Up to Day 28

Outcome Measure Data

Analysis Population Description

Participants in Group 1 and Group 2 who received ≥1 dose of each trial drug within a given IV treatment regimen, and who had a baseline bacterial pathogen that met inclusion criteria, are included. As per protocol, efficacy data from open-label Group 3 was considered exploratory and not included in the comparative analysis.

Arm/Group Title	Group 1: Imipenem+Cilastatin/Relebactam	Group 2: Colistimethate Sodium + Imipenem+Cilastatin	Group 3: Open-Label Imipenem+Cilastatin/Relebactam
Arm/Group Description	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Measure Participants	21	10	0
Number (95% Confidence Interval) [Percentage of Participants]	9.5 30.6%	30.0 187.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: Imipenem+Cilastatin/Relebactam, Group 2: Colistimethate Sodium + Imipenem+Cilastatin
	Comments
	Type of Statistical Test	Other
	Comments	Difference in mortality %
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in mortality %
	Estimated Value	-17.3
	Confidence Interval	(2-Sided) 90%; -46.4 to 6.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Miettinen and Nurminen method stratified by infection-site stratum

13. Secondary Outcome

Title	Percentage of Participants With FCR on Therapy (OTX)
Description	The percentage of participants with a FCR at OTX was determined for Groups 1 and 2. FCR at OTX was defined as "improved". Improved was defined as "all or most pretherapy signs and symptoms of index infection have improved or resolved, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures have been performed.
Time Frame	OTX (Day 3)

Outcome Measure Data

Analysis Population Description

Participants in Group 1 and Group 2 who received ≥1 dose of each trial drug within a given IV treatment regimen, and who had a baseline bacterial pathogen that met inclusion criteria, are included. As per protocol, efficacy data from open-label Group 3 was considered exploratory and not included in the comparative analysis.

Arm/Group Title	Group 1: Imipenem+Cilastatin/Relebactam	Group 2: Colistimethate Sodium + Imipenem+Cilastatin	Group 3: Open-Label Imipenem+Cilastatin/Relebactam
Arm/Group Description	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Measure Participants	21	10	0
Number (95% Confidence Interval) [Percentage of Participants]	81.0 261.3%	40.0 250%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: Imipenem+Cilastatin/Relebactam, Group 2: Colistimethate Sodium + Imipenem+Cilastatin
	Comments
	Type of Statistical Test	Other
	Comments	Adjusted difference in OTX FCR %
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted difference in OTX FCR %
	Estimated Value	33.9
	Confidence Interval	(2-Sided) 90%; 7.4 to 61.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Miettinen and Nurminen method stratified by infection-site stratum

14. Secondary Outcome

Title	Percentage of Participants With FCR at End of Therapy (EOT)
Description	The percentage of participants with FCR at EOT was determined for Groups 1 and 2. FCR at EOT was defined as "cure" or "improved". Cure was defined as "all pretherapy signs and symptoms of index infection resolved or returned to preinfection status, and no additional IV antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures performed". Improved was defined as "all or most pretherapy signs and symptoms of index infection have improved or resolved, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures have been performed.
Time Frame	At EOT (up to Day 21)

Outcome Measure Data

Analysis Population Description

Participants in Group 1 and Group 2 who received ≥1 dose of each trial drug within a given IV treatment regimen, and who had a baseline bacterial pathogen that met inclusion criteria, are included. As per protocol, efficacy data from open-label Group 3 was considered exploratory and not included in the comparative analysis.

Arm/Group Title	Group 1: Imipenem+Cilastatin/Relebactam	Group 2: Colistimethate Sodium + Imipenem+Cilastatin	Group 3: Open-Label Imipenem+Cilastatin/Relebactam
Arm/Group Description	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Measure Participants	21	10	0
Number (95% Confidence Interval) [Percentage of Participants]	90.5 291.9%	60.0 375%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: Imipenem+Cilastatin/Relebactam, Group 2: Colistimethate Sodium + Imipenem+Cilastatin
	Comments
	Type of Statistical Test	Other
	Comments	Adjusted difference in EOT FCR %
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted difference in EOT FCR %
	Estimated Value	25.4
	Confidence Interval	(2-Sided) 90%; 3.1 to 53.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Miettinen and Nurminen method stratified by infection-site stratum

15. Secondary Outcome

Title	Percentage of Participants With FCR at EFU
Description	The percentage of participants with FCR at EFU was determined for Groups 1 and 2. FCR at EFU was defined as "sustained cure" or "cure". Sustained cure (for participants with "cure" response at the prior visit) was defined as "all pretherapy signs and symptoms of index infection resolved with no evidence of resurgence and no additional antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures have been performed". Cure (for participants with "improved" response at EOT visit) was defined as "all pretherapy signs and symptoms of index infection resolved or returned to preinfection status, and no additional IV antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures performed".
Time Frame	EFU (Between Day 10 and Day 30 [5 to 9 Days after EOT])

Outcome Measure Data

Analysis Population Description

Participants in Group 1 and Group 2 who received ≥1 dose of each trial drug within a given IV treatment regimen, and who had a baseline bacterial pathogen that met inclusion criteria, are included. As per protocol, efficacy data from open-label Group 3 was considered exploratory and not included in the comparative analysis.

Arm/Group Title	Group 1: Imipenem+Cilastatin/Relebactam	Group 2: Colistimethate Sodium + Imipenem+Cilastatin	Group 3: Open-Label Imipenem+Cilastatin/Relebactam
Arm/Group Description	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Measure Participants	21	10	0
Number (95% Confidence Interval) [Percentage of Participants]	81.0 261.3%	50.0 312.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: Imipenem+Cilastatin/Relebactam, Group 2: Colistimethate Sodium + Imipenem+Cilastatin
	Comments
	Type of Statistical Test	Other
	Comments	Adjusted difference in EFU FCR %
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in EFU FCR %
	Estimated Value	24.7
	Confidence Interval	(2-Sided) 90%; 3.8 to 51.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Miettinen and Nurminen method stratified by infection-site stratum

16. Secondary Outcome

Title	Percentage of cUTI Participants With Favorable Microbiological Response (FMR) at OTX
Description	The percentage of participants with FMR at OTX was determined for participants with cUTI in Groups 1 and 2. FMR was defined as "urine culture results at OTX showing eradication (i.e., ≥10^5 colony forming units [CFU]/mL at baseline was reduced to <10^4 CFU/mL at OTX) of the uropathogen".
Time Frame	OTX (Day 3)

Outcome Measure Data

Analysis Population Description

Participants in Group 1 and Group 2 with cUTI who received ≥1 dose of each trial drug within a given IV treatment regimen, and who had a baseline bacterial pathogen that met inclusion criteria, are included. As per protocol, efficacy data from open-label Group 3 was considered exploratory and not included in the comparative analysis.

Arm/Group Title	Group 1: Imipenem+Cilastatin/Relebactam	Group 2: Colistimethate Sodium + Imipenem+Cilastatin	Group 3: Open-Label Imipenem+Cilastatin/Relebactam
Arm/Group Description	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Measure Participants	11	5	0
Number (95% Confidence Interval) [Percentage of Participants]	100.0 322.6%	100.0 625%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: Imipenem+Cilastatin/Relebactam, Group 2: Colistimethate Sodium + Imipenem+Cilastatin
	Comments
	Type of Statistical Test	Other
	Comments	Difference in percentages
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in FMR %
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 90%; -20.8 to 36.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Miettinen & Nurminen method

17. Secondary Outcome

Title	Percentage of cUTI Participants With FMR at EOT
Description	The percentage of participants with FMR at EOT was determined for participants with cUTI in Groups 1 and 2. FMR was defined as "urine culture results at EOT showing eradication (i.e., ≥10^5 CFU/mL at baseline was reduced to <10^4 CFU/mL at EOT) or sustained eradication (i.e., ≥10^5 CFU/mL at baseline that was reduced to <10^4 CFU/mL previously remained <10^4 CFU/mL at EOT) of the uropathogen".
Time Frame	At EOT (up to Day 21)

Outcome Measure Data

Analysis Population Description

Participants in Group 1 and Group 2 with cUTI who received ≥1 dose of each trial drug within a given IV treatment regimen, and who had a baseline bacterial pathogen that met inclusion criteria, are included. As per protocol, efficacy data from open-label Group 3 was considered exploratory and not included in the comparative analysis.

Arm/Group Title	Group 1: Imipenem+Cilastatin/Relebactam	Group 2: Colistimethate Sodium + Imipenem+Cilastatin	Group 3: Open-Label Imipenem+Cilastatin/Relebactam
Arm/Group Description	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Measure Participants	11	5	0
Number (95% Confidence Interval) [Percentage of Participants]	100.0 322.6%	100.0 625%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: Imipenem+Cilastatin/Relebactam, Group 2: Colistimethate Sodium + Imipenem+Cilastatin
	Comments
	Type of Statistical Test	Other
	Comments	Difference in percentages
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in FMR %
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 90%; -20.8 to 36.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Miettinen & Nurminen method

18. Secondary Outcome

Title	Percentage of cUTI Participants With FMR at EFU
Description	The percentage of participants with FMR at EFU was determined for participants with cUTI in Groups 1 and 2. FMR was defined as "urine culture results at EFU showing sustained eradication (i.e., ≥10^5 CFU/mL at baseline that was reduced to <10^4 CFU/mL previously remained <10^4 CFU/mL at EFU) of the uropathogen".
Time Frame	EFU (Between Day 10 and Day 30 [5 to 9 Days after EOT])

Outcome Measure Data

Analysis Population Description

Participants in Group 1 and Group 2 with cUTI who received ≥1 dose of each trial drug within a given IV treatment regimen, and who had a baseline bacterial pathogen that met inclusion criteria, are included. As per protocol, efficacy data from open-label Group 3 was considered exploratory and not included in the comparative analysis.

Arm/Group Title	Group 1: Imipenem+Cilastatin/Relebactam	Group 2: Colistimethate Sodium + Imipenem+Cilastatin	Group 3: Open-Label Imipenem+Cilastatin/Relebactam
Arm/Group Description	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Measure Participants	11	5	0
Number (95% Confidence Interval) [Percentage of Participants]	72.7 234.5%	100.0 625%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: Imipenem+Cilastatin/Relebactam, Group 2: Colistimethate Sodium + Imipenem+Cilastatin
	Comments
	Type of Statistical Test	Other
	Comments	Difference in percentages
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in FMR %
	Estimated Value	-27.3
	Confidence Interval	(2-Sided) 90%; -52.8 to 12.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Miettinen & Nurminen method

Adverse Events

Time Frame	Up to Day 35 (up to 14 days after EOT)
Adverse Event Reporting Description	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. All participants in Groups 1, 2, and 3 who received ≥1 dose of study drug are included. Any event(s) reported to the investigator outside the AE monitoring period are also included.
Arm/Group Title	Group 1: Imipenem+Cilastatin/Relebactam		Group 2: Colistimethate Sodium + Imipenem+Cilastatin		Group 3: Open-Label Imipenem+Cilastatin/Relebactam
Arm/Group Description	Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).		Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).		Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
All Cause Mortality
	Group 1: Imipenem+Cilastatin/Relebactam		Group 2: Colistimethate Sodium + Imipenem+Cilastatin		Group 3: Open-Label Imipenem+Cilastatin/Relebactam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/31 (6.5%)		3/16 (18.8%)		1/3 (33.3%)
Serious Adverse Events
	Group 1: Imipenem+Cilastatin/Relebactam		Group 2: Colistimethate Sodium + Imipenem+Cilastatin		Group 3: Open-Label Imipenem+Cilastatin/Relebactam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/31 (12.9%)		5/16 (31.3%)		3/3 (100%)
Cardiac disorders
Cardiac arrest	1/31 (3.2%)	1	0/16 (0%)	0	0/3 (0%)	0
Ventricular tachycardia	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Gastrointestinal disorders
Acute abdomen	0/31 (0%)	0	0/16 (0%)	0	1/3 (33.3%)	1
Duodenal perforation	0/31 (0%)	0	0/16 (0%)	0	1/3 (33.3%)	2
Upper gastrointestinal haemorrhage	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
General disorders
Systemic inflammatory response syndrome	1/31 (3.2%)	1	0/16 (0%)	0	0/3 (0%)	0
Hepatobiliary disorders
Hepatic haematoma	0/31 (0%)	0	0/16 (0%)	0	1/3 (33.3%)	1
Infections and infestations
Escherichia urinary tract infection	0/31 (0%)	0	0/16 (0%)	0	1/3 (33.3%)	1
Lung infection	1/31 (3.2%)	1	0/16 (0%)	0	0/3 (0%)	0
Pneumonia	0/31 (0%)	0	0/16 (0%)	0	2/3 (66.7%)	2
Septic shock	0/31 (0%)	0	1/16 (6.3%)	1	1/3 (33.3%)	1
Injury, poisoning and procedural complications
Abdominal wound dehiscence	0/31 (0%)	0	0/16 (0%)	0	1/3 (33.3%)	1
Subarachnoid haemorrhage	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Investigations
Alanine aminotransferase increased	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Aspartate aminotransferase increased	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Blood alkaline phosphatase increased	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Nervous system disorders
Generalised tonic-clonic seizure	0/31 (0%)	0	0/16 (0%)	0	1/3 (33.3%)	1
Psychiatric disorders
Mental status changes	0/31 (0%)	0	0/16 (0%)	0	1/3 (33.3%)	1
Renal and urinary disorders
Acute kidney injury	1/31 (3.2%)	1	0/16 (0%)	0	0/3 (0%)	0
Other (Not Including Serious) Adverse Events
	Group 1: Imipenem+Cilastatin/Relebactam		Group 2: Colistimethate Sodium + Imipenem+Cilastatin		Group 3: Open-Label Imipenem+Cilastatin/Relebactam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/31 (48.4%)		13/16 (81.3%)		3/3 (100%)
Blood and lymphatic system disorders
Anaemia	2/31 (6.5%)	2	1/16 (6.3%)	1	1/3 (33.3%)	1
Leukopenia	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Cardiac disorders
Arteriosclerosis coronary artery	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Atrial flutter	0/31 (0%)	0	0/16 (0%)	0	1/3 (33.3%)	1
Tachyarrhythmia	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Tachycardia	1/31 (3.2%)	1	1/16 (6.3%)	1	0/3 (0%)	0
Ear and labyrinth disorders
Hypoacusis	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Eye disorders
Visual acuity reduced	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Gastrointestinal disorders
Constipation	1/31 (3.2%)	1	0/16 (0%)	0	1/3 (33.3%)	1
Diarrhoea	1/31 (3.2%)	1	0/16 (0%)	0	1/3 (33.3%)	1
Gastritis	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Gastrooesophageal reflux disease	0/31 (0%)	0	1/16 (6.3%)	1	1/3 (33.3%)	1
Haematemesis	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Hypoaesthesia oral	0/31 (0%)	0	2/16 (12.5%)	2	0/3 (0%)	0
Ileus	0/31 (0%)	0	0/16 (0%)	0	1/3 (33.3%)	1
Large intestinal haemorrhage	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Large intestinal ulcer	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Large intestine perforation	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Nausea	2/31 (6.5%)	2	3/16 (18.8%)	3	0/3 (0%)	0
Retching	0/31 (0%)	0	0/16 (0%)	0	1/3 (33.3%)	1
Vomiting	1/31 (3.2%)	1	1/16 (6.3%)	1	0/3 (0%)	0
General disorders
Infusion site phlebitis	1/31 (3.2%)	1	2/16 (12.5%)	2	0/3 (0%)	0
Oedema	2/31 (6.5%)	2	0/16 (0%)	0	0/3 (0%)	0
Oedema peripheral	2/31 (6.5%)	2	0/16 (0%)	0	0/3 (0%)	0
Peripheral swelling	0/31 (0%)	0	0/16 (0%)	0	1/3 (33.3%)	1
Pyrexia	4/31 (12.9%)	5	2/16 (12.5%)	2	0/3 (0%)	0
Hepatobiliary disorders
Hepatic artery stenosis	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Hepatic failure	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Periportal oedema	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Immune system disorders
Chronic graft versus host disease in liver	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Infections and infestations
Abdominal infection	2/31 (6.5%)	2	0/16 (0%)	0	0/3 (0%)	0
Anorectal infection bacterial	1/31 (3.2%)	1	0/16 (0%)	0	1/3 (33.3%)	1
Bacteraemia	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Bacterial abdominal infection	1/31 (3.2%)	2	1/16 (6.3%)	1	0/3 (0%)	0
Biliary tract infection bacterial	0/31 (0%)	0	1/16 (6.3%)	3	0/3 (0%)	0
Biliary tract infection fungal	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Conjunctivitis	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Device related infection	0/31 (0%)	0	0/16 (0%)	0	1/3 (33.3%)	1
Ear infection bacterial	0/31 (0%)	0	0/16 (0%)	0	1/3 (33.3%)	1
Ear infection staphylococcal	0/31 (0%)	0	0/16 (0%)	0	1/3 (33.3%)	1
Enterococcal infection	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Lower respiratory tract infection bacterial	1/31 (3.2%)	1	1/16 (6.3%)	1	0/3 (0%)	0
Peritoneal candidiasis	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Peritonitis	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Respiratory moniliasis	1/31 (3.2%)	1	1/16 (6.3%)	1	0/3 (0%)	0
Serratia infection	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Staphylococcal bacteraemia	0/31 (0%)	0	1/16 (6.3%)	2	1/3 (33.3%)	1
Stenotrophomonas infection	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Streptococcal urinary tract infection	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Urinary tract infection	2/31 (6.5%)	2	0/16 (0%)	0	0/3 (0%)	0
Injury, poisoning and procedural complications
Biliary anastomosis complication	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Gastrointestinal stoma complication	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Incision site haemorrhage	0/31 (0%)	0	1/16 (6.3%)	2	0/3 (0%)	0
Laceration	0/31 (0%)	0	0/16 (0%)	0	1/3 (33.3%)	1
Investigations
Activated partial thromboplastin time prolonged	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Alanine aminotransferase increased	2/31 (6.5%)	2	2/16 (12.5%)	2	0/3 (0%)	0
Aspartate aminotransferase increased	3/31 (9.7%)	3	2/16 (12.5%)	2	0/3 (0%)	0
Blood alkaline phosphatase increased	1/31 (3.2%)	1	1/16 (6.3%)	1	0/3 (0%)	0
Blood bilirubin increased	0/31 (0%)	0	2/16 (12.5%)	2	0/3 (0%)	0
Blood creatinine increased	0/31 (0%)	0	4/16 (25%)	4	0/3 (0%)	0
Blood potassium decreased	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Blood urea increased	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
C-reactive protein increased	2/31 (6.5%)	2	0/16 (0%)	0	0/3 (0%)	0
Creatinine renal clearance decreased	2/31 (6.5%)	2	2/16 (12.5%)	2	0/3 (0%)	0
Gamma-glutamyltransferase increased	1/31 (3.2%)	1	2/16 (12.5%)	2	0/3 (0%)	0
Glomerular filtration rate decreased	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Haemoglobin decreased	1/31 (3.2%)	1	1/16 (6.3%)	1	0/3 (0%)	0
Liver function test increased	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	0/31 (0%)	0	0/16 (0%)	0	1/3 (33.3%)	1
Hyperkalaemia	0/31 (0%)	0	0/16 (0%)	0	1/3 (33.3%)	1
Hypomagnesaemia	0/31 (0%)	0	0/16 (0%)	0	1/3 (33.3%)	1
Musculoskeletal and connective tissue disorders
Gouty arthritis	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Nervous system disorders
Dizziness	0/31 (0%)	0	2/16 (12.5%)	2	0/3 (0%)	0
Product Issues
Device dislocation	1/31 (3.2%)	1	1/16 (6.3%)	1	0/3 (0%)	0
Device occlusion	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Psychiatric disorders
Agitation	0/31 (0%)	0	1/16 (6.3%)	2	0/3 (0%)	0
Depression	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Restlessness	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/31 (0%)	0	0/16 (0%)	0	1/3 (33.3%)	1
Renal cyst	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	3/31 (9.7%)	3	0/16 (0%)	0	0/3 (0%)	0
Epistaxis	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Haemoptysis	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Hydrothorax	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Tachypnoea	1/31 (3.2%)	1	1/16 (6.3%)	1	0/3 (0%)	0
Tracheal mass	0/31 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0
Skin and subcutaneous tissue disorders
Decubitus ulcer	1/31 (3.2%)	1	1/16 (6.3%)	1	0/3 (0%)	0
Vascular disorders
Hypotension	0/31 (0%)	0	1/16 (6.3%)	1	1/3 (33.3%)	1

Limitations/Caveats

[Not Specified]

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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 trial 45 days prior to submission for publication/presentation.