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Clinical Trial Results:
A Phase II, Randomized, Active Comparator-Controlled Clinical Trial to Study the Safety, Tolerability, and Efficacy of MK-7655 + Imipenem/Cilastatin Versus Imipenem/Cilastatin Alone in Patients with Complicated Intra-Abdominal Infection [cIAI]

Summary
EudraCT number	2011-005686-20
Trial protocol	DE ES PT GR LT LV EE BG PL
Global end of trial date	11 Aug 2014

Results information
Results version number	v2(current)
This version publication date	28 Jul 2019
First version publication date	01 Aug 2015
Other versions	v1
Version creation reason

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

7655-004

ISRCTN number

US NCT number

NCT01506271

WHO universal trial number (UTN)

Sponsor organisation name

Merck Sharp & Dohme Corp.

Sponsor organisation address

2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033

Public contact

Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com

Scientific contact

Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

11 Aug 2014

Is this the analysis of the primary completion data?

Yes

Primary completion date

11 Aug 2014

Global end of trial reached?

Yes

Global end of trial date

11 Aug 2014

Was the trial ended prematurely?

Main objective of the trial

The purpose of this study is to evaluate the efficacy, safety and tolerability of adding 125 mg or 250 mg doses of MK-7655 (Relebactam) to imipenem/cilastatin in adults 18 years or older with complicated intra-abdominal infection (cIAI). The primary hypothesis is that the relebactam + imipenem/cilastatin treatment regimen is non-inferior to treatment with imipenem/cilastatin alone with respect to the proportion of participants with a favorable clinical response at completion of intravenous (IV) study therapy.

Protection of trial subjects

This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.

Background therapy

Evidence for comparator

Actual start date of recruitment

31 May 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 3

Country: Number of subjects enrolled

Poland: 12

Country: Number of subjects enrolled

Portugal: 10

Country: Number of subjects enrolled

Bulgaria: 2

Country: Number of subjects enrolled

Estonia: 14

Country: Number of subjects enrolled

Germany: 9

Country: Number of subjects enrolled

Greece: 6

Country: Number of subjects enrolled

Latvia: 27

Country: Number of subjects enrolled

Lithuania: 21

Country: Number of subjects enrolled

Brazil: 3

Country: Number of subjects enrolled

Colombia: 1

Country: Number of subjects enrolled

Mexico: 6

Country: Number of subjects enrolled

Peru: 7

Country: Number of subjects enrolled

Romania: 62

Country: Number of subjects enrolled

Russian Federation: 21

Country: Number of subjects enrolled

South Africa: 12

Country: Number of subjects enrolled

Taiwan: 10

Country: Number of subjects enrolled

Turkey: 8

Country: Number of subjects enrolled

Ukraine: 96

Country: Number of subjects enrolled

United States: 21

Worldwide total number of subjects

351

EEA total number of subjects

163

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

271

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Adult males or females 18 years old or older, with cIAI requiring treatment with IV antibiotic therapy were enrolled in this trial.

Period 1 title

Overall Trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Relebactam 250 mg + IPM/CIL

Arm description

Relebactam 250 mg and imipenem/cilastatin (IPM/CIL) 500 mg were administered by IV separately, and concurrently over a 30-minute interval, every 6 hours for a minimum of 96 hours.

Arm type

Experimental

Investigational medicinal product name

Relebactam

Investigational medicinal product code

Other name

MK-7655

Pharmaceutical forms

Powder for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Relebactam 250 mg was administered by IV over a 30-minute interval, every 6 hours for a minimum of 96 hours.

Investigational medicinal product name

Imipenem/Cilastatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Imipenem/Cilastatin (IPM/CIL) 500 mg was administered by IV over a 30-minute interval, every 6 hours for a minimum of 96 hours.

Relebactam 125 mg + IPM/CIL

Arm description

Relebactam 125 mg and IPM/CIL 500 mg were administered by IV separately, and concurrently over a 30-minute interval, every 6 hours for a minimum of 96 hours.

Arm type

Experimental

Investigational medicinal product name

Imipenem/Cilastatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Imipenem/Cilastatin (IPM/CIL) 500 mg was administered by IV over a 30-minute interval, every 6 hours for a minimum of 96 hours.

Investigational medicinal product name

Relebactam

Investigational medicinal product code

Other name

MK-7655

Pharmaceutical forms

Powder for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Relebactam 125 mg was administered by IV over a 30-minute interval, every 6 hours for a minimum of 96 hours.

Placebo + IPM/CIL

Arm description

Placebo for relebactam and IPM/CIL 500 mg were administered by IV separately, and concurrently over a 30-minute interval, every 6 hours for a minimum of 96 hours.

Arm type

Placebo

Investigational medicinal product name

Imipenem/Cilastatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Imipenem/Cilastatin (IPM/CIL) 500 mg was administered by IV over a 30-minute interval, every 6 hours for a minimum of 96 hours.

Investigational medicinal product name

Placebo for relebactam

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Normal saline (0.9%) was administered by IV over a 30-minute interval, every 6 hours for a minimum of 96 hours.

Number of subjects in period 1	Relebactam 250 mg + IPM/CIL	Relebactam 125 mg + IPM/CIL	Placebo + IPM/CIL
Started	118	116	117
Treated	117	116	114
Completed	114	109	114
Not completed	4	7	3
Adverse event, serious fatal	-	1	-
Consent withdrawn by subject	-	1	1
Adverse event, non-fatal	-	2	-
Insufficient supply of study drug	1	-	-
Lost to follow-up	-	1	2
Progressive disease	-	1	-
Protocol deviation	3	1	-

Baseline characteristics

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Reporting group title

Relebactam 250 mg + IPM/CIL

Reporting group description

Relebactam 250 mg and imipenem/cilastatin (IPM/CIL) 500 mg were administered by IV separately, and concurrently over a 30-minute interval, every 6 hours for a minimum of 96 hours.

Reporting group title

Relebactam 125 mg + IPM/CIL

Reporting group description

Relebactam 125 mg and IPM/CIL 500 mg were administered by IV separately, and concurrently over a 30-minute interval, every 6 hours for a minimum of 96 hours.

Reporting group title

Placebo + IPM/CIL

Reporting group description

Placebo for relebactam and IPM/CIL 500 mg were administered by IV separately, and concurrently over a 30-minute interval, every 6 hours for a minimum of 96 hours.

Reporting group values	Relebactam 250 mg + IPM/CIL	Relebactam 125 mg + IPM/CIL	Placebo + IPM/CIL	Total
Number of subjects	118	116	117	351
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	48.3 ( 18.9 )	49.8 ( 17.4 )	49.1 ( 17.8 )	-
Gender categorical
Units: Subjects
Female	44	54	51	149
Male	74	62	66	202

End points

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Reporting group title

Relebactam 250 mg + IPM/CIL

Reporting group description

Relebactam 250 mg and imipenem/cilastatin (IPM/CIL) 500 mg were administered by IV separately, and concurrently over a 30-minute interval, every 6 hours for a minimum of 96 hours.

Reporting group title

Relebactam 125 mg + IPM/CIL

Reporting group description

Relebactam 125 mg and IPM/CIL 500 mg were administered by IV separately, and concurrently over a 30-minute interval, every 6 hours for a minimum of 96 hours.

Reporting group title

Placebo + IPM/CIL

Reporting group description

Placebo for relebactam and IPM/CIL 500 mg were administered by IV separately, and concurrently over a 30-minute interval, every 6 hours for a minimum of 96 hours.

Primary: Percentage of participants with a favorable clinical response at completion of IV study therapy

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End point title

Percentage of participants with a favorable clinical response at completion of IV study therapy

End point description

A favorable clinical response is assessed by the clinical investigator as a cure, and is defined as a situation where all or most pre-therapy signs and symptoms of the index infection have resolved, or returned to pre-infection status, and no additional antibiotic therapy is required. The microbiologically evaluable (ME) population was analyzed, defined as participants who: (1) met the protocol definition of cIAI; (2) had a pre-study/post operative culture from the site of infection grew at least one Gram-negative enteric and/or anaerobic pathogen; (3) had no significant deviations from the protocol that could impact the efficacy assessment; and (4) received ≥ 96 hours of IV study therapy.

End point type

Primary

End point timeframe

4 to 14 days post initiation of IV study therapy (up to post-randomization day 14)

End point values	Relebactam 250 mg + IPM/CIL	Relebactam 125 mg + IPM/CIL	Placebo + IPM/CIL
Number of subjects analysed	81 ^[1]	86 ^[2]	83 ^[3]
Units: Percentage of Participants
number (confidence interval 95%)	96.3 (89.6 to 99.2)	98.8 (93.7 to 100)	95.2 (88.1 to 98.7)

Notes
[1] - Two participants with indeterminate or missing responses are excluded from the analysis
[2] - One participant with indeterminate or missing responses is excluded from the analysis
[3] - Two participants with indeterminate or missing responses are excluded from the analysis

Relebactam 250 mg - Placebo: Treatment Difference

Statistical analysis description

Non-inferiority test based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

164

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Difference

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-6.2

upper limit

8.6

Relebactam 125 mg - Placebo: Treatment Difference

Statistical analysis description

Non-inferiority test based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

169

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Difference

Point estimate

3.7

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

10.8

Primary: Percentage of participants with an elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) laboratory values that are greater than or equal to 5X the upper limit of normal (ULN)

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End point title

Percentage of participants with an elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) laboratory values that are greater than or equal to 5X the upper limit of normal (ULN)

End point description

Pre-specified events of interest were confirmed (i.e., verified by repeat testing) elevated AST or ALT laboratory value that is greater than or equal to 5 X ULN as a result of within-protocol-specific testing or unscheduled testing. The population analyzed was all randomized participants who received at least one dose of IV study therapy, based on the therapy they actually received.

End point type

Primary

End point timeframe

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

End point values	Relebactam 250 mg + IPM/CIL	Relebactam 125 mg + IPM/CIL	Placebo + IPM/CIL
Number of subjects analysed	117	116	114
Units: Percentage of participants
number (not applicable)	1.7	0	1.8

Relebactam 250 mg - Placebo: Percent Difference

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other ^[4]

P-value

= 0.979

Method

Miettinen and Nurminen

Parameter type

Percentage Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-4.7

upper limit

4.5

Notes
[4] - The analysis type is a traditional test for a non-zero difference.

Relebactam 125 mg - Placebo: Percent Difference

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other ^[5]

P-value

= 0.153

Method

Miettinen and Nurminen

Parameter type

Percentage Difference

Point estimate

-1.8

Confidence interval

level

95%

sides

2-sided

lower limit

-6.2

upper limit

1.5

Notes
[5] - The analysis type is a traditional test for a non-zero difference.

Primary: Percentage of participants with elevated AST or ALT laboratory values that are greater than or equal to 3X the ULN, as well as elevated total bilirubin greater than or equal to 2X the ULN, and alkaline phosphatase values that are less than 2X the ULN

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End point title

Percentage of participants with elevated AST or ALT laboratory values that are greater than or equal to 3X the ULN, as well as elevated total bilirubin greater than or equal to 2X the ULN, and alkaline phosphatase values that are less than 2X the ULN

End point description

Pre-specified events of interest were confirmed (i.e., verified by repeat testing) elevated AST or ALT laboratory value that is greater than or equal to 3 X ULN, as well as elevated total bilirubin greater than or equal to 2X the ULN, and alkaline phosphatase values that are less than 2X the ULN, as a result of within-protocol-specific testing or unscheduled testing. The population analyzed was all randomized participants who received at least one dose of IV study therapy, based on the therapy they actually received.

End point type

Primary

End point timeframe

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

End point values	Relebactam 250 mg + IPM/CIL	Relebactam 125 mg + IPM/CIL	Placebo + IPM/CIL
Number of subjects analysed	117	116	114
Units: Percentage of participants
number (not applicable)	0.9	0	0

Relebactam 250 mg - Placebo: Percent Difference

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other ^[6]

P-value

= 0.324

Method

Miettinen and Nurminen

Parameter type

Percentage Difference

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-2.4

upper limit

4.7

Notes
[6] - The analysis type is a traditional test for a non-zero difference.

Relebactam 125 mg - Placebo: Percent Difference

Comparison groups

Placebo + IPM/CIL v Relebactam 125 mg + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other ^[7]

P-value

> 0.999

Method

Miettinen and Nurminen

Parameter type

Percentage Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-3.3

upper limit

3.2

Notes
[7] - The analysis type is a traditional test for a non-zero difference.

Primary: Percentage of participants with any adverse event (AE)

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End point title

Percentage of participants with any adverse event (AE)

End point description

An AE is any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an AE. The population analyzed was all randomized participants who received at least one dose of IV study therapy, based on the therapy they actually received.

End point type

Primary

End point timeframe

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

End point values	Relebactam 250 mg + IPM/CIL	Relebactam 125 mg + IPM/CIL	Placebo + IPM/CIL
Number of subjects analysed	117	116	114
Units: Percentage of participants
number (not applicable)	48.7	47.4	41.2

Relebactam 250 mg - Placebo: Treatment Difference

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

7.5

Confidence interval

level

95%

sides

2-sided

lower limit

-5.4

upper limit

20.1

Relebactam 125 mg - Placebo: Treatment Difference

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

6.2

Confidence interval

level

95%

sides

2-sided

lower limit

-6.7

upper limit

18.8

Primary: Percentage of participants with any serious adverse event (SAE)

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End point title

Percentage of participants with any serious adverse event (SAE)

End point description

A SAE is any AE occurring at any dose that is life threatening; results in a persistent or significant disability/incapacity; prolongs an existing inpatient hospitalization; is a congenital anomaly/birth defect; or results in death. The population analyzed was all randomized participants who received at least one dose of IV study therapy, based on the therapy they actually received.

End point type

Primary

End point timeframe

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

End point values	Relebactam 250 mg + IPM/CIL	Relebactam 125 mg + IPM/CIL	Placebo + IPM/CIL
Number of subjects analysed	117	116	114
Units: Percentage of participants
number (not applicable)	3.4	9.5	7

Relebactam 250 mg - Placebo: Treatment Difference

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-3.6

Confidence interval

level

95%

sides

2-sided

lower limit

-10.3

upper limit

2.4

Relebactam 125 mg - Placebo: Treatment Difference

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

2.5

Confidence interval

level

95%

sides

2-sided

lower limit

-5

upper limit

10.1

Primary: Percentage of participants with any drug-related AE

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End point title

Percentage of participants with any drug-related AE

End point description

An AE is any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an AE. A drug-related AE is an AE determined by the investigator to be possibly, probably or definitely related to drug treatment. The population analyzed was all randomized participants who received at least one dose of IV study therapy, based on the therapy they actually received.

End point type

Primary

End point timeframe

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

End point values	Relebactam 250 mg + IPM/CIL	Relebactam 125 mg + IPM/CIL	Placebo + IPM/CIL
Number of subjects analysed	117	116	114
Units: Percentage of participants
number (not applicable)	13.7	13.8	9.6

Relebactam 250 mg - Placebo: Treatment Difference

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-4.5

upper limit

12.7

Relebactam 125 mg - Placebo: Treatment Difference

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

4.1

Confidence interval

level

95%

sides

2-sided

lower limit

-4.4

upper limit

12.8

Primary: Percentage of participants with any serious drug-related AE

Top of page

End point title

Percentage of participants with any serious drug-related AE

End point description

A SAE is any AE occurring at any dose that is life threatening; results in a persistent or significant disability/incapacity; prolongs an existing inpatient hospitalization; is a congenital anomaly/birth defect; or results in death. A drug-related SAE is a SAE determined by the investigator to be possibly, probably or definitely related to drug treatment. The population analyzed was all randomized participants who received at least one dose of IV study therapy, based on the therapy they actually received.

End point type

Primary

End point timeframe

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

End point values	Relebactam 250 mg + IPM/CIL	Relebactam 125 mg + IPM/CIL	Placebo + IPM/CIL
Number of subjects analysed	117	116	114
Units: Percentage of participants
number (not applicable)	0.9	0	0.9

Relebactam 250 mg - Placebo: Treatment Difference

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-4

upper limit

3.9

Relebactam 125 mg - Placebo: Treatment Difference

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-4.8

upper limit

2.4

Primary: Percentage of participants who discontinued IV study therapy due to an AE

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End point title

Percentage of participants who discontinued IV study therapy due to an AE

End point description

An AE is any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an AE. AEs assessed by the investigator that caused discontinuation of participant treatment are presented. The population analyzed was all randomized participants who received at least one dose of IV study therapy, based on the therapy they actually received.

End point type

Primary

End point timeframe

Up to 14 days post initiation of IV study therapy

End point values	Relebactam 250 mg + IPM/CIL	Relebactam 125 mg + IPM/CIL	Placebo + IPM/CIL
Number of subjects analysed	117	116	114
Units: Percentage of participants
number (not applicable)	0.9	4.3	2.6

Relebactam 250 mg - Placebo: Treatment Difference

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-1.8

Confidence interval

level

95%

sides

2-sided

lower limit

-6.7

upper limit

2.3

Relebactam 125 mg - Placebo: Treatment Difference

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

1.7

Confidence interval

level

95%

sides

2-sided

lower limit

-3.7

upper limit

7.4

Primary: Percentage of participants who discontinued IV study therapy due to a drug-related AE

Top of page

End point title

Percentage of participants who discontinued IV study therapy due to a drug-related AE

End point description

An AE is any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an AE. A drug-related AE is an AE determined by the investigator to be possibly, probably or definitely related to drug treatment. Drug-related AEs assessed by the investigator that caused discontinuation of participant treatment are presented. The population analyzed was all randomized participants who received at least one dose of IV study therapy, based on the therapy they actually received.

End point type

Primary

End point timeframe

Up to 14 days post initiation of IV study therapy

End point values	Relebactam 250 mg + IPM/CIL	Relebactam 125 mg + IPM/CIL	Placebo + IPM/CIL
Number of subjects analysed	117	116	114
Units: Percentage of participants
number (not applicable)	0	0.9	2.6

Relebactam 250 mg - Placebo: Treatment Difference

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-2.6

Confidence interval

level

95%

sides

2-sided

lower limit

-7.5

upper limit

0.6

Relebactam 125 mg - Placebo: Treatment Difference

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-1.8

Confidence interval

level

95%

sides

2-sided

lower limit

-6.7

upper limit

2.4

Primary: Percentage of participants with AEs with incidence of >= 4 participants in one treatment group

Top of page

End point title

Percentage of participants with AEs with incidence of >= 4 participants in one treatment group

End point description

An AE is any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an AE. AE preferred terms with incidence greater than or equal to 4 in one treatment group are presented. AEs preferred terms which did not achieve this threshold are not reported. AE preferred terms are based on MedDRA version 17.0. The population analyzed was all randomized participants who received at least one dose of IV study therapy, based on the therapy they actually received.

End point type

Primary

End point timeframe

Up to 14 days post initiation of IV study therapy (up to Day 28)

End point values	Relebactam 250 mg + IPM/CIL	Relebactam 125 mg + IPM/CIL	Placebo + IPM/CIL
Number of subjects analysed	117	116	114
Units: Percentage of participants
number (not applicable)
Diarrhoea	6	6	4.4
Nausea	6.8	7.8	7
Vomiting	6	7.8	2.6
Post-operative wound infection	2.6	1.7	4.4
Seroma	0.9	4.3	0
ALT increased	4.3	4.3	3.5
AST increased	4.3	4.3	2.6
Lipase increased	2.6	1.7	3.5
Hypertension	0	2.6	3.5

Relebactam 250 mg - Placebo: % Diff. - Diarrhoea

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

1.6

Confidence interval

level

95%

sides

2-sided

lower limit

-4.7

upper limit

8.1

Relebactam 125 mg - Placebo: % Diff. - Diarrhoea

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Placebo + IPM/CIL v Relebactam 125 mg + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

1.6

Confidence interval

level

95%

sides

2-sided

lower limit

-4.6

upper limit

8.2

Relebactam 250 mg - Placebo: % Diff. - Nausea

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-7.3

upper limit

6.9

Relebactam 125 mg - Placebo: % Difference - Nausea

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-6.5

upper limit

Relebactam 250 mg - Placebo: % Diff. - Vomiting

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

3.4

Confidence interval

level

95%

sides

2-sided

lower limit

-2.3

upper limit

9.6

Relebactam 125 mg - Placebo: % Diff. - Vomiting

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

5.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

11.8

Relebactam 250 mg - Placebo: % Diff. - Post.inf.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-1.8

Confidence interval

level

95%

sides

2-sided

lower limit

-7.6

upper limit

3.5

Relebactam 125 mg - Placebo: % Diff. - Post.inf.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-2.7

Confidence interval

level

95%

sides

2-sided

lower limit

-8.4

upper limit

2.2

Relebactam 250 mg - Placebo: % Difference - Seroma

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-2.4

upper limit

4.7

Relebactam 125 mg - Placebo: % Difference - Seroma

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

4.3

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

9.7

Relebactam 250 mg - Placebo: % Diff. - ALT inc.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-5

upper limit

6.6

Relebactam 125 mg - Placebo: % Diff. - ALT inc.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-4.9

upper limit

6.7

Relebactam 250 mg - Placebo: % Diff. - AST inc.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

1.6

Confidence interval

level

95%

sides

2-sided

lower limit

-3.7

upper limit

7.3

Relebactam 125 mg - Placebo: % Diff. - AST inc.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Placebo + IPM/CIL v Relebactam 125 mg + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

1.7

Confidence interval

level

95%

sides

2-sided

lower limit

-3.7

upper limit

7.4

Relebactam 250 mg - Placebo: % Diff.-Lip. inc.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-6.5

upper limit

4.2

Relebactam 125 mg - Placebo: % Diff.-Lip. inc.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-1.8

Confidence interval

level

95%

sides

2-sided

lower limit

-7.2

upper limit

Relebactam 250 mg - Placebo: % Diff. - Hyp.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-3.5

Confidence interval

level

95%

sides

2-sided

lower limit

-8.7

upper limit

-0.3

Relebactam 125 mg - Placebo: % Diff. - Hyp.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-6.4

upper limit

4.3

Primary: Percentage of participants with predefined limit of change (PDLC) with incidence of >= 4 participants in one treatment group

Top of page

End point title

Percentage of participants with predefined limit of change (PDLC) with incidence of >= 4 participants in one treatment group ^[8]

End point description

PDLC are presented based on values from the following laboratory tests on serum: alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (Bil), and alkaline phosphatase (AP). Results are presented for PDLC from tests with reported incidence greater than or equal to 4 participants in one treatment group. Laboratory tests which did not achieve the PDLC threshold are not reported. The population analyzed was all randomized participants who received at least one dose of IV study therapy, based on the therapy they actually received.

End point type

Primary

End point timeframe

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

Notes
[8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics are provided. Statistical comparisons between arms were not performed for this primary endpoint.

End point values	Relebactam 250 mg + IPM/CIL	Relebactam 125 mg + IPM/CIL	Placebo + IPM/CIL
Number of subjects analysed	117	116	114
Units: Percentage of participants
number (not applicable)
ALT >2.5-5.0 X Baseline	3.6	2.6	9.1
ALT >5.0 X Baseline	4.5	6.1	3.6
AST >2.5-5.0 X Baseline	14.5	14	9.2
AP >2.5-5.0 X Baseline	6.3	2.6	5.5

No statistical analyses for this end point

Primary: Percentage of participants with system organ class (SOC) AE incidence of >= 4 participants in one treatment group

Top of page

End point title

Percentage of participants with system organ class (SOC) AE incidence of >= 4 participants in one treatment group

End point description

A SOC is the highest level of terminology used to describe disorders of the human body, and distinguishes by either anatomical or physiological systems, disease origin or purpose. SOC AE incidence greater than or equal to 4 in one treatment group are presented. SOC AE incidence which did not achieve this threshold are not reported. SOC are based on MedDRA version 17.0. The population analyzed was all randomized participants who received at least one dose of IV study therapy, based on the therapy they actually received.

End point type

Primary

End point timeframe

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

End point values	Relebactam 250 mg + IPM/CIL	Relebactam 125 mg + IPM/CIL	Placebo + IPM/CIL
Number of subjects analysed	117	116	114
Units: Percentage of participants
number (not applicable)
Blood and lymphatic system disorders	4.3	0.9	5.3
Cardiac disorders	2.6	3.4	2.6
Gastrointestinal disorders	18.8	17.2	13.2
General disorders admin. site conditions	7.7	5.2	3.5
Infections and infestations	11.1	7.8	7
Injury, poisoning, procedural complications	4.3	6.9	5.3
Investigations	11.1	10.3	12.3
Nervous system disorders	1.7	3.4	4.4
Psychiatric disorders	3.4	3.4	3.5
Renal and urinary disorders	1.7	1.7	3.5
Respiratory, thoracic, mediastinal disorders	1.7	4.3	6.1
Skin, subcutaneous tissue disorders	4.3	1.7	1.8
Vascular disorders	2.6	6	6.1

Relebactam 250 mg - Placebo: % Diff. - Blood

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-7.3

upper limit

5.1

Relebactam 125 mg - Placebo: % Diff. - Blood

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-4.4

Confidence interval

level

95%

sides

2-sided

lower limit

-10.3

upper limit

0.1

Relebactam 250 mg - Placebo: % Diff.-Card. dis.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-5.2

upper limit

Relebactam 125 mg - Placebo: % Diff. -Card. dis.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-4.5

upper limit

6.3

Relebactam 250 mg - Placebo: % Diff. - GI Dis.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

5.6

Confidence interval

level

95%

sides

2-sided

lower limit

-3.9

upper limit

15.3

Relebactam 125 mg - Placebo: % Diff. - GI Dis.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

4.1

Confidence interval

level

95%

sides

2-sided

lower limit

-5.4

upper limit

13.6

Relebactam 250 mg - Placebo: % Diff. -Gen.dis.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

4.2

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

Relebactam 125 mg - Placebo: % Diff. -Gen.dis.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

1.7

Confidence interval

level

95%

sides

2-sided

lower limit

-4.2

upper limit

7.8

Relebactam 250 mg - Placebo: % Diff. - Infct.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

4.1

Confidence interval

level

95%

sides

2-sided

lower limit

-3.6

upper limit

Relebactam 125 mg - Placebo: % Diff. - Infct.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-6.5

upper limit

Relebactam 250 mg - Placebo: % Diff. -Inj.Pois.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-7.3

upper limit

5.1

Relebactam 125 mg - Placebo: % Diff. -Inj.Pois.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

1.6

Confidence interval

level

95%

sides

2-sided

lower limit

-5

upper limit

8.5

Relebactam 250 mg - Placebo: % Diff. - Inv.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-9.8

upper limit

7.4

Relebactam 125 mg - Placebo: % Diff. - Inv.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-1.9

Confidence interval

level

95%

sides

2-sided

lower limit

-10.5

upper limit

6.5

Relebactam 250 mg - Placebo: % Diff. - Nerv.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-2.7

Confidence interval

level

95%

sides

2-sided

lower limit

-8.4

upper limit

2.2

Relebactam 125 mg - Placebo: % Diff. - Nerv.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-6.9

upper limit

4.7

Relebactam 250 mg - Placebo: % Diff. - Psych.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-5.7

upper limit

5.4

Relebactam 125 mg - Placebo: % Diff. - Psych.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-5.7

upper limit

5.5

Relebactam 250 mg - Placebo: % Diff. - Renal

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Placebo + IPM/CIL v Relebactam 250 mg + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-1.8

Confidence interval

level

95%

sides

2-sided

lower limit

-7.2

upper limit

Relebactam 125 mg - Placebo: % Diff. - Renal

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-1.8

Confidence interval

level

95%

sides

2-sided

lower limit

-7.2

upper limit

Relebactam 250 mg - Placebo: % Diff.- Resp.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-4.4

Confidence interval

level

95%

sides

2-sided

lower limit

-10.7

upper limit

0.7

Relebactam 125 mg - Placebo: % Diff.- Resp.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-1.8

Confidence interval

level

95%

sides

2-sided

lower limit

-8.4

upper limit

4.4

Relebactam 250 mg - Placebo: % Diff. - Skin

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

2.5

Confidence interval

level

95%

sides

2-sided

lower limit

-2.4

upper limit

8.1

Relebactam 125 mg - Placebo: % Diff. - Skin

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-4.7

upper limit

4.5

Relebactam 250 mg - Placebo: % Diff. - Vasc.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-3.6

Confidence interval

level

95%

sides

2-sided

lower limit

-9.9

upper limit

Relebactam 125 mg - Placebo: % Diff. - Vasc.

Statistical analysis description

Difference in percentage based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Percentage Difference

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-6.9

upper limit

6.6

Secondary: Percentage of participants with a favorable clinical response at completion of IV study therapy in participants who have imipenem-resistant, gram-negative cIAI infections.

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End point title

Percentage of participants with a favorable clinical response at completion of IV study therapy in participants who have imipenem-resistant, gram-negative cIAI infections.

End point description

A favorable clinical response is assessed by the clinical investigator as a cure, and is defined as a situation where all or most pre-therapy signs and symptoms of the index infection have resolved, or returned to pre-infection status, and no additional antibiotic therapy is required. The ME population was analyzed, defined as participants who: (1) met the protocol definition of cIAI; (2) had a pre-study/post operative culture from the site of infection grew at least one Gram-negative enteric and/or anaerobic pathogen; (3) had no significant deviations from the protocol that could impact the efficacy assessment; (4) received ≥ 96 hours of IV study therapy; and (5) had imipenem-resistant, gram negative cIAI infections.

End point type

Secondary

End point timeframe

4 to 14 days post initiation of IV study therapy (up to postrandomization Day 14).

End point values	Relebactam 250 mg + IPM/CIL	Relebactam 125 mg + IPM/CIL	Placebo + IPM/CIL
Number of subjects analysed	14 ^[9]	9 ^[10]	11 ^[11]
Units: Percentage of participants
number (confidence interval 95%)	100 (76.8 to 100)	100 (66.4 to 100)	100 (71.5 to 100)

Notes
[9] - Had imipenem-resistant, gram negative cIAI infections.
[10] - Had imipenem-resistant, gram negative cIAI infections.
[11] - Had imipenem-resistant, gram negative cIAI infections.

Relebactam 250 mg - Placebo: Treatment Difference

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

> 0.999

Method

Fisher exact

Parameter type

Percentage Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Relebactam 125 mg - Placebo: Treatment Difference

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

> 0.999

Method

Fisher exact

Parameter type

Percentage Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: Percentage of participants with a favorable clinical response at early follow-up

Top of page

End point title

Percentage of participants with a favorable clinical response at early follow-up

End point description

A favorable clinical response is assessed by the clinical investigator as a cure, and is defined as a situation where all or most pre-therapy signs and symptoms of the index infection have resolved, or returned to pre-infection status, and no additional antibiotic therapy is required. The ME population was analyzed, defined as participants who: (1) met the protocol definition of cIAI; (2) had a pre-study/post operative culture from the site of infection grew at least one Gram-negative enteric and/or anaerobic pathogen; (3) had no significant deviations from the protocol that could impact the efficacy assessment; and (4) received ≥ 96 hours of IV study therapy.

End point type

Secondary

End point timeframe

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

End point values	Relebactam 250 mg + IPM/CIL	Relebactam 125 mg + IPM/CIL	Placebo + IPM/CIL
Number of subjects analysed	79	86	81
Units: Percentage of participants
number (confidence interval 95%)	94.9 (87.5 to 98.6)	94.2 (87 to 98.1)	96.3 (89.6 to 99.2)

Relebactam 250 mg - Placebo: Treatment Difference

Statistical analysis description

Non-inferiority test based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Difference

Point estimate

-1.4

Confidence interval

level

95%

sides

2-sided

lower limit

-9.1

upper limit

Relebactam 125 mg - Placebo: Treatment Difference

Statistical analysis description

Non-inferiority test based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

167

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.002

Method

Miettinen and Nurminen

Parameter type

Percentage Difference

Point estimate

-2.1

Confidence interval

level

95%

sides

2-sided

lower limit

-9.7

upper limit

5.3

Secondary: Percentage of participants with a favorable microbiological response at completion of IV study therapy

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End point title

Percentage of participants with a favorable microbiological response at completion of IV study therapy

End point description

A favorable microbiological response is assessed by the clinical investigator, and is defined as the eradication or presumptive eradication of all bacterial pathogens identified at baseline. The ME population was analyzed, defined as participants who: (1) met the protocol definition of cIAI; (2) had a pre-study/post operative culture from the site of infection grew at least one Gram-negative enteric and/or anaerobic pathogen; (3) had no significant deviations from the protocol that could impact the efficacy assessment; and (4) received ≥ 96 hours of IV study therapy.

End point type

Secondary

End point timeframe

Up to 14 days post-initiation of IV study therapy (up to postrandomization Day 14)

End point values	Relebactam 250 mg + IPM/CIL	Relebactam 125 mg + IPM/CIL	Placebo + IPM/CIL
Number of subjects analysed	83	86	84
Units: Percentage of participants
number (confidence interval 95%)	97.6 (91.6 to 99.7)	100 (95.8 to 100)	97.6 (91.7 to 99.7)

Relebactam 250 mg - Placebo: Treatment Difference

Statistical analysis description

Non-inferiority test based on unconditional asymptotic Miettinen and Nurminen method without stratification. Two participants with indeterminate or missing response were excluded from the analysis.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

167

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-6.3

upper limit

6.2

Relebactam 125 mg - Placebo: Treatment Difference

Statistical analysis description

Non-inferiority test based on unconditional asymptotic Miettinen and Nurminen method without stratification. Two participants with indeterminate or missing response were excluded from the analysis.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

170

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Difference

Point estimate

2.4

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

8.3

Secondary: Percentage of participants with a favorable microbiological response at early follow-up

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End point title

Percentage of participants with a favorable microbiological response at early follow-up

End point description

End point type

Secondary

End point timeframe

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

End point values	Relebactam 250 mg + IPM/CIL	Relebactam 125 mg + IPM/CIL	Placebo + IPM/CIL
Number of subjects analysed	78	82	80
Units: Percentage of participants
number (confidence interval 95%)	97.4 (91 to 99.7)	97.6 (91.5 to 99.7)	97.5 (91.3 to 99.7)

Relebactam 250 mg - Placebo: Treatment Difference

Statistical analysis description

Non-inferiority test based on unconditional asymptotic Miettinen and Nurminen method without stratification. Eight participants with indeterminate or missing response were excluded from the analysis.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

158

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Difference

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-6.7

upper limit

6.4

Relebactam 125 mg - Placebo: Treatment Difference

Statistical analysis description

Non-inferiority test based on unconditional asymptotic Miettinen and Nurminen method without stratification. Eight participants with indeterminate or missing response were excluded from the analysis.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

162

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Difference

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-6.3

upper limit

6.5

Secondary: Percentage of participants with a favorable clinical response at late follow-up

Top of page

End point title

Percentage of participants with a favorable clinical response at late follow-up

End point description

A favorable clinical response is assessed by the clinical investigator as a cure, and is defined as a situation where all or most pre-therapy signs and symptoms of the index infection have resolved, or returned to pre-infection status, and no additional antibiotic therapy is required. The ME population was analyzed, defined as participants who: (1) met the protocol definition of cIAI; (2) had a pre-study/post operative culture from the site of infection grew at least one Gram-negative enteric and/or anaerobic pathogen; (3) had no significant deviations from the protocol that could impact the efficacy assessment; and (4) received ≥ 96 hours of IV study therapy.

End point type

Secondary

End point timeframe

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

End point values	Relebactam 250 mg + IPM/CIL	Relebactam 125 mg + IPM/CIL	Placebo + IPM/CIL
Number of subjects analysed	79	85	79
Units: Percentage of participants
number (confidence interval 95%)	93.7 (85.8 to 97.9)	95.3 (88.4 to 98.7)	94.9 (87.5 to 98.6)

Relebactam 250 mg - Placebo: Treatment Difference

Statistical analysis description

Non-inferiority test based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

158

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.002

Method

Miettinen and Nurminen

Parameter type

Percentage Difference

Point estimate

-1.3

Confidence interval

level

95%

sides

2-sided

lower limit

-9.6

upper limit

6.9

Relebactam 125 mg - Placebo: Treatment Difference

Statistical analysis description

Non-inferiority test based on unconditional asymptotic Miettinen and Nurminen method without stratification.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

164

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Difference

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-7.2

upper limit

8.2

Secondary: Percentage of participants with a favorable microbiological response at late follow-up

Top of page

End point title

Percentage of participants with a favorable microbiological response at late follow-up

End point description

End point type

Secondary

End point timeframe

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

End point values	Relebactam 250 mg + IPM/CIL	Relebactam 125 mg + IPM/CIL	Placebo + IPM/CIL
Number of subjects analysed	78	81	78
Units: Percentage of participants
number (confidence interval 95%)	96.2 (89.2 to 99.2)	97.5 (91.4 to 99.7)	96.2 (89.2 to 99.2)

Relebactam 250 mg - Placebo: Treatment Difference

Statistical analysis description

Non-inferiority test based on unconditional asymptotic Miettinen and Nurminen method without stratification. Eight participants with indeterminate or missing response were excluded from the analysis.

Comparison groups

Relebactam 250 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

156

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-7.4

upper limit

7.4

Relebactam 125 mg - Placebo: Treatment Difference

Statistical analysis description

Non-inferiority test based on unconditional asymptotic Miettinen and Nurminen method without stratification. Eight participants with indeterminate or missing response were excluded from the analysis.

Comparison groups

Relebactam 125 mg + IPM/CIL v Placebo + IPM/CIL

Number of subjects included in analysis

159

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Difference

Point estimate

1.4

Confidence interval

level

95%

sides

2-sided

lower limit

-5.2

upper limit

8.6

Adverse events

Top of page

Timeframe for reporting adverse events

During study therapy and the protocol-specified follow-up period following end of study therapy (up to 28 days for non-serious AEs and up to 56 days for serious drug-related AEs)

Adverse event reporting additional description

Population analyzed is all randomized participants who received at least one dose of IV study therapy. Participants with All-Cause Mortality were determined by the investigator to include some participants discontinued due to an adverse event, and progressive disease.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Relebactam 250 mg + IPM/CIL

Reporting group description

Relebactam 250 mg and imipenem/cilastatin (IPM/CIL) 500 mg were administered by IV separately, and concurrently over a 30-minute interval, every 6 hours for a minimum of 96 hours.

Reporting group title

Relebactam 125 mg + IPM/CIL

Reporting group description

Relebactam 125 mg and IPM/CIL 500 mg were administered by IV separately, and concurrently over a 30-minute interval, every 6 hours for a minimum of 96 hours.

Reporting group title

Placebo + IPM/CIL

Reporting group description

Placebo for relebactam and IPM/CIL 500 mg were administered by IV separately, and concurrently over a 30-minute interval, every 6 hours for a minimum of 96 hours.

Serious adverse events	Relebactam 250 mg + IPM/CIL	Relebactam 125 mg + IPM/CIL	Placebo + IPM/CIL
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 117 (3.42%)	11 / 116 (9.48%)	8 / 114 (7.02%)
number of deaths (all causes)	0	3	0
number of deaths resulting from adverse events	0	3	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign gastrointestinal neoplasm
subjects affected / exposed	0 / 117 (0.00%)	1 / 116 (0.86%)	0 / 114 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mucinous adenocarcinoma of appendix
subjects affected / exposed	0 / 117 (0.00%)	0 / 116 (0.00%)	1 / 114 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Post procedural bile leak
subjects affected / exposed	0 / 117 (0.00%)	1 / 116 (0.86%)	0 / 114 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Procedural pain
subjects affected / exposed	0 / 117 (0.00%)	0 / 116 (0.00%)	1 / 114 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound dehiscence
subjects affected / exposed	0 / 117 (0.00%)	0 / 116 (0.00%)	1 / 114 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound evisceration
subjects affected / exposed	1 / 117 (0.85%)	0 / 116 (0.00%)	0 / 114 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Suture rupture
subjects affected / exposed	0 / 117 (0.00%)	1 / 116 (0.86%)	0 / 114 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac failure chronic
subjects affected / exposed	1 / 117 (0.85%)	0 / 116 (0.00%)	0 / 114 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 117 (0.00%)	1 / 116 (0.86%)	0 / 114 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	0 / 117 (0.00%)	1 / 116 (0.86%)	0 / 114 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	0 / 117 (0.00%)	1 / 116 (0.86%)	0 / 114 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Thrombocytosis
subjects affected / exposed	0 / 117 (0.00%)	0 / 116 (0.00%)	1 / 114 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 117 (0.00%)	1 / 116 (0.86%)	0 / 114 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ileus paralytic
subjects affected / exposed	1 / 117 (0.85%)	0 / 116 (0.00%)	0 / 114 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal infarction
subjects affected / exposed	0 / 117 (0.00%)	1 / 116 (0.86%)	0 / 114 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 117 (0.00%)	0 / 116 (0.00%)	1 / 114 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 117 (0.00%)	1 / 116 (0.86%)	0 / 114 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 117 (0.00%)	1 / 116 (0.86%)	0 / 114 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis obstructive
subjects affected / exposed	0 / 117 (0.00%)	0 / 116 (0.00%)	1 / 114 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	0 / 117 (0.00%)	0 / 116 (0.00%)	1 / 114 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung consolidation
subjects affected / exposed	0 / 117 (0.00%)	1 / 116 (0.86%)	0 / 114 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 117 (0.00%)	1 / 116 (0.86%)	0 / 114 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 117 (0.00%)	0 / 116 (0.00%)	2 / 114 (1.75%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal failure acute
subjects affected / exposed	0 / 117 (0.00%)	1 / 116 (0.86%)	0 / 114 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Abdominal abscess
subjects affected / exposed	0 / 117 (0.00%)	1 / 116 (0.86%)	1 / 114 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	0 / 117 (0.00%)	1 / 116 (0.86%)	0 / 114 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Liver abscess
subjects affected / exposed	1 / 117 (0.85%)	0 / 116 (0.00%)	0 / 114 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	0 / 117 (0.00%)	1 / 116 (0.86%)	0 / 114 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 117 (0.00%)	1 / 116 (0.86%)	0 / 114 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	1 / 1

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Relebactam 250 mg + IPM/CIL	Relebactam 125 mg + IPM/CIL	Placebo + IPM/CIL
Total subjects affected by non serious adverse events
subjects affected / exposed	16 / 117 (13.68%)	15 / 116 (12.93%)	13 / 114 (11.40%)
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	7 / 117 (5.98%)	6 / 116 (5.17%)	5 / 114 (4.39%)
occurrences all number	8	6	5
Nausea
subjects affected / exposed	8 / 117 (6.84%)	9 / 116 (7.76%)	8 / 114 (7.02%)
occurrences all number	9	9	9
Vomiting
subjects affected / exposed	7 / 117 (5.98%)	9 / 116 (7.76%)	3 / 114 (2.63%)
occurrences all number	7	9	3

More information

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: ﻿A Phase II, Randomized, Active Comparator-Controlled Clinical Trial to Study the Safety, Tolerability, and Efficacy of MK-7655 + Imipenem/Cilastatin Versus Imipenem/Cilastatin Alone in Patients with Complicated Intra-Abdominal Infection [cIAI]

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of participants with a favorable clinical response at completion of IV study therapy

Primary: Percentage of participants with a favorable clinical response at completion of IV study therapy

Primary: Percentage of participants with an elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) laboratory values that are greater than or equal to 5X the upper limit of normal (ULN)

Primary: Percentage of participants with an elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) laboratory values that are greater than or equal to 5X the upper limit of normal (ULN)

Primary: Percentage of participants with elevated AST or ALT laboratory values that are greater than or equal to 3X the ULN, as well as elevated total bilirubin greater than or equal to 2X the ULN, and alkaline phosphatase values that are less than 2X the ULN

Primary: Percentage of participants with elevated AST or ALT laboratory values that are greater than or equal to 3X the ULN, as well as elevated total bilirubin greater than or equal to 2X the ULN, and alkaline phosphatase values that are less than 2X the ULN

Primary: Percentage of participants with any adverse event (AE)

Primary: Percentage of participants with any adverse event (AE)

Primary: Percentage of participants with any serious adverse event (SAE)

Primary: Percentage of participants with any serious adverse event (SAE)

Primary: Percentage of participants with any drug-related AE

Primary: Percentage of participants with any drug-related AE

Primary: Percentage of participants with any serious drug-related AE

Primary: Percentage of participants with any serious drug-related AE

Primary: Percentage of participants who discontinued IV study therapy due to an AE

Primary: Percentage of participants who discontinued IV study therapy due to an AE

Primary: Percentage of participants who discontinued IV study therapy due to a drug-related AE

Primary: Percentage of participants who discontinued IV study therapy due to a drug-related AE

Primary: Percentage of participants with AEs with incidence of >= 4 participants in one treatment group

Primary: Percentage of participants with AEs with incidence of >= 4 participants in one treatment group

Primary: Percentage of participants with predefined limit of change (PDLC) with incidence of >= 4 participants in one treatment group

Primary: Percentage of participants with predefined limit of change (PDLC) with incidence of >= 4 participants in one treatment group

Primary: Percentage of participants with system organ class (SOC) AE incidence of >= 4 participants in one treatment group

Primary: Percentage of participants with system organ class (SOC) AE incidence of >= 4 participants in one treatment group

Secondary: Percentage of participants with a favorable clinical response at completion of IV study therapy in participants who have imipenem-resistant, gram-negative cIAI infections.

Secondary: Percentage of participants with a favorable clinical response at completion of IV study therapy in participants who have imipenem-resistant, gram-negative cIAI infections.

Secondary: Percentage of participants with a favorable clinical response at early follow-up

Secondary: Percentage of participants with a favorable clinical response at early follow-up

Secondary: Percentage of participants with a favorable microbiological response at completion of IV study therapy

Secondary: Percentage of participants with a favorable microbiological response at completion of IV study therapy

Secondary: Percentage of participants with a favorable microbiological response at early follow-up

Secondary: Percentage of participants with a favorable microbiological response at early follow-up

Secondary: Percentage of participants with a favorable clinical response at late follow-up

Secondary: Percentage of participants with a favorable clinical response at late follow-up

Secondary: Percentage of participants with a favorable microbiological response at late follow-up

Secondary: Percentage of participants with a favorable microbiological response at late follow-up

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase II, Randomized, Active Comparator-Controlled Clinical Trial to Study the Safety, Tolerability, and Efficacy of MK-7655 + Imipenem/Cilastatin Versus Imipenem/Cilastatin Alone in Patients with Complicated Intra-Abdominal Infection [cIAI]