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Clinical Trial Results:
A Randomized, Active-Controlled Study to Evaluate the Efficacy and Safety of Intravenous Sulbactam-ETX2514 in the Treatment of Patients With Infections Caused by Acinetobacter baumannii-calcoaceticus Complex

Summary
EudraCT number	2018-002526-23
Trial protocol	HU LT GR
Global end of trial date	26 Jul 2021

Results information
Results version number	v2(current)
This version publication date	12 Oct 2022
First version publication date	20 Sep 2022
Other versions	v1
Version creation reason	Correction of full data set This study was not prematurely ended and a full data set was introduced.

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

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Trial information

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Sponsor protocol code

CS2514-2017-0004

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Entasis Therapeutics

Sponsor organisation address

Gatehouse Park BioHub , 35 Gatehouse Drive , Waltham, United States, MA 02451

Public contact

Chief Medical Officer, David Altarac, +1 781-810-0120, david.altarac@entasistx.com

Scientific contact

Chief Medical Officer, David Altarac, +1 781-810-0120, david.altarac@entasistx.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

18 Mar 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

26 Jul 2021

Global end of trial reached?

Yes

Global end of trial date

26 Jul 2021

Was the trial ended prematurely?

Main objective of the trial

•To compare the efficacy of ETX2514SUL plus imipenem/cilastatin to colistin plus imipenem/cilastatin in patients with carbapenem-resistant ABC (CRABC) infections in Part A; •To compare the incidence of nephrotoxicity, as measured by the Risk–Injury–Failure–Loss–End stage renal disease (RIFLE) criteria, of ETX2514SUL to colistin in patients with ABC infections in Part A.

Protection of trial subjects

All considerations regarding the protection of human subjects were carried out in accordance with the protocol, GCP, ICH Guidelines, the ethical principles that have their origin in the Declaration of Helsinki, and all applicable regulatory requirements. The investigator (according to applicable regulatory requirements) or a person designated by the investigator and under the investigator’s responsibility fully informed patients of all pertinent aspects of the clinical trial.

Background therapy

Evidence for comparator

The combination regimen (colistin + imipenem / cilastatin) was considered acceptable as the comparator by the Committee for Medicinal Products for Human Use (CHMP) during the Scientific Advice held with Entasis Therapeutics in 2018. Imipenem/cilastatin is a broad-spectrum beta-lactam antibiotic of the carbapenem class. Its bactericidal activity is against a broad spectrum of Gram-positive and Gram-negative bacteria, including anaerobic pathogens. The imipenem/cilastatin regimen (1g imipenem/1g cilastatin q6h infused over 60 mins) was considered acceptable by the CHMP as this is the maximum approved dose, making it appropriate for the patient population of the study. The dose adjustments by renal function are those in the EU imipenem SmPC. Colistin by intravenous (IV) administration is indicated in adults and children including neonates for the treatment of serious infections due to selected aerobic Gram-negative pathogens in patients with limited treatment options. Colistin is administered according to the protocol at 5 mg/kg of colistin base activity (CBA) divided into 2 doses 12 hours apart. Doses are adjusted to ideal body weight in obese patients, and doses do not exceed 300 mg of CBA per day. A single loading dose of 5 mg/kg (total dose not exceeding 300 mg CBA) given IV over 30 to 60 minutes is administered on Day 1. Colistin infusions beyond the loading dose on Day 1 begins 12 hours after the initial loading dose and are infused over 30 minutes. This dose regime was also considered acceptable by the CHMP even if it might not result in all patients receiving a daily colistin dose that would be recommended in the EU SmPC.

Actual start date of recruitment

05 Sep 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Greece: 9

Country: Number of subjects enrolled

Hungary: 17

Country: Number of subjects enrolled

Lithuania: 5

Country: Number of subjects enrolled

Belarus: 8

Country: Number of subjects enrolled

Brazil: 3

Country: Number of subjects enrolled

China: 47

Country: Number of subjects enrolled

India: 4

Country: Number of subjects enrolled

Israel: 16

Country: Number of subjects enrolled

Mexico: 9

Country: Number of subjects enrolled

Peru: 13

Country: Number of subjects enrolled

Korea, Republic of: 1

Country: Number of subjects enrolled

Russian Federation: 36

Country: Number of subjects enrolled

Thailand: 6

Country: Number of subjects enrolled

Turkey: 9

Country: Number of subjects enrolled

Taiwan: 22

Country: Number of subjects enrolled

United States: 2

Worldwide total number of subjects

207

EEA total number of subjects

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)

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

Eighty-five (85) clinical sites were activated, 71 clinical sites screened patients, and 59 clinical sites randomized/enrolled patients in Belarus, Brazil, China, Greece, Hungary, India, Israel, Lithuania, Mexico, Peru, Russia, South Korea, Taiwan, Thailand, Turkey, and the United States (US).From 05 September 2019 to 26 July 2021.

Screening details

A known infection caused by ABC (bacteremia, HABP, VABP, VP, complicated urinary tract infection [cUTI] or acute pyelonephritis [AP], or surgical or post-traumatic wound infections). A total of 531 patients were screened of which 324 (61%) were screen failures. The primary reason for screen failure was "Failure to meet inclusion/exclusion criteria

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

While study drugs were not masked due to logistical reasons, every attempt was made to maintain the blind for patients, all staff at the site, and the Sponsor or its designees, except for the treatment physician and other immediate healthcare providers. Clinical outcome assessments were performed by a blinded assessor, in addition to the unblinded Investigator. Whenever possible, the same blinded assessor completed all clinical outcome assessments for a study patient.

Are arms mutually exclusive

Part A - Group 1 - experimental group

Arm description

Part A was the pivotal, assessor-blind, randomized, comparative portion of the study in patients with documented ABC hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), ventilated pneumonia (VP), or bacteremia. While study drugs were not masked due to logistical reasons, every attempt was made to maintain the blind for patients, all staff at the site, and the Sponsor or its designees, except for the treatment physician and other immediate healthcare providers. Group 1 (experimental): 1.0 g sulbactam/1.0 g durlobactam IV infused over 3 hours every 6 hours (q6h) plus 1.0 g imipenem/1.0 g cilastatin IV infused over 1 hour q6h;

Arm type

Experimental

Investigational medicinal product name

Sulbactam

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1.0 g sulbactam IV infused over 3 hours every 6 hours (q6h). Day 1 was defined as the first day of study drug administration. The subsequent study days were defined by the number of treatment days thereafter. Treatment days constituted 24 hours of treatment. For those patients with no dose adjustments, the duration of antibiotic treatment with study drug therapy was 28 doses of sulbactam-durlobactam plus 28 doses of imipenem/cilastatin (ie, treatment for 7 days for those without dose adjustments), with a prolongation of therapy up to 14 days if clinically indicated.

Investigational medicinal product name

Durlobactam

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1.0 g durlobactam IV infused over 3 hours every 6 hours (q6h). Day 1 was defined as the first day of study drug administration. The subsequent study days were defined by the number of treatment days thereafter. Treatment days constituted 24 hours of treatment. For those patients with no dose adjustments, the duration of antibiotic treatment with study drug therapy was 28 doses of sulbactam-durlobactam plus 28 doses of imipenem/cilastatin (ie, treatment for 7 days for those without dose adjustments), with a prolongation of therapy up to 14 days if clinically indicated.

Investigational medicinal product name

Imipenem/Cilastatin 500 mg/500 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1.0 g imipenem/1.0 g cilastatin IV infused over 1 hour q6h. Day 1 was defined as the first day of study drug administration. The subsequent study days were defined by the number of treatment days thereafter. Treatment days constituted 24 hours of treatment. For those patients with no dose adjustments, the duration of antibiotic treatment with study drug therapy was 28 doses of sulbactam-durlobactam plus 28 doses of imipenem/cilastatin (ie, treatment for 7 days for those without dose adjustments), with a prolongation of therapy up to 14 days if clinically indicated.

Part A - Group 2 - control group

Arm description

Group 2 (control group): 2.5 mg/kg colistin IV infused over 30 minutes every 12 hours (after an initial loading dose of colistin 2.5 to 5 mg/kg) plus 1.0 g imipenem/1.0 g cilastatin IV infused over 1 hour q6h.

Arm type

Active comparator

Investigational medicinal product name

COLOMYCIN INJECTION 2 million IU/vial

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Colistin was administered at a daily dose of 5 mg/kg of CBA divided into 2 doses 12 hours apart. Doses were adjusted to ideal body weight in obese patients. Patients who weighed <60 kg with normal renal function received a flat dose of 300 mg CBA or 9 MIU/day. A single loading dose of 2.5 to 5 mg/kg (total dose not exceeding 300 mg CBA or 9 MIU and following local standard of care) given IV over 3 to 6 minutes (or according to standard of care) was administered on Day 1. Colistin infusions beyond the loading dose on Day 1 began 12 hours after the initial loading dose and were infused over 30 minutes.

Investigational medicinal product name

Imipenem/Cilastatin 500 mg/500 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Part B - Group 3

Arm description

Part B (Group 3) was the open-label, supportive portion of the study that included patients known to have HABP, VABP, VP, and/or bacteremia infections associated with ABC organisms resistant to colistin or polymyxin B, who failed a colistin or polymyxin B regimen prior to study entry or were on acute renal replacement therapy, and patients with infections due to colistin- or polymyxin B-resistant ABC with sources of infection other than HABP, VABP, VP, and/or bacteremia. Group 3: 1.0 g ETX2514/1.0 g sulbactam IV infused over 3 hours q6h plus 1.0 g imipenem/1.0 g cilastatin IV infused over 1 hour q6h.

Arm type

Experimental

Investigational medicinal product name

Sulbactam

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Durlobactam

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Imipenem/Cilastatin 500 mg/500 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Number of subjects in period 1 ^[1]	Part A - Group 1 - experimental group	Part A - Group 2 - control group	Part B - Group 3
Started	92	89	28
Completed	69	61	22
Not completed	23	28	6
Adverse event, serious fatal	15	21	4
Consent withdrawn by subject	2	3	1
No growth of ABC	2	1	-
Others	1	1	1
Adverse event, non-fatal	-	1	-
Transferred to other arm/group	1	1	-
Prohibited concomitant medication	1	-	-
Protocol deviation	1	-	-

Notes
[1] - The number of subjects transferring in and out of the arms in the period are not the same. It is expected the net number of transfers in and out of the arms in a period, will be zero.
Justification: Two (2) patients were transferred from Part A to part B. These patients were analyzed at each arm until/ from the time point of transfer. The number of patients who started in Part B (28) already includes the 2 patients transferred from Part A. the For this reason, the number of subjects transferring in and out of the arms in the period are not the same.

Baseline characteristics

Top of page

Reporting group title

Part A - Group 1 - experimental group

Reporting group description

Reporting group title

Part A - Group 2 - control group

Reporting group description

Reporting group title

Part B - Group 3

Reporting group description

Reporting group values	Part A - Group 1 - experimental group	Part A - Group 2 - control group	Part B - Group 3	Total
Number of subjects	92	89	28	207
Age categorical
Units: Subjects
Adults (18-64 years)	43	37	19	98
From 65-84 years	43	36	9	87
85 years and over	6	16	0	22
Gender categorical
Units: Subjects
Female	24	23	7	52
Male	68	66	21	155

End points

Top of page

Reporting group title

Part A - Group 1 - experimental group

Reporting group description

Reporting group title

Part A - Group 2 - control group

Reporting group description

Reporting group title

Part B - Group 3

Reporting group description

Subject analysis set title

CRABC m-MITT Population in Part A-Group 1

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

For Part A, the CRABC m-MITT Population included patients who met m-MITT criteria and had a baseline ABC organism that was confirmed to be carbapenem-resistant (MIC of imipenem/meropenem ≥8 ug/mL) by the central laboratory or by the local laboratory if the central laboratory was not able to characterize the isolate for any reason. Patients were excluded from the CRABC m-MITT Population if they had isolates that were deemed by the central laboratory to be resistant to sulbactam-durlobactam (MIC >4 ug/mL) or colistin (MIC ≥4 ug/mL), if their blood culture or respiratory samples were collected more than 72 hours prior to randomization, if they were transferred from Part A to Part B, or if they were enrolled with infections other than ABC pneumonia or bloodstream infection (ie, ABC infections other than HABP, VABP, VP, and bacteremia). Patients were enrolled until there were at least 120 patients in the CRABC Microbiologically Modified Intent-to-Treat (MITT) (m-MITT) Population in Part A.

Subject analysis set title

CRABC m-MITT Population in Part A-Group 2

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

ITT Population - Part A - Group 1

Subject analysis set type

Intention-to-treat

Subject analysis set description

The ITT Population included all patients randomized to study drug treatment (sulbactam-durlobactam + imipenem/cilastatin or colistin + imipenem/cilastatin) in Part A or enrolled in Part B, regardless of whether the patient actually received study drug. For Part A -Group 1, the total number of patients is 90 (excluding patients who withdrew consent).

Subject analysis set title

ITT Population - Part A - Group 2

Subject analysis set type

Intention-to-treat

Subject analysis set description

The ITT Population included all patients randomized to study drug treatment (sulbactam-durlobactam + imipenem/cilastatin or colistin + imipenem/cilastatin) in Part A or enrolled in Part B, regardless of whether the patient actually received study drug. For Part A -Group 2, the total number of patients is 85 (excluding patients who withdrew consent).

Subject analysis set title

m-MITT - Part A - Group 1

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

The Microbiologically Modified Intent-to-Treat (m-MITT) Population included patients who met MITT criteria and had an ABC organism isolated as the qualifying culture specimen, as confirmed by the central and/or local microbiology laboratory.

Subject analysis set title

m-MITT - Part A -Group 2

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

CE Population - Part A - Group 1

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

The Clinical Evaluable (CE) Population included patients who met m-MITT criteria and met evaluability criteria (met key inclusion criteria, did not meet key exclusion criteria, received at least 72 hours of study drug [ie, 12 doses of sulbactam-durlobactam plus 12 doses of imipenem/cilastatin or 6 doses of colistin plus 12 doses of imipenem/cilastatin in patients without dose adjustments] to be a clinical cure, received at least 48 hours of study drug [ie, 8 doses of sulbactam-durlobactam plus 8 doses of imipenem/cilastatin or 4 doses of colistin plus 8 doses of imipenem/cilastatin in patients without dose adjustments] to be a clinical failure, received ≥80% of anticipated doses, and did not have a clinical response of indeterminate at the TOC Visit);

Subject analysis set title

CE Population - Part A - Group 2

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

ME Population - Part A -Group 1

Subject analysis set type

Intention-to-treat

Subject analysis set description

The Microbiologic Evaluable (ME) Population included patients who met m-MITT criteria and CE criteria and had an appropriately collected culture specimen and interpretable culture result when specimen collection was clinically indicated at the TOC Visit;

Subject analysis set title

ME Population - Part A -Group 2

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

CRABC ME Population - Part A - Group 1

Subject analysis set type

Intention-to-treat

Subject analysis set description

The CRABC ME Population included patients who met ME criteria and who had a baseline ABC organism that was confirmed to be carbapenem-resistant (and susceptible to sulbactam-durlobactam for Parts A and B and susceptible to colistin for Part A)

Subject analysis set title

CRABC ME Population - Part A - Group 2

Subject analysis set type

Intention-to-treat

Subject analysis set description

Primary: 28-day all-cause mortality in the CRABC m-MITT Population in Part A

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End point title

28-day all-cause mortality in the CRABC m-MITT Population in Part A

End point description

The primary efficacy endpoint for the study was 28-day all-cause mortality in the CRABC m-MITT Population in Part A.

End point type

Primary

End point timeframe

Day 28

End point values	CRABC m-MITT Population in Part A-Group 1	CRABC m-MITT Population in Part A-Group 2
Number of subjects analysed	63	62
Units: patients	12	20

non-inferiority assessment

Statistical analysis description

The non-inferiority assessment was based on the 2-sided 95% CIs computed using a continuity-corrected Z-statistic for the difference ([sulbactam-durlobactam + imipenem/cilastatin] – [colistin + imipenem/cilastatin]) in 28-day all-cause mortality rates between the treatment groups. Non-inferiority was concluded if the upper limit of the 2-sided 95% CI was less than +20%. Superiority was concluded if the upper limit of the 2-sided 95% CI was less than 0.

Comparison groups

CRABC m-MITT Population in Part A-Group 2 v CRABC m-MITT Population in Part A-Group 1

Number of subjects included in analysis

125

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

Mean difference (net)

Point estimate

-13.2

Confidence interval

level

95%

sides

2-sided

lower limit

-30

upper limit

3.5

Variability estimate

Standard deviation

Primary: Incidence of nephrotoxicity (RIFLE) - Part A

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End point title

Incidence of nephrotoxicity (RIFLE) - Part A ^[1]

End point description

Analysis of patients with nephrotoxicity as measured by RIFLE criteria at any post-baseline visit based on the Investigator’s opinion for the Safety Population for Part A, excluding patients with chronic hemodialysis at baseline baseline.

End point type

Primary

End point timeframe

At any post-baseline visit

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Even if all 3 arms, Part A (Group 1 and 2) and Part B (Group 3) are all part of the baseline period, Part B data was summarized separately from Part A using descriptive statistics.

End point values	Part A - Group 1 - experimental group	Part A - Group 2 - control group
Number of subjects analysed	91	85
Units: patients	12	32

Nephrotoxicity as Measured by RIFLE

Statistical analysis description

Percentage of patients

Comparison groups

Part A - Group 1 - experimental group v Part A - Group 2 - control group

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

other ^[2]

P-value

= 0.0002 ^[3]

Method

Chi-squared

Confidence interval

Notes
[2] - p-value was obtained based on a Chi-Square test for treatment group differences
[3] - p-value was obtained based on a Chi-Square test for treatment group differences.

Secondary: 28-day all-cause mortality in the ITT Population PartA

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End point title

28-day all-cause mortality in the ITT Population PartA

End point description

Sulbactam-durlobactam + imipenem/cilastatin met the secondary endpoint of 28-day all-cause mortality compared to colistin + imipenem/cilastatin in all other populations of Part A. The mortality rate in the sulbactam-durlobactam + imipenem/cilastatin group was 21.1% (19 of 90 patients) compared to 32.9% (28 of 85 patients) in the colistin + imipenem/cilastatin group (treatment difference of -11.8%; 95% CI: -26.0%, 2.4%) for the ITT Population (excluding patients who withdrew consent ).

End point type

Secondary

End point timeframe

28 days

End point values	ITT Population - Part A - Group 1	ITT Population - Part A - Group 2
Number of subjects analysed	90	85
Units: patients	19	28

Treatment Difference

Comparison groups

ITT Population - Part A - Group 1 v ITT Population - Part A - Group 2

Number of subjects included in analysis

175

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

-11.8

Confidence interval

level

95%

sides

2-sided

lower limit

-26

upper limit

2.4

Variability estimate

Standard deviation

Secondary: Clinical cure at TOC in the CRABC m-MITT Population Part A

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End point title

Clinical cure at TOC in the CRABC m-MITT Population Part A

End point description

A significant treatment difference of 21.6% (95% CI: 2.9%, 40.3%) in clinical cure at TOC was observed with 61.9% (39 of 63) of patients in the sulbactam-durlobactam + imipenem/cilastatin group compared to 40.3% (25 of 62) of patients in the colistin + imipenem/cilastatin group achieving clinical cure for the CRABC m-MITT Population, excluding patients who withdrew consent.

End point type

Secondary

End point timeframe

The Test of Cure (TOC) Visit was completed 7 days (±2 days) after the end of treatment (EOT) Visit for all patients.

End point values	CRABC m-MITT Population in Part A-Group 1	CRABC m-MITT Population in Part A-Group 2
Number of subjects analysed	63	62
Units: patients	39	25

Treatment Difference

Statistical analysis description

Treatment difference was the difference in the clinical cure rate between the 2 treatment arms ([sulbactam-durlobactam + imipenem/cilastatin] – [colistin + imipenem/cilastatin]). The 95% CI (2-sided) was computed using a continuity-corrected Z-statistic.

Comparison groups

CRABC m-MITT Population in Part A-Group 1 v CRABC m-MITT Population in Part A-Group 2

Number of subjects included in analysis

125

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

21.6

Confidence interval

level

95%

sides

2-sided

lower limit

2.9

upper limit

40.3

Variability estimate

Standard deviation

Secondary: Clinical cure at TOC in the m-MITT Part A

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End point title

Clinical cure at TOC in the m-MITT Part A

End point description

A significant treatment difference of 25.2% (95% CI: 8.6, 41.7) in clinical cure at TOC was observed with 62.3% (48 of 77) of patients in the sulbactam-durlobactam + imipenem/cilastatin group compared to 37.2% (29 of 78) of patients in the colistin + imipenem/cilastatin group for the m-MITT Population

End point type

Secondary

End point timeframe

The Test of Cure (TOC) Visit was completed 7 days (±2 days) after the EOT Visit for all patients.

End point values	m-MITT - Part A - Group 1	m-MITT - Part A -Group 2
Number of subjects analysed	77	78
Units: patients	48	29

Treatment Difference

Statistical analysis description

Comparison groups

m-MITT - Part A - Group 1 v m-MITT - Part A -Group 2

Number of subjects included in analysis

155

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

25.2

Confidence interval

level

95%

sides

2-sided

lower limit

8.6

upper limit

41.7

Variability estimate

Standard deviation

Secondary: Clinical cure at TOC in the CE population Part A

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End point title

Clinical cure at TOC in the CE population Part A

End point description

A significant treatment difference of 29.2% (95% CI: 10.8%, 47.6%) in clinical cure at TOC was observed with 67.2% (45 of 67) of patients in the sulbactam-durlobactam + imipenem/cilastatin group compared to 37.9% (22 of 58) of patients in the colistin + imipenem/cilastatin group for the CE Population.

End point type

Secondary

End point timeframe

The Test of Cure (TOC) Visit was completed 7 days (±2 days) after the EOT Visit for all patients.

End point values	CE Population - Part A - Group 1	CE Population - Part A - Group 2
Number of subjects analysed	67	58
Units: patients	45	22

Treatment Difference

Statistical analysis description

Comparison groups

CE Population - Part A - Group 2 v CE Population - Part A - Group 1

Number of subjects included in analysis

125

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

29.2

Confidence interval

level

95%

sides

2-sided

lower limit

10.8

upper limit

47.6

Variability estimate

Standard deviation

Secondary: Clinical cure at TOC in the ME population Part A

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End point title

Clinical cure at TOC in the ME population Part A

End point description

A significant treatment difference of 31.7% (95% CI: 12.0%, 51.4%) in clinical cure at TOC was observed with 69.0% (40 of 58) of patients in the sulbactam-durlobactam + imipenem/cilastatin group compared to 37.3% (19 of 51) of patients in the colistin + imipenem/cilastatin group for the ME Population.

End point type

Secondary

End point timeframe

The Test of Cure (TOC) Visit was completed 7 days (±2 days) after the EOT Visit for all patients

End point values	ME Population - Part A -Group 1	ME Population - Part A -Group 2
Number of subjects analysed	58	51
Units: patients	40	19

Treatment Difference

Statistical analysis description

Comparison groups

ME Population - Part A -Group 1 v ME Population - Part A -Group 2

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

31.7

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

51.4

Variability estimate

Standard deviation

Secondary: Clinical cure at TOC in the CRABC ME Population Part A

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End point title

Clinical cure at TOC in the CRABC ME Population Part A

End point description

A significant treatment difference of 31.0% (95% CI: 9.2%, 52.9%) in clinical cure at TOC was observed with 67.4% (31 of 46) of patients in the sulbactam-durlobactam + imipenem/cilastatin group compared to 36.4% (16 of 44) of patients in the colistin + imipenem/cilastatin group for the CRABC ME Population

End point type

Secondary

End point timeframe

The Test of Cure (TOC) Visit was completed 7 days (±2 days) after the EOT Visit for all patients.

End point values	CRABC ME Population - Part A - Group 1	CRABC ME Population - Part A - Group 2
Number of subjects analysed	46	44
Units: patients	31	16

Treatment Difference

Statistical analysis description

Comparison groups

CRABC ME Population - Part A - Group 1 v CRABC ME Population - Part A - Group 2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

9.2

upper limit

52.9

Variability estimate

Standard deviation

Secondary: Clinical cure at EOT in the m-MITT population Part A

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End point title

Clinical cure at EOT in the m-MITT population Part A

End point description

A significant treatment difference of 29.2% (95% CI: 13.2%, 45.1%) in clinical cure at EOT was observed with 75.3% (58 of 77) of patients in the sulbactam-durlobactam + imipenem/cilastatin group compared to 46.2% (36 of 78) of patients in the colistin + imipenem/cilastatin group for the m-MITT Population in Part A

End point type

Secondary

End point timeframe

At end of treatment (EOT) visit (≥ Day 7 ≤ Day 14)

End point values	m-MITT - Part A - Group 1	m-MITT - Part A -Group 2
Number of subjects analysed	77	78
Units: patients	58	36

Treatment Difference

Comparison groups

m-MITT - Part A -Group 2 v m-MITT - Part A - Group 1

Number of subjects included in analysis

155

Analysis specification

Pre-specified

Analysis type

other ^[4]

Method

Parameter type

Mean difference (net)

Point estimate

29.2

Confidence interval

level

95%

sides

2-sided

lower limit

13.2

upper limit

45.1

Variability estimate

Standard deviation

Notes
[4] - Treatment difference was the difference in the clinical cure rate between the 2 treatment arms ([sulbactam-durlobactam + imipenem/cilastatin] – [colistin + imipenem/cilastatin]). The 95% CI (2-sided) was computed using a continuity-corrected Z-statistic.

Secondary: Clinical cure at EOT in the CRABC m-MITT population Part A

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End point title

Clinical cure at EOT in the CRABC m-MITT population Part A

End point description

A significant treatment difference of 29.4% (95% CI: 11.4%, 47.4%) in clinical cure at EOT was observed with 74.6% (47 of 63) of patients in the sulbactam-durlobactam + imipenem/cilastatin group compared to 45.2% (28 of 62) of patients in the colistin + imipenem/cilastatin group for the CRABC m-MITT Population excluding patients who withdrew consent.

End point type

Secondary

End point timeframe

At end of treatment (EOT) visit (≥ Day 7 ≤ Day 14)

End point values	CRABC m-MITT Population in Part A-Group 1	CRABC m-MITT Population in Part A-Group 2
Number of subjects analysed	63	62
Units: patients	47	28

Treatment Difference

Statistical analysis description

Comparison groups

CRABC m-MITT Population in Part A-Group 1 v CRABC m-MITT Population in Part A-Group 2

Number of subjects included in analysis

125

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

29.4

Confidence interval

level

95%

sides

2-sided

lower limit

11.4

upper limit

47.4

Variability estimate

Standard deviation

Secondary: Clinical cure at EOT in the CE population Part A

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End point title

Clinical cure at EOT in the CE population Part A

End point description

A significant treatment difference of 29.6% (95% CI: 11.6%, 47.6%) in clinical cure at EOT was observed with 76.1% (51 of 67) of patients in the sulbactam-durlobactam + imipenem/cilastatin group compared to 46.6% (27 of 58) of patients in the colistin + imipenem/cilastatin group for the CE Population in Part A

End point type

Secondary

End point timeframe

At end of treatment (EOT) visit (≥ Day 7 ≤ Day 14)

End point values	CE Population - Part A - Group 1	CE Population - Part A - Group 2
Number of subjects analysed	67	58
Units: patients	51	27

Treatment Difference

Statistical analysis description

Comparison groups

CE Population - Part A - Group 1 v CE Population - Part A - Group 2

Number of subjects included in analysis

125

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

29.6

Confidence interval

level

95%

sides

2-sided

lower limit

11.6

upper limit

47.6

Variability estimate

Standard deviation

Secondary: Clinical cure at EOT in the ME population Part A

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End point title

Clinical cure at EOT in the ME population Part A

End point description

A significant treatment difference of 30.5% (95% CI: 11.3%, 49.8%) in clinical cure at EOT was observed with 77.6% (45 of 58) of patients in the sulbactam-durlobactam + imipenem/cilastatin group compared to 47.1% (24 of 51) of patients in the colistin + imipenem/cilastatin group for the ME Population in Part A.

End point type

Secondary

End point timeframe

At end of treatment (EOT) visit (≥ Day 7 ≤ Day 14)

End point values	ME Population - Part A -Group 1	ME Population - Part A -Group 2
Number of subjects analysed	58	51
Units: patients	45	24

Treatment Difference

Statistical analysis description

Comparison groups

ME Population - Part A -Group 2 v ME Population - Part A -Group 1

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

30.5

Confidence interval

level

95%

sides

2-sided

lower limit

11.3

upper limit

49.8

Variability estimate

Standard deviation

Secondary: Clinical cure at EOT in the CRABC ME population Part A

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End point title

Clinical cure at EOT in the CRABC ME population Part A

End point description

A significant treatment difference of 30.7% (95% CI: 9.1%, 52.3%) in clinical cure at EOT was observed with 73.9% (34 of 46) of patients in the sulbactam-durlobactam + imipenem/cilastatin group compared to 43.2% (19 of 44) of patients in the colistin + imipenem/cilastatin group for the CRABC ME Population in Part A.

End point type

Secondary

End point timeframe

At end of treatment (EOT) visit (≥ Day 7 ≤ Day 14)

End point values	CRABC ME Population - Part A - Group 1	CRABC ME Population - Part A - Group 2
Number of subjects analysed	46	44
Units: patients	34	19

Treatment Difference

Statistical analysis description

Comparison groups

CRABC ME Population - Part A - Group 1 v CRABC ME Population - Part A - Group 2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

30.7

Confidence interval

level

95%

sides

2-sided

lower limit

9.1

upper limit

52.3

Variability estimate

Standard deviation

Secondary: Clinical cure at LFU in the m-MITT Part A

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End point title

Clinical cure at LFU in the m-MITT Part A

End point description

A treatment difference of 13.4% (95% CI: -2.8%, 29.5%) in clinical cure at LFU was observed in the sulbactam-durlobactam + imipenem/cilastatin group (41.6% [32 of 77] of patients) compared to the colistin + imipenem/cilastatin group (28.2% [22 of 78] of patients) for the m-MITT Population in Part A.

End point type

Secondary

End point timeframe

At late follow up (LFU) visit (> Day 21 ≤ Day 28)

End point values	m-MITT - Part A - Group 1	m-MITT - Part A -Group 2
Number of subjects analysed	77	78
Units: patients	32	22

Treatment Difference

Statistical analysis description

Comparison groups

m-MITT - Part A -Group 2 v m-MITT - Part A - Group 1

Number of subjects included in analysis

155

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

13.4

Confidence interval

level

95%

sides

2-sided

lower limit

-2.8

upper limit

29.5

Variability estimate

Standard deviation

Secondary: Clinical cure at LFU in the CRABC m-MITT Part A

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End point title

Clinical cure at LFU in the CRABC m-MITT Part A

End point description

A treatment difference of 12.2% (95% CI: -6.2%, 30.6%) in clinical cure at LFU was observed in the sulbactam-durlobactam + imipenem/cilastatin group (42.9% [27 of 63] of patients) compared to the colistin + imipenem/cilastatin group (30.6% [19 of 62] of patients) for the CRABC m-MITT Population, excluding patients who withdrew consent.

End point type

Secondary

End point timeframe

At late follow up (LFU) visit (> Day 21 ≤ Day 28)

End point values	CRABC m-MITT Population in Part A-Group 1	CRABC m-MITT Population in Part A-Group 2
Number of subjects analysed	63	62
Units: patients	27	19

Treatment Difference

Statistical analysis description

Comparison groups

CRABC m-MITT Population in Part A-Group 1 v CRABC m-MITT Population in Part A-Group 2

Number of subjects included in analysis

125

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

12.2

Confidence interval

level

95%

sides

2-sided

lower limit

-6.2

upper limit

30.6

Variability estimate

Standard deviation

Secondary: Clinical cure at LFU in the CE Part A

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End point title

Clinical cure at LFU in the CE Part A

End point description

A treatment difference of 10.5% (95% CI: -8.0%, 29.1%) in clinical cure at LFU was observed in the sulbactam-durlobactam + imipenem/cilastatin group (43.3% [29 of 67] of patients) compared to the colistin + imipenem/cilastatin group (32.8% [19 of 58] of patients) for the CE Population in Part A.

End point type

Secondary

End point timeframe

At late follow up (LFU) visit (> Day 21 ≤ Day 28)

End point values	CE Population - Part A - Group 1	CE Population - Part A - Group 2
Number of subjects analysed	67	58
Units: patients	29	19

Treatment Difference

Statistical analysis description

Comparison groups

CE Population - Part A - Group 1 v CE Population - Part A - Group 2

Number of subjects included in analysis

125

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

10.5

Confidence interval

level

95%

sides

2-sided

lower limit

-8

upper limit

29.1

Variability estimate

Standard deviation

Secondary: Clinical cure at LFU in the ME Part A

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End point title

Clinical cure at LFU in the ME Part A

End point description

A treatment difference of 8.0% (95% CI: -11.9%, 28.0%) in clinical cure at LFU was observed in the sulbactam-durlobactam + imipenem/cilastatin group (41.4% [24 of 58] of patients) compared to the colistin + imipenem/cilastatin group (33.3% [17 of 51] of patients) for the ME Population in Part A.

End point type

Secondary

End point timeframe

At late follow up (LFU) visit (> Day 21 ≤ Day 28)

End point values	ME Population - Part A -Group 1	ME Population - Part A -Group 2
Number of subjects analysed	58	51
Units: patients	24	17

Treatment Difference

Statistical analysis description

Comparison groups

ME Population - Part A -Group 2 v ME Population - Part A -Group 1

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-11.9

upper limit

Variability estimate

Standard deviation

Secondary: Clinical cure at LFU in the CRABC ME Part A

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End point title

Clinical cure at LFU in the CRABC ME Part A

End point description

A treatment difference of 9.5% (95% CI: -12.5%, 31.5%) in clinical cure at LFU was observed in the sulbactam-durlobactam + imipenem/cilastatin group (41.3% [19 of 46] of patients) compared to the colistin + imipenem/cilastatin group (31.8% [14 of 44] of patients) for the CRABC ME Population in Part A.

End point type

Secondary

End point timeframe

At late follow up (LFU) visit (> Day 21 ≤ Day 28)

End point values	CRABC ME Population - Part A - Group 1	CRABC ME Population - Part A - Group 2
Number of subjects analysed	46	44
Units: patients	19	14

Treatment Difference

Statistical analysis description

Comparison groups

CRABC ME Population - Part A - Group 1 v CRABC ME Population - Part A - Group 2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

9.5

Confidence interval

level

95%

sides

2-sided

lower limit

-12.5

upper limit

31.5

Variability estimate

Standard deviation

Secondary: Microbiological (overall) favorable assessment at EOT in the CRABC m-MITT population Part A

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End point title

Microbiological (overall) favorable assessment at EOT in the CRABC m-MITT population Part A

End point description

Overall, a significant treatment difference of 24.4% (95% CI: 7.9%, 40.9%) in microbiological favorable assessment at EOT was observed with 85.7% (54 of 63) of patients in the sulbactam-durlobactam + imipenem/cilastatin group compared to 61.3% (38 of 62) of patients in the colistin + imipenem/cilastatin group for the CRABC m-MITT Population, excluding patients who withdrew consent.

End point type

Secondary

End point timeframe

At end of treatment (EOT) visit (≥ Day 7 ≤ Day 14)

End point values	CRABC m-MITT Population in Part A-Group 1	CRABC m-MITT Population in Part A-Group 2
Number of subjects analysed	63	62
Units: patients	54	38

Treatment Difference

Statistical analysis description

Treatment difference was the difference in the clinical cure rate between the 2 treatment arms([sulbactam-durlobactam + imipenem/cilastatin] – [colistin + imipenem/cilastatin]). The 95% CI (2-sided) was computed using a continuity-corrected Z-statistic.

Comparison groups

CRABC m-MITT Population in Part A-Group 1 v CRABC m-MITT Population in Part A-Group 2

Number of subjects included in analysis

125

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

24.4

Confidence interval

level

95%

sides

2-sided

lower limit

7.9

upper limit

40.9

Variability estimate

Standard deviation

Secondary: Microbiological (overall) favorable assessment at TOC in the CRABC m-MITT population Part A

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End point title

Microbiological (overall) favorable assessment at TOC in the CRABC m-MITT population Part A

End point description

Overall, a significant treatment difference of 26.3% (95% CI: 7.9%, 44.7%) in microbiological favorable assessment at TOC was observed with 68.3% (43 of 63) of patients in the sulbactam-durlobactam + imipenem/cilastatin group compared to 41.9% (26 of 62) of patients in the colistin + imipenem/cilastatin group for the CRABC m-MITT Population, excluding patients who withdrew consent.

End point type

Secondary

End point timeframe

The Test of Cure (TOC) Visit was completed 7 days (±2 days) after the EOT Visit for all patients

End point values	CRABC m-MITT Population in Part A-Group 1	CRABC m-MITT Population in Part A-Group 2
Number of subjects analysed	63	62
Units: patients	43	26

Treatment Difference

Statistical analysis description

Treatment difference was the difference in the clinical cure rate between the 2 treatment arms([sulbactam-durlobactam + imipenem/cilastatin] – [colistin + imipenem/cilastatin]). The 95% CI (2-sided) was computed using a continuity-corrected Z-statistic.

Comparison groups

CRABC m-MITT Population in Part A-Group 1 v CRABC m-MITT Population in Part A-Group 2

Number of subjects included in analysis

125

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

26.3

Confidence interval

level

95%

sides

2-sided

lower limit

7.9

upper limit

44.7

Variability estimate

Standard deviation

Secondary: Microbiological (overall) favorable assessment at LFU in the CRABC m-MITT population Part A

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End point title

Microbiological (overall) favorable assessment at LFU in the CRABC m-MITT population Part A

End point description

A treatment difference of 7.3% (95% CI: -11.7%, 26.3%) in microbiological favorable assessment at LFU was observed in the sulbactam-durlobactam + imipenem/cilastatin group (47.6% [30 of 63] of patients) compared to the colistin + imipenem/cilastatin group (40.3% [25 of 62] of patients) for the CRABC m-MITT Population, excluding patients who withdrew consent.

End point type

Secondary

End point timeframe

At late follow up (LFU) visit (> Day 21 ≤ Day 28)

End point values	CRABC m-MITT Population in Part A-Group 1	CRABC m-MITT Population in Part A-Group 2
Number of subjects analysed	63	62
Units: patients	30	25

Treatment Difference

Statistical analysis description

Treatment difference was the difference in the clinical cure rate between the 2 treatment arms([sulbactam-durlobactam + imipenem/cilastatin] – [colistin + imipenem/cilastatin]). The 95% CI (2-sided) was computed using a continuity-corrected Z-statistic.

Comparison groups

CRABC m-MITT Population in Part A-Group 1 v CRABC m-MITT Population in Part A-Group 2

Number of subjects included in analysis

125

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

7.3

Confidence interval

level

95%

sides

2-sided

lower limit

-11.7

upper limit

26.3

Variability estimate

Standard deviation

Secondary: Microbiological (overall) favorable assessment at EOT in the m-MITT population Part A

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End point title

Microbiological (overall) favorable assessment at EOT in the m-MITT population Part A

End point description

A significant treatment difference of 21.6% (95% CI: 6.6%, 36.5%) in microbiological favorable assessment at EOT was observed with 83.1% (64 of 77) of patients in the sulbactam-durlobactam + imipenem/cilastatin group compared to 61.5% (48 of 78) of patients in the colistin + imipenem/cilastatin group for the m-MITT Population

End point type

Secondary

End point timeframe

At end of treatment (EOT) visit (≥ Day 7 ≤ Day 14)

End point values	m-MITT - Part A - Group 1	m-MITT - Part A -Group 2
Number of subjects analysed	77	78
Units: patients	64	48

Treatment Difference

Statistical analysis description

Treatment difference was the difference in the clinical cure rate between the 2 treatment arms([sulbactam-durlobactam + imipenem/cilastatin] – [colistin + imipenem/cilastatin]). The 95% CI (2-sided) was computed using a continuity-corrected Z-statistic.

Comparison groups

m-MITT - Part A - Group 1 v m-MITT - Part A -Group 2

Number of subjects included in analysis

155

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

21.6

Confidence interval

level

95%

sides

2-sided

lower limit

6.6

upper limit

36.5

Variability estimate

Standard deviation

Secondary: Microbiological (overall) favorable assessment at TOC in the m-MITT population Part A

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End point title

Microbiological (overall) favorable assessment at TOC in the m-MITT population Part A

End point description

A significant treatment difference of 25.2% (95% CI: 8.7%, 41.7%) in microbiological favorable assessment at TOC was observed with 66.2% (51 of 77) of patients in the sulbactam-durlobactam + imipenem/cilastatin group compared to 41.0% (32 of 78) of patients in the colistin + imipenem/cilastatin group for the m-MITT Population

End point type

Secondary

End point timeframe

The Test of Cure (TOC) Visit was completed 7 days (±2 days) after the EOT Visit for all patients.

End point values	m-MITT - Part A - Group 1	m-MITT - Part A -Group 2
Number of subjects analysed	77	78
Units: patients	51	32

Treatment Difference

Statistical analysis description

Treatment difference was the difference in the clinical cure rate between the 2 treatment arms([sulbactam-durlobactam + imipenem/cilastatin] – [colistin + imipenem/cilastatin]). The 95% CI (2-sided) was computed using a continuity-corrected Z-statistic.

Comparison groups

m-MITT - Part A - Group 1 v m-MITT - Part A -Group 2

Number of subjects included in analysis

155

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

25.2

Confidence interval

level

95%

sides

2-sided

lower limit

8.7

upper limit

41.7

Variability estimate

Standard deviation

Secondary: Microbiological (overall) favorable assessment at LFU in the m-MITT population Part A

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End point title

Microbiological (overall) favorable assessment at LFU in the m-MITT population Part A

End point description

A treatment difference (9.6% [95% CI: -7.2%, 26.4%]) in microbiological favorable assessment at LFU was observed with 48.1% (37 of 77) of patients in the sulbactam-durlobactam + imipenem/cilastatin group compared to 38.5% (30 of 78) of patients in the colistin + imipenem/cilastatin group for the m-MITT Population.

End point type

Secondary

End point timeframe

At late follow up (LFU) visit (> Day 21 ≤ Day 28)

End point values	m-MITT - Part A - Group 1	m-MITT - Part A -Group 2
Number of subjects analysed	77	78
Units: patients	37	30

Treatment Difference

Statistical analysis description

Treatment difference was the difference in the clinical cure rate between the 2 treatment arms([sulbactam-durlobactam + imipenem/cilastatin] – [colistin + imipenem/cilastatin]). The 95% CI (2-sided) was computed using a continuity-corrected Z-statistic.

Comparison groups

m-MITT - Part A - Group 1 v m-MITT - Part A -Group 2

Number of subjects included in analysis

155

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

9.6

Confidence interval

level

95%

sides

2-sided

lower limit

-7.2

upper limit

26.4

Variability estimate

Standard deviation

Secondary: Microbiological (overall) favorable assessment at EOT in the ME population Part A

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End point title

Microbiological (overall) favorable assessment at EOT in the ME population Part A

End point description

A significant treatment difference of 20.0% (95% CI: 1.7%, 38.3%) in microbiological favorable assessment at EOT was observed with 82.8% (48 of 58) of patients in the sulbactam-durlobactam + imipenem/cilastatin group compared to 62.7% (32 of 51) of patients in the colistin + imipenem/cilastatin group for the ME Population.

End point type

Secondary

End point timeframe

At end of treatment (EOT) visit (≥ Day 7 ≤ Day 14)

End point values	ME Population - Part A -Group 1	ME Population - Part A -Group 2
Number of subjects analysed	58	51
Units: patients	48	32

Treatment Difference

Statistical analysis description

Treatment difference was the difference in the clinical cure rate between the 2 treatment arms([sulbactam-durlobactam + imipenem/cilastatin] – [colistin + imipenem/cilastatin]). The 95% CI (2-sided) was computed using a continuity-corrected Z-statistic.

Comparison groups

ME Population - Part A -Group 1 v ME Population - Part A -Group 2

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

1.7

upper limit

38.3

Variability estimate

Standard deviation

Secondary: Microbiological (overall) favorable assessment at TOC in the ME population Part A

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End point title

Microbiological (overall) favorable assessment at TOC in the ME population Part A

End point description

A significant treatment difference of 26.1% (95% CI: 6.1%, 46.0%) in microbiological favorable assessment at TOC was observed with 67.2% (39 of 58) of patients in the sulbactam-durlobactam + imipenem/cilastatin group compared to 41.2% (21 of 51) of patients in the colistin + imipenem/cilastatin group for the ME Population

End point type

Secondary

End point timeframe

The Test of Cure (TOC) Visit was completed 7 days (±2 days) after the EOT Visit for all patients.

End point values	ME Population - Part A -Group 1	ME Population - Part A -Group 2
Number of subjects analysed	58	51
Units: patients	39	21

Treatment Difference

Statistical analysis description

Treatment difference was the difference in the clinical cure rate between the 2 treatment arms([sulbactam-durlobactam + imipenem/cilastatin] – [colistin + imipenem/cilastatin]). The 95% CI (2-sided) was computed using a continuity-corrected Z-statistic.

Comparison groups

ME Population - Part A -Group 1 v ME Population - Part A -Group 2

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

26.1

Confidence interval

level

95%

sides

2-sided

lower limit

6.1

upper limit

Variability estimate

Standard deviation

Secondary: Microbiological (overall) favorable assessment at LFU in the ME population Part A

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End point title

Microbiological (overall) favorable assessment at LFU in the ME population Part A

End point description

A treatment difference (7.1% [95% CI: -13.4%, 27.6%]) in microbiological favorable assessment at LFU was observed with 48.3% (28 of 58) of patients in the sulbactam-durlobactam + imipenem/cilastatin group compared to 41.2% (21 of 51) of patients in the colistin + imipenem/cilastatin group for the ME Population

End point type

Secondary

End point timeframe

At late follow up (LFU) visit (> Day 21 ≤ Day 28)

End point values	ME Population - Part A -Group 1	ME Population - Part A -Group 2
Number of subjects analysed	58	51
Units: patients	28	21

Treatment Difference

Statistical analysis description

Treatment difference was the difference in the clinical cure rate between the 2 treatment arms([sulbactam-durlobactam + imipenem/cilastatin] – [colistin + imipenem/cilastatin]). The 95% CI (2-sided) was computed using a continuity-corrected Z-statistic.

Comparison groups

ME Population - Part A -Group 2 v ME Population - Part A -Group 1

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

7.1

Confidence interval

level

95%

sides

2-sided

lower limit

-13.4

upper limit

27.6

Variability estimate

Standard deviation

Secondary: Microbiological (overall) favorable assessment at EOT in the CRABC ME population Part A

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End point title

Microbiological (overall) favorable assessment at EOT in the CRABC ME population Part A

End point description

A treatment difference (19.0% [95% CI: -1.2%, 39.1%]) in microbiological favorable assessment at EOT was observed with 82.6% (38 of 46) of patients in the sulbactam-durlobactam + imipenem/cilastatin group compared to 63.6% (28 of 44) of patients in the colistin + imipenem/cilastatin group for the CRABC ME Population

End point type

Secondary

End point timeframe

At end of treatment (EOT) visit (≥ Day 7 ≤ Day 14)

End point values	CRABC ME Population - Part A - Group 1	CRABC ME Population - Part A - Group 2
Number of subjects analysed	46	44
Units: patients	38	28

Treatment Difference

Statistical analysis description

Summarized by treatment group. Two-sided 95% CIs computed using a continuity-corrected Z-statistic for the difference in outcome rates between the treatment groups in Part A.

Comparison groups

CRABC ME Population - Part A - Group 1 v CRABC ME Population - Part A - Group 2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1.2

upper limit

39.1

Variability estimate

Standard deviation

Secondary: Microbiological (overall) favorable assessment at TOC in the CRABC ME population Part A

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End point title

Microbiological (overall) favorable assessment at TOC in the CRABC ME population Part A

End point description

A significant treatment difference of 28.7% (95% CI: 6.7%, 50.6%) in microbiological favorable assessment at TOC was observed with 69.6% (32 of 46) of patients in the sulbactam-durlobactam + imipenem/cilastatin group compared to 40.9% (18 of 44) of patients in the colistin + imipenem/cilastatin group for the CRABC ME Population

End point type

Secondary

End point timeframe

The Test of Cure (TOC) Visit was completed 7 days (±2 days) after the EOT Visit for all patients

End point values	CRABC ME Population - Part A - Group 1	CRABC ME Population - Part A - Group 2
Number of subjects analysed	46	44
Units: patients	32	18

Treatment Difference

Statistical analysis description

Treatment difference was the difference in the clinical cure rate between the 2 treatment arms([sulbactam-durlobactam + imipenem/cilastatin] – [colistin + imipenem/cilastatin]). The 95% CI (2-sided) was computed using a continuity-corrected Z-statistic.

Comparison groups

CRABC ME Population - Part A - Group 1 v CRABC ME Population - Part A - Group 2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

28.7

Confidence interval

level

95%

sides

2-sided

lower limit

6.7

upper limit

50.6

Variability estimate

Standard deviation

Secondary: Microbiological (overall) favorable assessment at LFU in the CRABC ME population Part A

Top of page

End point title

Microbiological (overall) favorable assessment at LFU in the CRABC ME population Part A

End point description

A treatment difference (6.9% [95% CI: -15.8%, 29.6%]) in microbiological favorable assessment at LFU was observed with 47.8% (22 of 46) of patients in the sulbactam-durlobactam + imipenem/cilastatin group compared to 40.9% (18 of 44) of patients in the colistin + imipenem/cilastatin group for the CRABC ME Population

End point type

Secondary

End point timeframe

At late follow up (LFU) visit (> Day 21 ≤ Day 28)

End point values	CRABC ME Population - Part A - Group 1	CRABC ME Population - Part A - Group 2
Number of subjects analysed	46	44
Units: patients	22	18

Treatment Difference

Statistical analysis description

Treatment difference was the difference in the clinical cure rate between the 2 treatment arms([sulbactam-durlobactam + imipenem/cilastatin] – [colistin + imipenem/cilastatin]). The 95% CI (2-sided) was computed using a continuity-corrected Z-statistic.

Comparison groups

CRABC ME Population - Part A - Group 1 v CRABC ME Population - Part A - Group 2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

6.9

Confidence interval

level

95%

sides

2-sided

lower limit

-15.8

upper limit

29.6

Variability estimate

Standard deviation

Secondary: 14-day all-cause mortality in the m-MITT Populations

Top of page

End point title

14-day all-cause mortality in the m-MITT Populations

End point description

Sulbactam-durlobactam + imipenem/cilastatin met the secondary efficacy endpoint of 14-day all-cause mortality compared to colistin + imipenem/cilastatin in the m-MITT Population for Part A. The 14-day all-cause mortality rate in the sulbactam-durlobactam + imipenem/cilastatin group was 7.8% (6 of 77 patients) compared to 19.5% (15 of 77 patients) in the colistin + imipenem/cilastatin group (treatment difference of -11.7%; 95% CI: -23.7%, 0.3%) for the m-MITT Population.

End point type

Secondary

End point timeframe

Day 14

End point values	m-MITT - Part A - Group 1	m-MITT - Part A -Group 2
Number of subjects analysed	77	77
Units: patients	6	15

Treatment Difference

Statistical analysis description

Summarized by treatment group. Two-sided 95% CIs computed using a continuity-corrected Z-statistic for the difference in outcome rates between the treatment groups in Part A.

Comparison groups

m-MITT - Part A - Group 1 v m-MITT - Part A -Group 2

Number of subjects included in analysis

154

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

-11.7

Confidence interval

level

95%

sides

2-sided

lower limit

-23.7

upper limit

0.3

Variability estimate

Standard deviation

Secondary: 14-day all-cause mortality in the CRABC m-MITT Population

Top of page

End point title

14-day all-cause mortality in the CRABC m-MITT Population

End point description

Treatment differences in 14-day all-cause mortality were observed for patients in the sulbactam-durlobactam + imipenem/cilastatin group compared to the imipenem/cilastatin group. The treatment difference between the 2 groups was -12.8% (95% CI: -25.7%, 0.1%). The mortality rate in the sulbactam-durlobactam + imipenem/cilastatin group was 6.3% (4 of 64 patients) compared to 19.0% (12 of 63 patients) in the colistin + imipenem/cilastatin group for the CRABC m-MITT Population.

End point type

Secondary

End point timeframe

Day 14

End point values	CRABC m-MITT Population in Part A-Group 1	CRABC m-MITT Population in Part A-Group 2
Number of subjects analysed	64	63
Units: patients	4	12

Treatment Difference

Statistical analysis description

Summarized by treatment group. Two-sided 95% CIs computed using a continuity-corrected Z-statistic for the difference in outcome rates between the treatment groups in Part A.

Comparison groups

CRABC m-MITT Population in Part A-Group 2 v CRABC m-MITT Population in Part A-Group 1

Number of subjects included in analysis

127

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

-12.8

Confidence interval

level

95%

sides

2-sided

lower limit

-25.7

upper limit

0.1

Variability estimate

Standard deviation

Secondary: 28-day all-cause mortality in the m-MITT Population

Top of page

End point title

28-day all-cause mortality in the m-MITT Population

End point description

The 28-day all-cause mortality rate in the sulbactam-durlobactam + imipenem/cilastatin group was 19.7% (15 of 76 patients) compared to 32.9% (25 of 76 patients) in the colistin + imipenem/cilastatin group (treatment difference of -13.2%; 95% CI: -28.3%, 2.0%) for the m-MITT Population.

End point type

Secondary

End point timeframe

Day 28

End point values	m-MITT - Part A - Group 1	m-MITT - Part A -Group 2
Number of subjects analysed	76	76
Units: patients	15	25

Treatment Difference

Statistical analysis description

Summarized by treatment group. Two-sided 95% CIs computed using a continuity-corrected Z-statistic for the difference in outcome rates between the treatment groups in Part A.

Comparison groups

m-MITT - Part A - Group 1 v m-MITT - Part A -Group 2

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

-13.2

Confidence interval

level

95%

sides

2-sided

lower limit

-28.3

upper limit

Variability estimate

Standard deviation

Secondary: 28-day all-cause mortality in the CRABC ME Population

Top of page

End point title

28-day all-cause mortality in the CRABC ME Population

End point description

The 28-day all-cause mortality rate in the sulbactam-durlobactam + imipenem/cilastatin group was 17.4% (8 of 46 patients) compared to 36.4% (16 of 44 patients) in the colistin + imipenem/cilastatin group (treatment difference of -19.0%; 95% CI: -39.1%, 1.2%) for the CRABC ME Population, which represents a Clinical Study Protocol-adherent population.

End point type

Secondary

End point timeframe

Day 28

End point values	CRABC ME Population - Part A - Group 1	CRABC ME Population - Part A - Group 2
Number of subjects analysed	46	44
Units: patients	8	16

Treatment Difference

Statistical analysis description

Summarized by treatment group. Two-sided 95% CIs computed using a continuity-corrected Z-statistic for the difference in outcome rates between the treatment groups in Part A.

Comparison groups

CRABC ME Population - Part A - Group 1 v CRABC ME Population - Part A - Group 2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (net)

Point estimate

-19

Confidence interval

level

95%

sides

2-sided

lower limit

-39.1

upper limit

1.2

Variability estimate

Standard deviation

Secondary: 28-day all-cause mortality in the ITT Population - Part B

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End point title

28-day all-cause mortality in the ITT Population - Part B ^[5]

End point description

For Part B, 28-day all-cause mortality was 17.9% (5 of 28 patients) (95% CI: 6.1%, 36.9%) for the ITT Population. The Part B 28-day all-cause mortality was similar to the sulbactam-durlobactam + imipenem/cilastatin group in Part A for the CRABC m-MITT Population (17.9% and 20.3%, respectively).

End point type

Secondary

End point timeframe

Day 28

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Even if all 3 arms, Part A (Group 1 and 2) and Part B (Group 3) are all part of the baseline period, Part B data was summarized separately from Part A using descriptive statistics.

End point values	Part B - Group 3
Number of subjects analysed	28
Units: patients	5

No statistical analyses for this end point

Secondary: Clinical cure at TOC in the CRABC m-MITT Population - Part B

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End point title

Clinical cure at TOC in the CRABC m-MITT Population - Part B ^[6]

End point description

For Part B, clinical cure at TOC was observed with 71.4% (20 of 28) of patients for the CRABC m-MITT Population.

End point type

Secondary

End point timeframe

The Test of Cure (TOC) Visit was completed 7 days (±2 days) after the EOT Visit for all patients

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Even if all 3 arms, Part A (Group 1 and 2) and Part B (Group 3) are all part of the baseline period, Part B data was summarized separately from Part A using descriptive statistics.

End point values	Part B - Group 3
Number of subjects analysed	28
Units: patients	20

No statistical analyses for this end point

Secondary: Clinical cure at TOC in the m-MITT Population - Part B

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End point title

Clinical cure at TOC in the m-MITT Population - Part B ^[7]

End point description

For Part B, clinical cure at TOC was observed with 71.4% (20 of 28) of patients for the m-MITT Population.

End point type

Secondary

End point timeframe

The Test of Cure (TOC) Visit was completed 7 days (±2 days) after the EOT Visit for all patients

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Even if all 3 arms, Part A (Group 1 and 2) and Part B (Group 3) are all part of the baseline period, Part B data was summarized separately from Part A using descriptive statistics.

End point values	Part B - Group 3
Number of subjects analysed	28
Units: patients	20

No statistical analyses for this end point

Secondary: Clinical cure at TOC in the CE, ME, and CRABC ME Population - Part B

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End point title

Clinical cure at TOC in the CE, ME, and CRABC ME Population - Part B ^[8]

End point description

For Part B, clinical cure at TOC was observed with 78.3% (18 of 23) of patients each for the CE, ME, and CRABC ME Populations.

End point type

Secondary

End point timeframe

The Test of Cure (TOC) Visit was completed 7 days (±2 days) after the EOT Visit for all patients

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Even if all 3 arms, Part A (Group 1 and 2) and Part B (Group 3) are all part of the baseline period, Part B data was summarized separately from Part A using descriptive statistics.

End point values	Part B - Group 3
Number of subjects analysed	23
Units: patients	18

No statistical analyses for this end point

Secondary: Clinical cure at EOT in the CRABC m-MITT Population -Part B

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End point title

Clinical cure at EOT in the CRABC m-MITT Population -Part B ^[9]

End point description

For Part B, clinical cure at EOT was observed with 82.1% (23 of 28) of patients for the CRABC m-MITT Population.

End point type

Secondary

End point timeframe

At end of treatment (EOT) visit (≥ Day 7 ≤ Day 14)

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Even if all 3 arms, Part A (Group 1 and 2) and Part B (Group 3) are all part of the baseline period, Part B data was summarized separately from Part A using descriptive statistics.

End point values	Part B - Group 3
Number of subjects analysed	28
Units: patients	23

No statistical analyses for this end point

Secondary: Clinical cure at LFU in the CRABC m-MITT Population -Part B

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End point title

Clinical cure at LFU in the CRABC m-MITT Population -Part B ^[10]

End point description

For Part B, clinical cure at LFU was observed with 46.4% (13 of 28) of patients for the CRABC m-MITT Population

End point type

Secondary

End point timeframe

At late follow up (LFU) visit (> Day 21 ≤ Day 28)

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Even if all 3 arms, Part A (Group 1 and 2) and Part B (Group 3) are all part of the baseline period, Part B data was summarized separately from Part A using descriptive statistics.

End point values	Part B - Group 3
Number of subjects analysed	28
Units: patients	13

No statistical analyses for this end point

Secondary: Clinical cure at EOT in the m-MITT Population -Part B

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End point title

Clinical cure at EOT in the m-MITT Population -Part B ^[11]

End point description

For Part B, clinical cure at EOT was observed with 82.1% (23 of 28) of patients for the m-MITT Population.

End point type

Secondary

End point timeframe

At end of treatment (EOT) visit (≥ Day 7 ≤ Day 14)

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Even if all 3 arms, Part A (Group 1 and 2) and Part B (Group 3) are all part of the baseline period, Part B data was summarized separately from Part A using descriptive statistics.

End point values	Part B - Group 3
Number of subjects analysed	28
Units: patients	23

No statistical analyses for this end point

Secondary: Clinical cure at LFU in the m-MITT Population -Part B

Top of page

End point title

Clinical cure at LFU in the m-MITT Population -Part B ^[12]

End point description

For Part B, clinical cure at LFU was observed with 46.4% (13 of 28) of patients for the m-MITT Population.

End point type

Secondary

End point timeframe

At late follow up (LFU) visit (> Day 21 ≤ Day 28)

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Even if all 3 arms, Part A (Group 1 and 2) and Part B (Group 3) are all part of the baseline period, Part B data was summarized separately from Part A using descriptive statistics.

End point values	Part B - Group 3
Number of subjects analysed	28
Units: patients	13

No statistical analyses for this end point

Secondary: Clinical cure at EOT in the CE, ME and CRABC ME Populations -Part B

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End point title

Clinical cure at EOT in the CE, ME and CRABC ME Populations -Part B ^[13]

End point description

For Part B, clinical cure at EOT was observed with 82.6% (19 of 23) of patients for the CE, ME and CRABC ME populations.

End point type

Secondary

End point timeframe

At end of treatment (EOT) visit (≥ Day 7 ≤ Day 14)

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Even if all 3 arms, Part A (Group 1 and 2) and Part B (Group 3) are all part of the baseline period, Part B data was summarized separately from Part A using descriptive statistics.

End point values	Part B - Group 3
Number of subjects analysed	23
Units: patients	19

No statistical analyses for this end point

Secondary: Clinical cure at LFU in the CE, ME and CRABC ME Populations -Part B

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End point title

Clinical cure at LFU in the CE, ME and CRABC ME Populations -Part B ^[14]

End point description

For Part B, clinical cure at LFU was observed with 52.2% (12 of 23) of patients for the CE, ME and CRABC ME populations.

End point type

Secondary

End point timeframe

At late follow up (LFU) visit (> Day 21 ≤ Day 28)

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Even if all 3 arms, Part A (Group 1 and 2) and Part B (Group 3) are all part of the baseline period, Part B data was summarized separately from Part A using descriptive statistics.

End point values	Part B - Group 3
Number of subjects analysed	23
Units: patients	12

No statistical analyses for this end point

Secondary: Microbiological (overall) favorable assessment at EOT in the m-MITT and CRABC m-MITT population - Part B

Top of page

End point title

Microbiological (overall) favorable assessment at EOT in the m-MITT and CRABC m-MITT population - Part B ^[15]

End point description

Overall, microbiological favorable assessment at EOT was observed with 89.3% (25 of 28) of patients for the CRABC m-MITT Population.

End point type

Secondary

End point timeframe

At end of treatment (EOT) visit (≥ Day 7 ≤ Day 14)

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Even if all 3 arms, Part A (Group 1 and 2) and Part B (Group 3) are all part of the baseline period, Part B data was summarized separately from Part A using descriptive statistics.

End point values	Part B - Group 3
Number of subjects analysed	28
Units: patients	25

No statistical analyses for this end point

Secondary: Microbiological (overall) favorable assessment at LFU in the m-MITT and CRABC m-MITT population - Part B

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End point title

Microbiological (overall) favorable assessment at LFU in the m-MITT and CRABC m-MITT population - Part B ^[16]

End point description

Overall, microbiological favorable assessment at LFU was observed with 53.6% (15 of 28) of patients.

End point type

Secondary

End point timeframe

At late follow up (LFU) visit (> Day 21 ≤ Day 28)

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Even if all 3 arms, Part A (Group 1 and 2) and Part B (Group 3) are all part of the baseline period, Part B data was summarized separately from Part A using descriptive statistics.

End point values	Part B - Group 3
Number of subjects analysed	28
Units: patients	15

No statistical analyses for this end point

Secondary: Microbiological (overall) favorable assessment at TOC in the m-MITT and CRABC m-MITT population - Part B

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End point title

Microbiological (overall) favorable assessment at TOC in the m-MITT and CRABC m-MITT population - Part B ^[17]

End point description

Overall, microbiological favorable assessment at TOC was observed with 78.6% (22 of 28) of patients

End point type

Secondary

End point timeframe

The Test of Cure (TOC) Visit was completed 7 days (±2 days) after the EOT Visit for all patients.

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Even if all 3 arms, Part A (Group 1 and 2) and Part B (Group 3) are all part of the baseline period, Part B data was summarized separately from Part A using descriptive statistics.

End point values	Part B - Group 3
Number of subjects analysed	28
Units: patients	22

No statistical analyses for this end point

Secondary: Microbiological (overall) favorable assessment at EOT in the ME and CRABC ME populations – Part B

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End point title

Microbiological (overall) favorable assessment at EOT in the ME and CRABC ME populations – Part B ^[18]

End point description

Overall, microbiological favorable assessment at EOT was observed with 95.7% (22 of 23) of patients for the ME and CRABC ME populations.

End point type

Secondary

End point timeframe

At end of treatment (EOT) visit (≥ Day 7 ≤ Day 14)

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Even if all 3 arms, Part A (Group 1 and 2) and Part B (Group 3) are all part of the baseline period, Part B data was summarized separately from Part A using descriptive statistics.

End point values	Part B - Group 3
Number of subjects analysed	23
Units: patients	22

No statistical analyses for this end point

Secondary: Microbiological (overall) favorable assessment at TOC in the ME and CRABC ME populations – Part B

Top of page

End point title

Microbiological (overall) favorable assessment at TOC in the ME and CRABC ME populations – Part B ^[19]

End point description

Overall, microbiological favorable assessment at TOC was observed with 87.0% (20 of 23) of patients for the ME and CRABC ME populations.

End point type

Secondary

End point timeframe

The Test of Cure (TOC) Visit was completed 7 days (±2 days) after the EOT Visit for all patients.

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Even if all 3 arms, Part A (Group 1 and 2) and Part B (Group 3) are all part of the baseline period, Part B data was summarized separately from Part A using descriptive statistics.

End point values	Part B - Group 3
Number of subjects analysed	23
Units: patients	20

No statistical analyses for this end point

Secondary: Microbiological (overall) favorable assessment at LFU in the ME and CRABC ME populations – Part B

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End point title

Microbiological (overall) favorable assessment at LFU in the ME and CRABC ME populations – Part B ^[20]

End point description

Overall, microbiological favorable assessment at LFU was observed with 60.9% (14 of 23) of patients for the ME and CRABC ME populations.

End point type

Secondary

End point timeframe

At late follow up (LFU) visit (> Day 21 ≤ Day 28)

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Even if all 3 arms, Part A (Group 1 and 2) and Part B (Group 3) are all part of the baseline period, Part B data was summarized separately from Part A using descriptive statistics.

End point values	Part B - Group 3
Number of subjects analysed	23
Units: patients	14

No statistical analyses for this end point

Secondary: 14-day all-cause mortality in the CRABC m-MITT and m-MITT Populations - Part B

Top of page

End point title

14-day all-cause mortality in the CRABC m-MITT and m-MITT Populations - Part B ^[21]

End point description

For Part B, 14-day all-cause mortality was 10.7% (3 of 28) of patients each (95% CI: 2.3%, 28.2%) for both the m-MITT and CRABC m-MITT Populations. The Part B 14-day all-cause mortality was similar to the sulbactam-durlobactam + imipenem/cilastatin group in Part A for the CRABC m-MITT Population (10.7% and 6.3%, respectively).

End point type

Secondary

End point timeframe

Day 14

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Even if all 3 arms, Part A (Group 1 and 2) and Part B (Group 3) are all part of the baseline period, Part B data was summarized separately from Part A using descriptive statistics.

End point values	Part B - Group 3
Number of subjects analysed	28
Units: patients	3

No statistical analyses for this end point

Secondary: 28-day all-cause mortality in the m-MITT Population - Part B

Top of page

End point title

28-day all-cause mortality in the m-MITT Population - Part B ^[22]

End point description

For Part B, 28-day all-cause mortality was 17.9% (5 of 28) of patients (95% CI: 6.1%, 36.9%) for the m-MITT Population.

End point type

Secondary

End point timeframe

Day 28

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Even if all 3 arms, Part A (Group 1 and 2) and Part B (Group 3) are all part of the baseline period, Part B data was summarized separately from Part A using descriptive statistics.

End point values	Part B - Group 3
Number of subjects analysed	28
Units: patients	5

No statistical analyses for this end point

Secondary: 28-day all-cause mortality in the CRABC ME Population - Part B

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End point title

28-day all-cause mortality in the CRABC ME Population - Part B ^[23]

End point description

For Part B, 28-day all-cause mortality was 8.7% (2 of 23) of patients (95% CI: 1.1%, 28.0%) for the CRABC ME Population.

End point type

Secondary

End point timeframe

Day 28

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Even if all 3 arms, Part A (Group 1 and 2) and Part B (Group 3) are all part of the baseline period, Part B data was summarized separately from Part A using descriptive statistics.

End point values	Part B - Group 3
Number of subjects analysed	23
Units: patients	2

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse event monitoring starts from the time the patient consents to the study until they complete the trial.

Adverse event reporting additional description

A Treatment-emergent adverse event (TEAE) was defined as an adverse event (AE) that occurred on or after the administration of the first dose of study drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

Safety Population- Part A - Group 1 - experimental group

Reporting group description

In total, 91 patients received any amount of study drug treatment in Part A - Group 1 and were considered the Safety Population for this group.

Reporting group title

Safety Population-Part A - Group 2 - control group

Reporting group description

In total, 86 patients received any amount of study drug treatment in Part A - Group 2 – control group and were considered the Safety Population for this group.

Reporting group title

Safety Population-Part B - Group 3

Reporting group description

There were 28 patients who received any amount of study drug in Part B and were included in the Safety Population for Part B.

Serious adverse events	Safety Population- Part A - Group 1 - experimental group	Safety Population-Part A - Group 2 - control group	Safety Population-Part B - Group 3
Total subjects affected by serious adverse events
subjects affected / exposed	36 / 91 (39.56%)	42 / 86 (48.84%)	9 / 28 (32.14%)
number of deaths (all causes)	25	31	4
number of deaths resulting from adverse events	24	30	4
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Metastases to central nervous system
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (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
Metastases to lung
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (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
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (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
Peripheral artery thrombosis
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Shock
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Shock haemorrhagic
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
General disorders and administration site conditions
Multiple organ dysfunction syndrome
subjects affected / exposed	1 / 91 (1.10%)	4 / 86 (4.65%)	2 / 28 (7.14%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 4	0 / 2
Disease progression
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome
subjects affected / exposed	2 / 91 (2.20%)	2 / 86 (2.33%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 2	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 91 (1.10%)	2 / 86 (2.33%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0
Respiratory failure
subjects affected / exposed	2 / 91 (2.20%)	1 / 86 (1.16%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Bronchial obstruction
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (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
Hypercapnia
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (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
Pleural effusion
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Pneumonia aspiration
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (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
Tracheomalacia
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (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
Investigations
Liver function test abnormal
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (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
Injury, poisoning and procedural complications
Alcohol poisoning
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Chemical peritonitis
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (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
Craniocerebral injury
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (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
Post procedural haemorrhage
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (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
Tracheostomy malfunction
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (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
Weaning failure
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Congenital, familial and genetic disorders
Tracheo-oesophageal fistula
subjects affected / exposed	2 / 91 (2.20%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac arrest
subjects affected / exposed	2 / 91 (2.20%)	4 / 86 (4.65%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 2	0 / 0
Acute myocardial infarction
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Arteriosclerosis coronary artery
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (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
Bradycardia
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (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
Cardio-respiratory arrest
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (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 tachycardia
subjects affected / exposed	0 / 91 (0.00%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Nervous system disorders
Brain oedema
subjects affected / exposed	2 / 91 (2.20%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 1	0 / 0
Seizure
subjects affected / exposed	0 / 91 (0.00%)	3 / 86 (3.49%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Haemorrhage intracranial
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 91 (0.00%)	2 / 86 (2.33%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Agranulocytosis
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (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
Neutropenia
subjects affected / exposed	0 / 91 (0.00%)	0 / 86 (0.00%)	1 / 28 (3.57%)
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
Gastrointestinal haemorrhage
subjects affected / exposed	2 / 91 (2.20%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Colitis ulcerative
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (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
Duodenal ulcer perforation
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (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
Gastrointestinal perforation
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (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
Intestinal ischaemia
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Gastrointestinal obstruction
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (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
Intra-abdominal haemorrhage
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Thrombosis mesenteric vessel
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 91 (0.00%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticulum intestinal haemorrhagic
subjects affected / exposed	0 / 91 (0.00%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Drug-induced liver injury
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (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
Hepatic function abnormal
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ischaemic hepatitis
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (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
Primary biliary cholangitis
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (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
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 91 (1.10%)	2 / 86 (2.33%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Septic shock
subjects affected / exposed	7 / 91 (7.69%)	7 / 86 (8.14%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 9	0 / 7	0 / 0
deaths causally related to treatment / all	0 / 5	0 / 5	0 / 0
Pneumonia
subjects affected / exposed	1 / 91 (1.10%)	4 / 86 (4.65%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 4	0 / 0
Sepsis
subjects affected / exposed	2 / 91 (2.20%)	3 / 86 (3.49%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 2	0 / 0
Acinetobacter infection
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia pseudomonal
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Bacterial sepsis
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Cholecystitis infective
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (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
Clostridium difficile colitis
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (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
Coronavirus infection
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (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
Encephalitis
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Klebsiella sepsis
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (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
Mastoiditis
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (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
Meningitis bacterial
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (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
Peritonitis
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (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
Pneumonia klebsiella
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (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
Pseudomembranous colitis
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pseudomonas infection
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Systemic candida
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Liver abscess
subjects affected / exposed	0 / 91 (0.00%)	0 / 86 (0.00%)	1 / 28 (3.57%)
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 infection
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0

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

Non-serious adverse events	Safety Population- Part A - Group 1 - experimental group	Safety Population-Part A - Group 2 - control group	Safety Population-Part B - Group 3
Total subjects affected by non serious adverse events
subjects affected / exposed	76 / 91 (83.52%)	78 / 86 (90.70%)	23 / 28 (82.14%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Meningioma
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Vascular disorders
Hypotension
subjects affected / exposed	5 / 91 (5.49%)	5 / 86 (5.81%)	1 / 28 (3.57%)
occurrences all number	5	5	1
Hypertensive crisis
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	3	0	0
Venous thrombosis limb
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	1 / 28 (3.57%)
occurrences all number	2	1	1
Deep vein thrombosis
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	1 / 28 (3.57%)
occurrences all number	1	1	1
Hypertension
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	1	1	0
Shock
subjects affected / exposed	0 / 91 (0.00%)	2 / 86 (2.33%)	0 / 28 (0.00%)
occurrences all number	0	2	0
Thrombophlebitis
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	1	1	0
Blood pressure inadequately controlled
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Brachiocephalic vein thrombosis
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Distributive shock
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Hypoperfusion
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Peripheral artery occlusion
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Phlebitis
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Venous thrombosis
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	9 / 91 (9.89%)	8 / 86 (9.30%)	1 / 28 (3.57%)
occurrences all number	14	11	1
Oedema peripheral
subjects affected / exposed	2 / 91 (2.20%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	9	1	0
Asthenia
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Catheter site inflammation
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Catheter site injury
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
General physical health deterioration
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Hypothermia
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Infusion site extravasation
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Localised oedema
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Multiple organ dysfunction syndrome
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Peripheral swelling
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Chest pain
subjects affected / exposed	0 / 91 (0.00%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1
Immune system disorders
Anaphylactic shock
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Hypersensitivity
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Respiratory, thoracic and mediastinal disorders
Hydrothorax
subjects affected / exposed	3 / 91 (3.30%)	2 / 86 (2.33%)	0 / 28 (0.00%)
occurrences all number	3	3	0
Pneumothorax
subjects affected / exposed	3 / 91 (3.30%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences all number	4	0	1
Respiratory acidosis
subjects affected / exposed	1 / 91 (1.10%)	2 / 86 (2.33%)	0 / 28 (0.00%)
occurrences all number	1	3	0
Acute respiratory distress syndrome
subjects affected / exposed	3 / 91 (3.30%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	3	0	0
Atelectasis
subjects affected / exposed	3 / 91 (3.30%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences all number	3	0	1
Pulmonary oedema
subjects affected / exposed	2 / 91 (2.20%)	1 / 86 (1.16%)	1 / 28 (3.57%)
occurrences all number	2	1	1
Wheezing
subjects affected / exposed	2 / 91 (2.20%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	2	1	0
Bronchial obstruction
subjects affected / exposed	2 / 91 (2.20%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	0	0
Cough
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences all number	2	0	1
Haemoptysis
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	1	1	0
Hypoxia
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	1	1	0
Pleurisy
subjects affected / exposed	2 / 91 (2.20%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	0	0
Respiratory alkalosis
subjects affected / exposed	0 / 91 (0.00%)	2 / 86 (2.33%)	0 / 28 (0.00%)
occurrences all number	0	2	0
Acute respiratory failure
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Bronchitis chronic
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences all number	1	0	1
Dyspnoea
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Hiccups
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Respiratory distress
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Rhinorrhoea
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Sputum decreased
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Tracheal mass
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Tracheal stenosis
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Increased bronchial secretion
subjects affected / exposed	0 / 91 (0.00%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1
Pharyngeal haemorrhage
subjects affected / exposed	0 / 91 (0.00%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1
Psychiatric disorders
Delirium
subjects affected / exposed	2 / 91 (2.20%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	2	1	0
Anxiety
subjects affected / exposed	2 / 91 (2.20%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	0	0
Insomnia
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	1	1	0
Agitation
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Delusion
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Depression
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Tic
subjects affected / exposed	0 / 91 (0.00%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1
Investigations
Blood creatinine increased
subjects affected / exposed	2 / 91 (2.20%)	7 / 86 (8.14%)	3 / 28 (10.71%)
occurrences all number	6	10	3
Aspartate aminotransferase increased
subjects affected / exposed	3 / 91 (3.30%)	2 / 86 (2.33%)	1 / 28 (3.57%)
occurrences all number	4	3	1
Blood bilirubin increased
subjects affected / exposed	3 / 91 (3.30%)	2 / 86 (2.33%)	1 / 28 (3.57%)
occurrences all number	5	2	1
Alanine aminotransferase increased
subjects affected / exposed	3 / 91 (3.30%)	2 / 86 (2.33%)	1 / 28 (3.57%)
occurrences all number	4	2	1
Bilirubin conjugated increased
subjects affected / exposed	2 / 91 (2.20%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	5	1	0
Electrocardiogram QT prolonged
subjects affected / exposed	3 / 91 (3.30%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	3	1	0
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 91 (1.10%)	2 / 86 (2.33%)	2 / 28 (7.14%)
occurrences all number	2	2	2
Neutrophil count increased
subjects affected / exposed	2 / 91 (2.20%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	4	0	0
Protein urine present
subjects affected / exposed	3 / 91 (3.30%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	3	1	0
Blood albumin decreased
subjects affected / exposed	2 / 91 (2.20%)	1 / 86 (1.16%)	2 / 28 (7.14%)
occurrences all number	2	1	2
Blood glucose increased
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	1	2	0
Blood lactate dehydrogenase increased
subjects affected / exposed	1 / 91 (1.10%)	2 / 86 (2.33%)	1 / 28 (3.57%)
occurrences all number	1	2	1
Blood urine present
subjects affected / exposed	2 / 91 (2.20%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	2	1	0
Lipase increased
subjects affected / exposed	1 / 91 (1.10%)	2 / 86 (2.33%)	1 / 28 (3.57%)
occurrences all number	1	2	1
Liver function test abnormal
subjects affected / exposed	0 / 91 (0.00%)	3 / 86 (3.49%)	0 / 28 (0.00%)
occurrences all number	0	3	0
Platelet count decreased
subjects affected / exposed	1 / 91 (1.10%)	2 / 86 (2.33%)	0 / 28 (0.00%)
occurrences all number	1	2	0
Platelet count increased
subjects affected / exposed	0 / 91 (0.00%)	3 / 86 (3.49%)	0 / 28 (0.00%)
occurrences all number	0	3	0
Staphylococcus test positive
subjects affected / exposed	2 / 91 (2.20%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	3	0	0
Transaminases increased
subjects affected / exposed	1 / 91 (1.10%)	2 / 86 (2.33%)	1 / 28 (3.57%)
occurrences all number	1	2	1
Blood calcium decreased
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	0	0
Blood calcium increased
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	1 / 28 (3.57%)
occurrences all number	1	1	1
Blood urea increased
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences all number	2	0	1
C-reactive protein increased
subjects affected / exposed	2 / 91 (2.20%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	0	0
Creatinine renal clearance decreased
subjects affected / exposed	0 / 91 (0.00%)	2 / 86 (2.33%)	0 / 28 (0.00%)
occurrences all number	0	2	0
QRS axis abnormal
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	1	1	0
Albumin globulin ratio decreased
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Bilirubin urine present
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	2 / 28 (7.14%)
occurrences all number	0	1	2
Blood chloride decreased
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Blood creatine phosphokinase decreased
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Blood glucose decreased
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Blood lactic acid increased
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Blood uric acid increased
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Computerised tomogram kidney abnormal
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Creatinine renal clearance increased
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Electrocardiogram high voltage
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
False positive investigation result
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Hepatic enzyme increased
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Mycobacterium tuberculosis complex test positive
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Prothrombin time prolonged
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Pseudomonas test positive
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Red blood cells urine positive
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Urine ketone body present
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Urobilinogen urine increased
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Enterococcus test positive
subjects affected / exposed	0 / 91 (0.00%)	0 / 86 (0.00%)	3 / 28 (10.71%)
occurrences all number	0	0	3
Proteus test positive
subjects affected / exposed	0 / 91 (0.00%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Joint dislocation
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Neck injury
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Post procedural haemorrhage
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Post-traumatic pain
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Spinal compression fracture
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Thermal burn
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Urethral injury
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Wound haemorrhage
subjects affected / exposed	0 / 91 (0.00%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1
Congenital, familial and genetic disorders
Porencephaly
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Tracheo-oesophageal fistula
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Cardiac disorders
Tachycardia
subjects affected / exposed	3 / 91 (3.30%)	4 / 86 (4.65%)	1 / 28 (3.57%)
occurrences all number	3	6	1
Atrial fibrillation
subjects affected / exposed	3 / 91 (3.30%)	2 / 86 (2.33%)	0 / 28 (0.00%)
occurrences all number	3	2	0
Supraventricular tachycardia
subjects affected / exposed	0 / 91 (0.00%)	2 / 86 (2.33%)	0 / 28 (0.00%)
occurrences all number	0	5	0
Sinus tachycardia
subjects affected / exposed	3 / 91 (3.30%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	3	0	0
Bundle branch block left
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	1	1	0
Aortic valve disease mixed
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Arrhythmia
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Bradycardia
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences all number	1	0	1
Cardiac arrest
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Cardiac failure
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Cardiac failure congestive
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Mitral valve disease mixed
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Myocardial ischaemia
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences all number	1	0	1
Pericardial mass
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Sinus bradycardia
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Sinus node dysfunction
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Supraventricular extrasystoles
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Torsade de pointes
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Tricuspid valve incompetence
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Ventricular tachycardia
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Nervous system disorders
Seizure
subjects affected / exposed	1 / 91 (1.10%)	3 / 86 (3.49%)	0 / 28 (0.00%)
occurrences all number	1	5	0
Intensive care unit acquired weakness
subjects affected / exposed	2 / 91 (2.20%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	2	1	0
Neuralgia
subjects affected / exposed	3 / 91 (3.30%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	3	0	0
Hydrocephalus
subjects affected / exposed	2 / 91 (2.20%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	0	0
Polyneuropathy
subjects affected / exposed	0 / 91 (0.00%)	2 / 86 (2.33%)	0 / 28 (0.00%)
occurrences all number	0	2	0
Encephalopathy
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Epilepsy
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Generalised tonic-clonic seizure
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Sciatica
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Headache
subjects affected / exposed	0 / 91 (0.00%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	12 / 91 (13.19%)	10 / 86 (11.63%)	3 / 28 (10.71%)
occurrences all number	31	21	4
Leukocytosis
subjects affected / exposed	3 / 91 (3.30%)	2 / 86 (2.33%)	0 / 28 (0.00%)
occurrences all number	4	2	0
Thrombocytopenia
subjects affected / exposed	5 / 91 (5.49%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	5	1	0
Coagulopathy
subjects affected / exposed	0 / 91 (0.00%)	2 / 86 (2.33%)	0 / 28 (0.00%)
occurrences all number	0	2	0
Haemorrhagic anaemia
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	0	0
Disseminated intravascular coagulation
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Hypofibrinogenaemia
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Lymphadenopathy
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Splenomegaly
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Thrombocytosis
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Eye disorders
Conjunctival oedema
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Ocular hyperaemia
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Retinal vascular disorder
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	15 / 91 (16.48%)	9 / 86 (10.47%)	2 / 28 (7.14%)
occurrences all number	16	11	2
Constipation
subjects affected / exposed	5 / 91 (5.49%)	5 / 86 (5.81%)	0 / 28 (0.00%)
occurrences all number	7	6	0
Vomiting
subjects affected / exposed	4 / 91 (4.40%)	3 / 86 (3.49%)	0 / 28 (0.00%)
occurrences all number	5	3	0
Gastrointestinal haemorrhage
subjects affected / exposed	2 / 91 (2.20%)	3 / 86 (3.49%)	0 / 28 (0.00%)
occurrences all number	2	3	0
Abdominal discomfort
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	1 / 28 (3.57%)
occurrences all number	0	4	1
Nausea
subjects affected / exposed	0 / 91 (0.00%)	2 / 86 (2.33%)	2 / 28 (7.14%)
occurrences all number	0	3	2
Dyspepsia
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	0	0
Flatulence
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	1	1	0
Abdominal compartment syndrome
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Abdominal distension
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Colitis
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Duodenogastric reflux
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Dysbacteriosis
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Gastric polyps
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Gastroduodenal haemorrhage
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Haematochezia
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Haemorrhoids
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Impaired gastric emptying
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Oral discomfort
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Pancreatitis
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Abdominal pain lower
subjects affected / exposed	0 / 91 (0.00%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1
Hepatobiliary disorders
Liver injury
subjects affected / exposed	2 / 91 (2.20%)	4 / 86 (4.65%)	0 / 28 (0.00%)
occurrences all number	3	5	0
Hepatic failure
subjects affected / exposed	1 / 91 (1.10%)	2 / 86 (2.33%)	0 / 28 (0.00%)
occurrences all number	1	2	0
Hepatic function abnormal
subjects affected / exposed	1 / 91 (1.10%)	2 / 86 (2.33%)	0 / 28 (0.00%)
occurrences all number	1	2	0
Cholecystitis
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Cholelithiasis
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Drug-induced liver injury
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Hepatic cirrhosis
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Hepatic mass
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Hepatitis acute
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Hepatitis alcoholic
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Hyperbilirubinaemia
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Skin and subcutaneous tissue disorders
Decubitus ulcer
subjects affected / exposed	5 / 91 (5.49%)	3 / 86 (3.49%)	4 / 28 (14.29%)
occurrences all number	5	3	4
Rash
subjects affected / exposed	4 / 91 (4.40%)	2 / 86 (2.33%)	1 / 28 (3.57%)
occurrences all number	4	2	1
Dermatitis
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Dermatitis allergic
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Dermatitis contact
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Eczema
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Pruritus generalised
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Subcutaneous emphysema
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Drug eruption
subjects affected / exposed	0 / 91 (0.00%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1
Urticaria
subjects affected / exposed	0 / 91 (0.00%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	3 / 91 (3.30%)	9 / 86 (10.47%)	0 / 28 (0.00%)
occurrences all number	3	12	0
Renal impairment
subjects affected / exposed	0 / 91 (0.00%)	6 / 86 (6.98%)	1 / 28 (3.57%)
occurrences all number	0	9	1
Nephropathy toxic
subjects affected / exposed	0 / 91 (0.00%)	4 / 86 (4.65%)	0 / 28 (0.00%)
occurrences all number	0	6	0
Proteinuria
subjects affected / exposed	2 / 91 (2.20%)	1 / 86 (1.16%)	1 / 28 (3.57%)
occurrences all number	2	1	1
Renal failure
subjects affected / exposed	0 / 91 (0.00%)	3 / 86 (3.49%)	1 / 28 (3.57%)
occurrences all number	0	3	1
Glycosuria
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	1	1	0
Anuria
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Bilirubinuria
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Chronic kidney disease
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Cystitis haemorrhagic
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Haematuria
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Myoglobinuria
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Neurogenic bladder
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Endocrine disorders
Euthyroid sick syndrome
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	1	1	0
Back pain
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Fistula
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Joint swelling
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Muscle spasms
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Muscle twitching
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Muscular weakness
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Musculoskeletal discomfort
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Osteoarthritis
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Infections and infestations
Urinary tract infection
subjects affected / exposed	7 / 91 (7.69%)	8 / 86 (9.30%)	1 / 28 (3.57%)
occurrences all number	11	9	1
Pneumonia pseudomonal
subjects affected / exposed	4 / 91 (4.40%)	2 / 86 (2.33%)	1 / 28 (3.57%)
occurrences all number	4	2	1
Septic shock
subjects affected / exposed	2 / 91 (2.20%)	3 / 86 (3.49%)	0 / 28 (0.00%)
occurrences all number	3	3	0
Tracheobronchitis
subjects affected / exposed	5 / 91 (5.49%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	5	1	0
Clostridium difficile colitis
subjects affected / exposed	1 / 91 (1.10%)	4 / 86 (4.65%)	1 / 28 (3.57%)
occurrences all number	1	4	1
Coronavirus infection
subjects affected / exposed	2 / 91 (2.20%)	3 / 86 (3.49%)	0 / 28 (0.00%)
occurrences all number	2	3	0
Pneumonia
subjects affected / exposed	4 / 91 (4.40%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	5	0	0
Staphylococcal infection
subjects affected / exposed	2 / 91 (2.20%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	5	0	0
Klebsiella infection
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	4	0	0
Pneumonia bacterial
subjects affected / exposed	3 / 91 (3.30%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	3	1	0
Pseudomonas infection
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	3	1	0
Candida pneumonia
subjects affected / exposed	3 / 91 (3.30%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	3	0	0
Conjunctivitis
subjects affected / exposed	3 / 91 (3.30%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	3	0	0
Sinusitis
subjects affected / exposed	0 / 91 (0.00%)	3 / 86 (3.49%)	0 / 28 (0.00%)
occurrences all number	0	3	0
Urinary tract infection fungal
subjects affected / exposed	2 / 91 (2.20%)	1 / 86 (1.16%)	1 / 28 (3.57%)
occurrences all number	2	1	1
Bacteraemia
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	1	1	0
Bronchitis
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Candidiasis of trachea
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	0	0
Cystitis
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	1	1	0
Cytomegalovirus infection
subjects affected / exposed	0 / 91 (0.00%)	2 / 86 (2.33%)	0 / 28 (0.00%)
occurrences all number	0	2	0
Device related infection
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	1	1	0
Infectious pleural effusion
subjects affected / exposed	2 / 91 (2.20%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	0	0
Mastoiditis
subjects affected / exposed	0 / 91 (0.00%)	2 / 86 (2.33%)	0 / 28 (0.00%)
occurrences all number	0	2	0
Oropharyngeal candidiasis
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	0	0
Pharyngitis bacterial
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	0	0
Staphylococcal bacteraemia
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	2	0
Bacterial infection
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Bacterial pyelonephritis
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Bacterial tracheitis
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Burkholderia infection
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Candida infection
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Central nervous system infection
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Clostridium difficile infection
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Device related sepsis
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Enterococcal bacteraemia
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Enterococcal infection
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Fungal cystitis
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Fungal skin infection
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Impetigo
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Infected skin ulcer
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Klebsiella sepsis
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Lung abscess
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Meningitis bacterial
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Myringitis
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Nasal candidiasis
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Oral fungal infection
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Peritonitis
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Pneumocystis jirovecii infection
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Pneumonia acinetobacter
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Pneumonia cytomegaloviral
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Postoperative wound infection
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Pulmonary mucormycosis
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Pyelonephritis
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Skin bacterial infection
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Staphylococcal skin infection
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Stenotrophomonas sepsis
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Systemic mycosis
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Tracheitis
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Tuberculosis
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Urinary tract infection bacterial
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Urinary tract infection enterococcal
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Wound abscess
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Wound infection pseudomonas
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Wound infection staphylococcal
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Corynebacterium infection
subjects affected / exposed	0 / 91 (0.00%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1
Enterococcal sepsis
subjects affected / exposed	0 / 91 (0.00%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1
Herpes virus infection
subjects affected / exposed	0 / 91 (0.00%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1
Malaria
subjects affected / exposed	0 / 91 (0.00%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1
Pseudomonas bronchitis
subjects affected / exposed	0 / 91 (0.00%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1
Systemic candida
subjects affected / exposed	0 / 91 (0.00%)	0 / 86 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1
Lung infection pseudomonal
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Candiduria
subjects affected / exposed	2 / 91 (2.20%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	0	0
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	13 / 91 (14.29%)	9 / 86 (10.47%)	0 / 28 (0.00%)
occurrences all number	21	19	0
Hypocalcaemia
subjects affected / exposed	1 / 91 (1.10%)	5 / 86 (5.81%)	0 / 28 (0.00%)
occurrences all number	1	8	0
Hypomagnesaemia
subjects affected / exposed	2 / 91 (2.20%)	4 / 86 (4.65%)	0 / 28 (0.00%)
occurrences all number	3	6	0
Hyponatraemia
subjects affected / exposed	3 / 91 (3.30%)	4 / 86 (4.65%)	1 / 28 (3.57%)
occurrences all number	4	4	1
Hypernatraemia
subjects affected / exposed	3 / 91 (3.30%)	4 / 86 (4.65%)	0 / 28 (0.00%)
occurrences all number	3	4	0
Hyperkalaemia
subjects affected / exposed	4 / 91 (4.40%)	2 / 86 (2.33%)	0 / 28 (0.00%)
occurrences all number	4	2	0
Hypochloraemia
subjects affected / exposed	2 / 91 (2.20%)	3 / 86 (3.49%)	0 / 28 (0.00%)
occurrences all number	3	3	0
Hypoglycaemia
subjects affected / exposed	3 / 91 (3.30%)	2 / 86 (2.33%)	0 / 28 (0.00%)
occurrences all number	4	2	0
Hypophosphataemia
subjects affected / exposed	2 / 91 (2.20%)	3 / 86 (3.49%)	0 / 28 (0.00%)
occurrences all number	2	4	0
Hyperchloraemia
subjects affected / exposed	1 / 91 (1.10%)	3 / 86 (3.49%)	0 / 28 (0.00%)
occurrences all number	1	3	0
Electrolyte imbalance
subjects affected / exposed	2 / 91 (2.20%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	2	1	0
Hyperglycaemia
subjects affected / exposed	3 / 91 (3.30%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	3	0	0
Hyperphosphataemia
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	1	2	0
Hypoproteinaemia
subjects affected / exposed	0 / 91 (0.00%)	3 / 86 (3.49%)	0 / 28 (0.00%)
occurrences all number	0	3	0
Acidosis
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	1	1	0
Hypercalcaemia
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	1	1	0
Hyperuricaemia
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	1	1	0
Hypoalbuminaemia
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	1	1	0
Malnutrition
subjects affected / exposed	1 / 91 (1.10%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	1	1	0
Metabolic acidosis
subjects affected / exposed	2 / 91 (2.20%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	0	0
Metabolic alkalosis
subjects affected / exposed	2 / 91 (2.20%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	0	0
Alkalosis
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Diabetic metabolic decompensation
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Hypermagnesaemia
subjects affected / exposed	0 / 91 (0.00%)	1 / 86 (1.16%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Hypertriglyceridaemia
subjects affected / exposed	1 / 91 (1.10%)	0 / 86 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0

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Were there any global substantial amendments to the protocol? Yes

29 Apr 2019

Protocol Amendment 1 (version 2.0, dated 29 April 2019) was instituted before any enrollment and updated the Clinical Study Protocol in the following ways: • In response to queries from the Spanish regulatory authority, the following clarifications were made: o Language regarding the informed consent process and use of a legally authorized representative was updated and expanded; and o Rationale was added regarding the timing of the initiation of Part B of the study, namely, that PK from Part A must be verified prior to beginning Part B. In addition, language was added to allow for patients who are responding to therapy to remain in Part A even with a colistin resistant culture. • In response to queries from the Chinese regulatory authority, intense PK sampling was conducted for the first approximately 20 patients enrolled at sites in China Mainland. Due to this change, stratification for Part A also included geography (China Mainland versus Rest of World); • Removed neutropenia requirements from diagnosis of bacteremia in Part A-specific inclusion criteria; • Language for entry into Part B was updated to allow for patients who previously failed a polymyxin-based regimen and additional clarifications were made to clarify the patient population for Part B; • Text was added to inclusion criterion 4 to clarify definition of enrollment as prior to first dose of study drug; • Removed required elevated serum lactate level from exclusion criterion 5; • Clarified that “study drug” in exclusion criterion 25 refers to durlobactam; • Language added from imipenem/cilastatin package insert to note instructions for patients who experienced focal tremors, myoclonus, or seizures at any point during the study; • Text updated throughout that, in the event of a discrepancy between the assessment of the blinded assessor and unblinded Investigator, the assessment from the blinded assessor would prevail; • Clarification added for discontinuation due to severe li

14 Jan 2020

Protocol Amendment 2 (version 3.0, dated 14 January 2020) updated the Clinical Study Protocol in the following ways: • The target population was expanded to allow patients with VP into Parts A and B of the study; • The following changes were made to the inclusion and exclusion criteria: o The definition for bacteremia was simplified; o Qualifying scores for the APACHE II and SOFA were made uniform for both Parts A and B; o Language was added allowing ultrasound for diagnosis; o Pleural fluid was added as an acceptable source for specimen collection; o Contraception language was updated based on the nonclinical study package as follows: -Female contraception language was updated to require only 1 highly effective method of contraception; and -Male contraception language was removed. o Acceptable comorbidities and permitted treatments were updated. • The secondary efficacy endpoint of attributable mortality was changed to all mortality; • Resistance to carbapenems was added to the exploratory efficacy endpoints; • The sample size was increased as required to allow for the interim analysis; • Language was added to clarify that an adjudication committee may be organized for endpoint adjudication; • Clarified that specimens were cultured at the local lab with pure cultures of isolates sent to the central laboratory; • Language was added to allow patients receiving antibiotic prophylaxis for immunosuppression; • The timeframe and process for retesting following an indeterminate or negative result for the BPP were defined; • Clarified the timeframe for AE collection was to begin with signing of the main informed consent, not limited scope informed consent; and • Clarified that if the first 3 of Hy’s Laws were met it must be reported as an SAE.

17 Dec 2020

Protocol Amendment 3 (version 4.0, dated 17 December 2020) updated the Clinical Study Protocol in the following ways: • The Part B-specific inclusion criterion requiring patients to have acute kidney injury and were receiving renal replacement therapy at study entry was removed, so that patients who only met this criterion were not enrolled in Part B. Instead, this criterion was added as 1 of the potential requirements for patients with HABP, VABP, VP, or bacteremia, and for patients with cUTI, AP, or surgical or post-traumatic wound infections; • COVID-19 infection without clinical improvement was added to exclusion criteria as an example of a pulmonary disease that would preclude evaluation of a therapeutic response; • Clarification was added for the imipenem/cilastatin dose adjustments for patients with severe renal impairment; • Language of the required repeat imaging for the chest X-ray, MRI, CT scan, or ultrasound obtained >48 hours prior to randomization, was updated to avoid confusion at study sites; • Language was updated to clarify that an ABC positive culture collected within 72 hours prior to randomization rather than screening, was acceptable for enrollment; • Mortality in the CRABC m-MITT Population was removed from the secondary efficacy endpoints since the primary efficacy endpoint for the study was 28-day all-cause mortality in the CRABC m-MITT Population in Part A; • The definition of clinical indeterminate was updated; • Language was added to clarify that the local laboratory could be used to confirm if the baseline ABC organism was carbapenem resistant when the central laboratory was not able to characterize the isolate for any reason; • Additional requirements for the exclusion of patients from the CRABC m-MITT Population were added; • After the conversation with the Food and Drug Administration (FDA) (reference ID: 4667476), the non-inferiority margin was increased, and as a result, the total sample size for Part A and the sam

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 Randomized, Active-Controlled Study to Evaluate the Efficacy and Safety of Intravenous Sulbactam-ETX2514 in the Treatment of Patients With Infections Caused by Acinetobacter baumannii-calcoaceticus Complex

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 28-day all-cause mortality in the CRABC m-MITT Population in Part A

Primary: 28-day all-cause mortality in the CRABC m-MITT Population in Part A

Primary: Incidence of nephrotoxicity (RIFLE) - Part A

Primary: Incidence of nephrotoxicity (RIFLE) - Part A

Secondary: 28-day all-cause mortality in the ITT Population PartA

Secondary: 28-day all-cause mortality in the ITT Population PartA

Secondary: Clinical cure at TOC in the CRABC m-MITT Population Part A

Secondary: Clinical cure at TOC in the CRABC m-MITT Population Part A

Secondary: Clinical cure at TOC in the m-MITT Part A

Secondary: Clinical cure at TOC in the m-MITT Part A

Secondary: Clinical cure at TOC in the CE population Part A

Secondary: Clinical cure at TOC in the CE population Part A

Secondary: Clinical cure at TOC in the ME population Part A

Secondary: Clinical cure at TOC in the ME population Part A

Secondary: Clinical cure at TOC in the CRABC ME Population Part A

Secondary: Clinical cure at TOC in the CRABC ME Population Part A

Secondary: Clinical cure at EOT in the m-MITT population Part A

Secondary: Clinical cure at EOT in the m-MITT population Part A

Secondary: Clinical cure at EOT in the CRABC m-MITT population Part A

Secondary: Clinical cure at EOT in the CRABC m-MITT population Part A

Secondary: Clinical cure at EOT in the CE population Part A

Secondary: Clinical cure at EOT in the CE population Part A

Secondary: Clinical cure at EOT in the ME population Part A

Secondary: Clinical cure at EOT in the ME population Part A

Secondary: Clinical cure at EOT in the CRABC ME population Part A

Secondary: Clinical cure at EOT in the CRABC ME population Part A

Secondary: Clinical cure at LFU in the m-MITT Part A

Secondary: Clinical cure at LFU in the m-MITT Part A

Secondary: Clinical cure at LFU in the CRABC m-MITT Part A

Secondary: Clinical cure at LFU in the CRABC m-MITT Part A

Secondary: Clinical cure at LFU in the CE Part A

Secondary: Clinical cure at LFU in the CE Part A

Secondary: Clinical cure at LFU in the ME Part A

Secondary: Clinical cure at LFU in the ME Part A

Secondary: Clinical cure at LFU in the CRABC ME Part A

Secondary: Clinical cure at LFU in the CRABC ME Part A

Secondary: Microbiological (overall) favorable assessment at EOT in the CRABC m-MITT population Part A

Secondary: Microbiological (overall) favorable assessment at EOT in the CRABC m-MITT population Part A

Secondary: Microbiological (overall) favorable assessment at TOC in the CRABC m-MITT population Part A

Secondary: Microbiological (overall) favorable assessment at TOC in the CRABC m-MITT population Part A

Secondary: Microbiological (overall) favorable assessment at LFU in the CRABC m-MITT population Part A

Secondary: Microbiological (overall) favorable assessment at LFU in the CRABC m-MITT population Part A

Secondary: Microbiological (overall) favorable assessment at EOT in the m-MITT population Part A

Secondary: Microbiological (overall) favorable assessment at EOT in the m-MITT population Part A

Secondary: Microbiological (overall) favorable assessment at TOC in the m-MITT population Part A

Secondary: Microbiological (overall) favorable assessment at TOC in the m-MITT population Part A

Secondary: Microbiological (overall) favorable assessment at LFU in the m-MITT population Part A

Secondary: Microbiological (overall) favorable assessment at LFU in the m-MITT population Part A

Secondary: Microbiological (overall) favorable assessment at EOT in the ME population Part A

Secondary: Microbiological (overall) favorable assessment at EOT in the ME population Part A

Secondary: Microbiological (overall) favorable assessment at TOC in the ME population Part A

Secondary: Microbiological (overall) favorable assessment at TOC in the ME population Part A

Secondary: Microbiological (overall) favorable assessment at LFU in the ME population Part A

Secondary: Microbiological (overall) favorable assessment at LFU in the ME population Part A

Secondary: Microbiological (overall) favorable assessment at EOT in the CRABC ME population Part A

Secondary: Microbiological (overall) favorable assessment at EOT in the CRABC ME population Part A

Secondary: Microbiological (overall) favorable assessment at TOC in the CRABC ME population Part A

Secondary: Microbiological (overall) favorable assessment at TOC in the CRABC ME population Part A

Secondary: Microbiological (overall) favorable assessment at LFU in the CRABC ME population Part A

Secondary: Microbiological (overall) favorable assessment at LFU in the CRABC ME population Part A

Secondary: 14-day all-cause mortality in the m-MITT Populations

Secondary: 14-day all-cause mortality in the m-MITT Populations

Secondary: 14-day all-cause mortality in the CRABC m-MITT Population

Secondary: 14-day all-cause mortality in the CRABC m-MITT Population

Secondary: 28-day all-cause mortality in the m-MITT Population

Secondary: 28-day all-cause mortality in the m-MITT Population

Secondary: 28-day all-cause mortality in the CRABC ME Population

Secondary: 28-day all-cause mortality in the CRABC ME Population

Secondary: 28-day all-cause mortality in the ITT Population - Part B

Secondary: 28-day all-cause mortality in the ITT Population - Part B

Clinical Trial Results:
A Randomized, Active-Controlled Study to Evaluate the Efficacy and Safety of Intravenous Sulbactam-ETX2514 in the Treatment of Patients With Infections Caused by Acinetobacter baumannii-calcoaceticus Complex