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Clinical Trial Results:
A Phase 2b, Randomized, Double-Blind, Placebo Controlled, Safety and Efficacy Trial of Multiple Dosing Regimens of ABT-719 for the Prevention of Acute Kidney Injury in Subjects Undergoing High Risk Major Surgery

Summary
EudraCT number	2012-005710-19
Trial protocol	DK
Global end of trial date	08 Apr 2014

Results information
Results version number	v1(current)
This version publication date	20 Apr 2016
First version publication date	25 Jul 2015
Other versions

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

M13-958

ISRCTN number

US NCT number

NCT01897519

WHO universal trial number (UTN)

Sponsor organisation name

Abbvie Deutschland GmbH & Co.KG

Sponsor organisation address

Abbott House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6 4XE

Public contact

Global Medical Information, AbbVie, 001 800-633-9110,

Scientific contact

Ann Eldred, MD, AbbVie , ann.eldred@abbvie.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

08 Apr 2014

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

08 Apr 2014

Was the trial ended prematurely?

Yes

Main objective of the trial

- To determine the safety and pharmacokinetics of 800 mcg/kg intravenous (IV) infusions of ABT-719 in the first 6 subjects enrolled who are at risk of acute kidney injury (AKI) and undergoing high risk major surgery. -To compare the safety and efficacy of doses of 800 mcg/kg, 1600 mcg/kg and 2100 mcg/kg IV infusions of ABT-719 to placebo in subjects who are at risk of AKI and undergoing high risk major surgery.

Protection of trial subjects

Participant and/or legal guardian read and understood the information provided about the study and gave written permission.

Background therapy

Evidence for comparator

Actual start date of recruitment

21 May 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Denmark: 7

Country: Number of subjects enrolled

United States: 49

Worldwide total number of subjects

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

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Recruitment details

This subject population was selected for having a high-risk for developing AKI while undergoing high risk major surgery.

Screening details

Part 1 was an open-label, multiple-center study to evaluate the safety and pharmacokinetics of 800 mcg/kg of ABT-719 in 6 subjects. Part 2 was a placebo-controlled, double-blind, parallel group, randomized, multiple-center study to evaluate the safety and efficacy of ABT-719. Subjects had a screening visit 5 to 28 days prior to surgery.

Period 1 title

Part 1 and Part 2 (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Assessor

Are arms mutually exclusive

Yes

Part 1: 800 mcg/kg ABT-719

Arm description

Subjects received 800 mcg/kg ABT-719 divided in 3 doses given as 10 minute infusions of 200 mcg/kg, 400 mcg/kg, and 200 mcg/kg on Day 0 (the day of surgery).

Arm type

Experimental

Investigational medicinal product name

ABT-719

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

10 mg/mL solution for intravenous injection

Part 2: Placebo

Arm description

Subjects received 6 infusions of placebo beginning on Day 0 (the day of surgery) and at 2 hours after the first dose and 6, 12, 24 and 48 hours after the second dose.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Normal saline solution for intravenous injection

Part 2: 800 mcg/kg ABT-719

Arm description

Subjects received up to 800 mcg/kg ABT-719 divided in 3 doses given as 10 minute infusions of 200 mcg/kg on Day 0 at the start of surgery, 200–400 mcg/kg 2 hours after the first dose and 200 mcg/kg 6 hours after the second dose and placebo injections at 12, 24 and 48 hours after the second dose.

Arm type

Experimental

Investigational medicinal product name

ABT-719

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

10 mg/mL solution for intravenous injection

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Normal saline solution for intravenous injection

Part 2: 1600 mcg/kg ABT-719

Arm description

Subjects received up to 1600 mcg/kg ABT-719 divided in 5 doses given as 10 minute infusions of 300 mcg/kg on Day 0 at the start of surgery, 300–600 mcg/kg 2 hours after the first dose, 300 mcg/kg 6 hours after the second dose, 200 mcg/kg at 12 and 24 hours after the second dose and placebo at 48 hours after the second dose.

Arm type

Experimental

Investigational medicinal product name

ABT-719

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

10 mg/mL solution for intravenous injection

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Normal saline solution for intravenous injection

Part 2: 2100 mcg/kg ABT-719

Arm description

Subjects received up to 2100 mcg/kg ABT-719 divided in 6 doses given as 10 minute infusions of 300 mcg/kg on Day 0 at the start of surgery, 300–600 mcg/kg 2 hours after the first dose and 300 mcg/kg 6, 12, 24, and 48 hours after the second dose.

Arm type

Experimental

Investigational medicinal product name

ABT-719

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

10 mg/mL solution for intravenous injection

Number of subjects in period 1	Part 1: 800 mcg/kg ABT-719	Part 2: Placebo	Part 2: 800 mcg/kg ABT-719	Part 2: 1600 mcg/kg ABT-719	Part 2: 2100 mcg/kg ABT-719
Started	6	13	12	12	13
Received treatment	4	7	9	10	10
Completed	4	7	7	10	8
Not completed	2	6	5	2	5
Other	-	-	1	-	-
Adverse event	-	-	1	-	2
Discontinued prior to receiving treatment	2	6	3	2	3

Baseline characteristics

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Reporting group title

Part 1: 800 mcg/kg ABT-719

Reporting group description

Subjects received 800 mcg/kg ABT-719 divided in 3 doses given as 10 minute infusions of 200 mcg/kg, 400 mcg/kg, and 200 mcg/kg on Day 0 (the day of surgery).

Reporting group title

Part 2: Placebo

Reporting group description

Subjects received 6 infusions of placebo beginning on Day 0 (the day of surgery) and at 2 hours after the first dose and 6, 12, 24 and 48 hours after the second dose.

Reporting group title

Part 2: 800 mcg/kg ABT-719

Reporting group description

Reporting group title

Part 2: 1600 mcg/kg ABT-719

Reporting group description

Reporting group title

Part 2: 2100 mcg/kg ABT-719

Reporting group description

Reporting group values	Part 1: 800 mcg/kg ABT-719	Part 2: Placebo	Part 2: 800 mcg/kg ABT-719	Part 2: 1600 mcg/kg ABT-719	Part 2: 2100 mcg/kg ABT-719	Total
Number of subjects	6	13	12	12	13	56
Age categorical
Units: Subjects
< 65 years	1	3	5	3	2	14
>= 65 years	5	10	7	9	11	42
Age continuous
Units: years
arithmetic mean (standard deviation)	73.2 ± 11.86	70.5 ± 7.75	66.2 ± 13.22	71.3 ± 8.72	71.2 ± 7.72	-
Gender categorical
Units: Subjects
Female	4	3	3	4	4	18
Male	2	10	9	8	9	38

End points

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Reporting group title

Part 1: 800 mcg/kg ABT-719

Reporting group description

Subjects received 800 mcg/kg ABT-719 divided in 3 doses given as 10 minute infusions of 200 mcg/kg, 400 mcg/kg, and 200 mcg/kg on Day 0 (the day of surgery).

Reporting group title

Part 2: Placebo

Reporting group description

Subjects received 6 infusions of placebo beginning on Day 0 (the day of surgery) and at 2 hours after the first dose and 6, 12, 24 and 48 hours after the second dose.

Reporting group title

Part 2: 800 mcg/kg ABT-719

Reporting group description

Reporting group title

Part 2: 1600 mcg/kg ABT-719

Reporting group description

Reporting group title

Part 2: 2100 mcg/kg ABT-719

Reporting group description

Primary: Maximal change from Baseline in urine neutrophil gelatinase-associated lipocalin (NGAL) until Day 7 or discharge

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End point title

Maximal change from Baseline in urine neutrophil gelatinase-associated lipocalin (NGAL) until Day 7 or discharge ^[1]

End point description

Raw urine NGAL data were log transformed for analysis of change from Baseline. The Full Analysis Set (FAS) was defined as the set of all randomized subjects who received at least 1 infusion of study drug. Subjects with a negative maximal change were removed from the analysis.

End point type

Primary

End point timeframe

Baseline to Day 7

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: Efficacy endpoints were only assessed in Part 2 subjects

End point values	Part 2: Placebo	Part 2: 800 mcg/kg ABT-719	Part 2: 1600 mcg/kg ABT-719	Part 2: 2100 mcg/kg ABT-719
Number of subjects analysed	7	9	10	8
Units: ng/mL
least squares mean (standard error)	118.9 ± 1.7	207.3 ± 1.6	411.3 ± 1.6	196.6 ± 1.7

Primary efficacy analysis

Statistical analysis description

The primary efficacy analysis of each ABT-719 dose group versus placebo in the mean maximal change from baseline in urine NGAL (on log scale) until Day 7 or discharge was performed using an analysis of covariance (ANCOVA) model with fixed factors of treatment group and randomization stratification as fixed factors and baseline urine NGAL as a covariate. Comparisons versus placebo were based on a 1-sided significance level of 0.050.

Comparison groups

Part 2: Placebo v Part 2: 800 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.45

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.7

Primary efficacy analysis

Statistical analysis description

Comparison groups

Part 2: Placebo v Part 2: 1600 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.081

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2

upper limit

2.6

Variability estimate

Standard error of the mean

Dispersion value

0.7

Primary efficacy analysis

Statistical analysis description

Comparison groups

Part 2: Placebo v Part 2: 2100 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.499

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.7

Secondary: Maximal change from Baseline in serum NGAL until Day 7 or discharge

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End point title

Maximal change from Baseline in serum NGAL until Day 7 or discharge ^[2]

End point description

Raw serum NGAL data were log transformed for analysis of change from Baseline. The per-protocol analysis set was defined as the set of all randomized subjects who received all 6 infusions of study drug and underwent the pre-defined surgery. Subjects with a negative maximal change were removed from the analysis.

End point type

Secondary

End point timeframe

Baseline to Day 7

Notes
[2] - 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: Efficacy endpoints were only assessed in Part 2 subjects

End point values	Part 2: Placebo	Part 2: 800 mcg/kg ABT-719	Part 2: 1600 mcg/kg ABT-719	Part 2: 2100 mcg/kg ABT-719
Number of subjects analysed	7	5	10	6
Units: ng/mL
least squares mean (standard error)	360.3 ± 1.3	477.7 ± 1.4	619.6 ± 1.3	436.3 ± 1.4

Comparison 1

Comparison groups

Part 2: Placebo v Part 2: 800 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.54 ^[3]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.6

upper limit

1.2

Variability estimate

Standard error of the mean

Dispersion value

0.5

Notes
[3] - ANCOVA model with treatment group as the factor and baseline as a covariate .

Comparison 2

Comparison groups

Part 2: Placebo v Part 2: 1600 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.15 ^[4]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2

upper limit

1.3

Variability estimate

Standard error of the mean

Dispersion value

0.4

Notes
[4] - ANCOVA model with treatment group as the factor and baseline as a covariate.

Comparison 3

Comparison groups

Part 2: Placebo v Part 2: 2100 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.656 ^[5]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

1.1

Variability estimate

Standard error of the mean

Dispersion value

0.4

Notes
[5] - ANCOVA model with treatment group as the factor and baseline as a covariate.

Secondary: Maximal change from baseline in urine interleukin-18 until Day 7 or discharge

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End point title

Maximal change from baseline in urine interleukin-18 until Day 7 or discharge ^[6]

End point description

Raw urine interleukin-18 data were log transformed for analysis of change from Baseline. The per-protocol analysis set was defined as the set of all randomized subjects who received all 6 infusions of study drug and underwent the pre-defined surgery. Subjects with a negative maximal change were removed from the analysis.

End point type

Secondary

End point timeframe

Baseline to Day 7

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: Efficacy endpoints were only assessed in Part 2 subjects

End point values	Part 2: Placebo	Part 2: 800 mcg/kg ABT-719	Part 2: 1600 mcg/kg ABT-719	Part 2: 2100 mcg/kg ABT-719
Number of subjects analysed	6	5	9	6
Units: pg/mL
least squares mean (standard error)	43.7 ± 1.7	41.6 ± 1.7	53.5 ± 1.6	48.8 ± 1.6

Comparison 1

Comparison groups

Part 2: Placebo v Part 2: 800 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.948 ^[7]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1.6

upper limit

1.5

Variability estimate

Standard error of the mean

Dispersion value

0.8

Notes
[7] - ANCOVA model with treatment group as the factor and baseline as a covariate.

Comparison 2

Comparison groups

Part 2: Placebo v Part 2: 1600 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.752 ^[8]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-1.1

upper limit

1.5

Variability estimate

Standard error of the mean

Dispersion value

0.6

Notes
[8] - ANCOVA model with treatment group as the factor and baseline as a covariate.

Comparison 3

Comparison groups

Part 2: Placebo v Part 2: 2100 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.879 ^[9]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-1.4

upper limit

1.6

Variability estimate

Standard error of the mean

Dispersion value

0.7

Notes
[9] - ANCOVA model with treatment group as the factor and baseline as a covariate.

Secondary: Maximal change from Baseline in urine kidney injury molecule (KIM-1) until Day 7 or discharge

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End point title

Maximal change from Baseline in urine kidney injury molecule (KIM-1) until Day 7 or discharge ^[10]

End point description

Raw urine KIM-1 data were log transformed for analysis of change from Baseline. The per-protocol analysis set was defined as the set of all randomized subjects who received all 6 infusions of study drug and underwent the pre-defined surgery. Subjects with a negative maximal change were removed from the analysis.

End point type

Secondary

End point timeframe

Baseline to Day 7

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: Efficacy endpoints were only assessed in Part 2 subjects

End point values	Part 2: Placebo	Part 2: 800 mcg/kg ABT-719	Part 2: 1600 mcg/kg ABT-719	Part 2: 2100 mcg/kg ABT-719
Number of subjects analysed	7	4	10	6
Units: ng/mL
least squares mean (standard error)	0.9 ± 1.6	2.8 ± 2	1.1 ± 1.5	1.1 ± 1.7

Comparison 1

Comparison groups

Part 2: Placebo v Part 2: 800 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.179 ^[11]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.6

upper limit

2.9

Variability estimate

Standard error of the mean

Dispersion value

0.8

Notes
[11] - ANCOVA model with treatment group as the factor and baseline as a covariate.

Comparison 2

Comparison groups

Part 2: Placebo v Part 2: 1600 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.731 ^[12]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-1.1

upper limit

1.5

Variability estimate

Standard error of the mean

Dispersion value

0.6

Notes
[12] - ANCOVA model with treatment group as the factor and baseline as a covariate.

Comparison 3

Comparison groups

Part 2: Placebo v Part 2: 2100 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.739 ^[13]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-1.3

upper limit

1.8

Variability estimate

Standard error of the mean

Dispersion value

0.8

Notes
[13] - ANCOVA model with treatment group as the factor and baseline as a covariate.

Secondary: Number of subjects developing acute kidney injury (AKI) as defined by the AKIN scoring criteria

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End point title

Number of subjects developing acute kidney injury (AKI) as defined by the AKIN scoring criteria ^[14]

End point description

the Acute Kidney Injury Network (AKIN) classification/staging system of acute kidney injury: Stage 1: Increased serum creatinine ≥ 26.5 μmol/L (≥ 0.3 mg/dL) or an increase ≥ 1.5 x Baseline; urine output < 0.5 mL/kg/hr for more than 6 hours. Stage 2: Increased serum creatinine 2 x Baseline; urine output < 0.5 mL/kg/hr for more than 12 hours. Stage 3: Increased serum creatinine 3 x Baseline or if Baseline creatinine ≥ 353.6 μmol/L (≥ 4 mg/dL) an increase of ≥ 44.2 μmol/L (≥ 0.5 mg/dL); urine output < 0.3 mL/kg/hr for 24 hours or anuria for 12 hours.

End point type

Secondary

End point timeframe

90 days

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: Efficacy endpoints were only assessed in Part 2 subjects

End point values	Part 2: Placebo	Part 2: 800 mcg/kg ABT-719	Part 2: 1600 mcg/kg ABT-719	Part 2: 2100 mcg/kg ABT-719
Number of subjects analysed	7 ^[15]	5 ^[16]	10 ^[17]	8 ^[18]
Units: subjects
Stage 1	2	0	2	2
Stage 2	1	1	3	2
Stage 3	1	0	3	2

Notes
[15] - Per protocol analysis set
[16] - Per protocol analysis set
[17] - Per protocol analysis set
[18] - Per protocol analysis set

Comparison 1

Comparison groups

Part 2: Placebo v Part 2: 800 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.293

Method

Fisher exact

Confidence interval

Comparison 2

Comparison groups

Part 2: Placebo v Part 2: 1600 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.593

Method

Fisher exact

Confidence interval

Comparison 3

Comparison groups

Part 2: 2100 mcg/kg ABT-719 v Part 2: Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.608

Method

Fisher exact

Confidence interval

Secondary: Number of subjects developing one of the composite events: death, renal replacement therapy (RRT), or ≥ 25% reduction in serum creatinine based estimated glomerular filtration rate (eGFR) at Day 90

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End point title

Number of subjects developing one of the composite events: death, renal replacement therapy (RRT), or ≥ 25% reduction in serum creatinine based estimated glomerular filtration rate (eGFR) at Day 90 ^[19]

End point description

The number of subjects developing at least one of the composite events: • death, • needing RRT during the 90-day post-operative period, or • a ≥ 25% reduction in serum creatinine (SCr) based estimated glomerular filtration rate (eGFR) at the Day 90 post-surgery visit.

End point type

Secondary

End point timeframe

90 days

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: Efficacy endpoints were only assessed in Part 2 subjects

End point values	Part 2: Placebo	Part 2: 800 mcg/kg ABT-719	Part 2: 1600 mcg/kg ABT-719	Part 2: 2100 mcg/kg ABT-719
Number of subjects analysed	7 ^[20]	5 ^[21]	10 ^[22]	8
Units: subjects	0	0	2	3

Notes
[20] - Per protocol analysis set
[21] - Per protocol analysis set
[22] - Per protocol analysis set

Comparison 1

Comparison groups

Part 2: Placebo v Part 2: 1600 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.485

Method

Fisher exact

Confidence interval

Comparison 2

Comparison groups

Part 2: Placebo v Part 2: 2100 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2

Method

Fisher exact

Confidence interval

Secondary: Number of subjects developing one of the composite events: death, RRT or ≥ 25% reduction in SCr based GFR at Day 60

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End point title

Number of subjects developing one of the composite events: death, RRT or ≥ 25% reduction in SCr based GFR at Day 60 ^[23]

End point description

The number of subjects developing at least one of the composite events: - death, - needing RRT during the 60-day post-operative period, or - having a ≥ 25% reduction in SCr based eGFR or measured GFR at Day 60 post-surgery visit.

End point type

Secondary

End point timeframe

60 days

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: Efficacy endpoints were only assessed in Part 2 subjects

End point values	Part 2: Placebo	Part 2: 800 mcg/kg ABT-719	Part 2: 1600 mcg/kg ABT-719	Part 2: 2100 mcg/kg ABT-719
Number of subjects analysed	7 ^[24]	5 ^[25]	10 ^[26]	8 ^[27]
Units: subjects	0	0	4	4

Notes
[24] - Per protocol analysis set
[25] - Per protocol analysis set
[26] - Per protocol analysis set
[27] - Per protocol analysis set

Comparison 1

Comparison groups

Part 2: Placebo v Part 2: 1600 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.103

Method

Fisher exact

Confidence interval

Comparison 2

Comparison groups

Part 2: Placebo v Part 2: 2100 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.077

Method

Fisher exact

Confidence interval

Secondary: Number of subjects developing one of the composite events: death, RRT, or ≥ 25% reduction in S-Cystatin C based eGFR at Day 90

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End point title

Number of subjects developing one of the composite events: death, RRT, or ≥ 25% reduction in S-Cystatin C based eGFR at Day 90 ^[28]

End point description

Number of subjects developing at least one of the composite events: - death, - needing RRT during the 90-day post-operative period, or - having a ≥ 25% reduction in S-Cystatin C based eGFR or measured GFR at Day 90 post surgery visit

End point type

Secondary

End point timeframe

90 days

Notes
[28] - 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: Efficacy endpoints were only assessed in Part 2 subjects

End point values	Part 2: Placebo	Part 2: 800 mcg/kg ABT-719	Part 2: 1600 mcg/kg ABT-719	Part 2: 2100 mcg/kg ABT-719
Number of subjects analysed	7 ^[29]	5 ^[30]	10 ^[31]	8 ^[32]
Units: subjects	0	0	5	2

Notes
[29] - Per protocol analysis set
[30] - Per protocol analysis set
[31] - Per protocol analysis set
[32] - Per protocol analysis set

Comparison 1

Comparison groups

Part 2: Placebo v Part 2: 1600 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.044

Method

Fisher exact

Confidence interval

Comparison 2

Comparison groups

Part 2: Placebo v Part 2: 2100 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.467

Method

Fisher exact

Confidence interval

Secondary: Number of subjects developing one of the composite events: death, or ≥ 25% reduction in S-Cystatin C based eGFR at Day 60

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End point title

Number of subjects developing one of the composite events: death, or ≥ 25% reduction in S-Cystatin C based eGFR at Day 60 ^[33]

End point description

Number of subjects developing at least one of the composite events: - death, - needing RRT during the 60-day post-operative period, or - having a ≥ 25% reduction in S-Cystatin C based eGFR or measured GFR at Day 60 post surgery visit.

End point type

Secondary

End point timeframe

60 days

Notes
[33] - 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: Efficacy endpoints were only assessed in Part 2 subjects

End point values	Part 2: Placebo	Part 2: 800 mcg/kg ABT-719	Part 2: 1600 mcg/kg ABT-719	Part 2: 2100 mcg/kg ABT-719
Number of subjects analysed	7 ^[34]	5 ^[35]	10 ^[36]	8 ^[37]
Units: subjects	0	0	6	2

Notes
[34] - Per protocol analysis set
[35] - Per protocol analysis set
[36] - Per protocol analysis set
[37] - Per protocol analysis set

Comparison 1

Comparison groups

Part 2: Placebo v Part 2: 1600 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.035

Method

Fisher exact

Confidence interval

Comparison 2

Comparison groups

Part 2: Placebo v Part 2: 2100 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.467

Method

Fisher exact

Confidence interval

Secondary: Number of subjects developing AKI as defined by the RIFLE scoring criteria

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End point title

Number of subjects developing AKI as defined by the RIFLE scoring criteria ^[38]

End point description

The RIFLE classification defines three grades of severity of AKI (Risk, Injury and Failure) based on changes to serum creatinine, urine output and two clinical outcomes (Loss and End-stage). The 3 severity grades are defined on the basis of the changes in serum creatinine or urine output where the worst of each criterion is used. The 2 outcome criteria, Loss and End Stage Kidney Disease, are defined by the duration of loss of kidney function. Stage 1 (Risk): Increased serum creatinine × 1.5 or decreased GFR > 25%; urine output < 0.5 mL/kg/hr for more than 6 hours. Stage 2 (Injury): Increased serum creatinine × 2 or a decrease in GFR > 50%; urine output < 0.5 mL/kg/hr for more than 12 hours. Stage 3 (Failure): Increased serum creatinine × 3 or a decrease in GFR >75% or if baseline SCr ≥ 353.6 μmol/L (≥ 4 mg/dL), increased SCr > 44.2 μmol/L (> 0.5 mg/dL); urine output < 0.3 mL/kg/hr for 24 hours or anuria for 12 hours.

End point type

Secondary

End point timeframe

90 days

Notes
[38] - 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: Efficacy endpoints were only assessed in Part 2 subjects

End point values	Part 2: Placebo	Part 2: 800 mcg/kg ABT-719	Part 2: 1600 mcg/kg ABT-719	Part 2: 2100 mcg/kg ABT-719
Number of subjects analysed	7 ^[39]	5 ^[40]	10 ^[41]	8 ^[42]
Units: subjects
Stage 1	1	0	2	2
Stage 2	2	1	3	2
Stage 3	1	0	3	2

Notes
[39] - Per protocol analysis set
[40] - Per protocol analysis set
[41] - Per protocol analysis set
[42] - Per protocol analysis set

Comparison 1

Comparison groups

Part 2: Placebo v Part 2: 800 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.293

Method

Fisher exact

Confidence interval

Comparison 2

Comparison groups

Part 2: Placebo v Part 2: 1600 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.593

Method

Fisher exact

Confidence interval

Comparison 3

Comparison groups

Part 2: Placebo v Part 2: 2100 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.608

Method

Fisher exact

Confidence interval

Secondary: Number of subjects who developed AKI as determined by the Kidney Disease Improving Global Outcomes (KDIGO) Scoring criteria

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End point title

Number of subjects who developed AKI as determined by the Kidney Disease Improving Global Outcomes (KDIGO) Scoring criteria ^[43]

End point description

Kidney Disease Improving Global Outcomes (KDIGO) defined AKI as: increase in serum creatinine (SCr) by ≥ 0.3 mg/dl (≥ 26.5 µmol/l) within 48 hours; or increase in SCr to ≥ 1.5 times Baseline, which is known or presumed to have occurred within the prior 7 days; or urine volume < 0.5 mL/kg/h for 6 hours. Stage 1: Serum creatinine 1.5 – 1.9 x Baseline OR ≥ 0.3 mg/dl (≥ 26.5 µmol/l) increase; urine output < 0.5 mL/kg/hr for 6 – 12 hours. Stage 2: Serum creatinine 2.0 – 2.9 x Baseline; urine output < 0.5 mL/kg/hr for ≥ 12 hours. Stage 3: Serum creatinine 3.0 x Baseline OR Increase in serum creatinine to ≥ 4.0 mg/dl (≥ 353.6 µmol/l) OR Initiation of renal replacement therapy OR In patients < 18 years, decrease in eGFR to < 35 mL/min per 1.73 m²; urine output < 0.3 mL/kg/hr for ≥ 24 hours OR Anuria for ≥ 12 hours.

End point type

Secondary

End point timeframe

90 days

Notes
[43] - 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: Efficacy endpoints were only assessed in Part 2 subjects

End point values	Part 2: Placebo	Part 2: 800 mcg/kg ABT-719	Part 2: 1600 mcg/kg ABT-719	Part 2: 2100 mcg/kg ABT-719
Number of subjects analysed	7 ^[44]	5 ^[45]	10 ^[46]	8 ^[47]
Units: subjects
Stage 1	2	0	2	2
Stage 2	1	1	3	2
Stage 3	1	0	3	2

Notes
[44] - Per protocol analysis set
[45] - Per protocol analysis set
[46] - Per protocol analysis set
[47] - Per protocol analysis set

Comparison 1

Comparison groups

Part 2: Placebo v Part 2: 800 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.293

Method

Fisher exact

Confidence interval

Comparison 2

Comparison groups

Part 2: Placebo v Part 2: 1600 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.593

Method

Fisher exact

Confidence interval

Comparison 3

Comparison groups

Part 2: Placebo v Part 2: 2100 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.608

Method

Fisher exact

Confidence interval

Secondary: Changes from Baseline in serum creatinine (SCr) and S-Cystatin C at all study visits from Day 0 to Day 90

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End point title

Changes from Baseline in serum creatinine (SCr) and S-Cystatin C at all study visits from Day 0 to Day 90 ^[48]

End point description

End point type

Secondary

End point timeframe

Baseline to Day 90

Notes
[48] - 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: Efficacy endpoints were only assessed in Part 2 subjects

End point values	Part 2: Placebo	Part 2: 800 mcg/kg ABT-719	Part 2: 1600 mcg/kg ABT-719	Part 2: 2100 mcg/kg ABT-719
Number of subjects analysed	0 ^[49]	0 ^[50]	0 ^[51]	0 ^[52]
Units: mg/dL
arithmetic mean (standard deviation)	±	±	±	±

Notes
[49] - Not analyzed due to study termination
[50] - Not analyzed due to study termination
[51] - Not analyzed due to study termination
[52] - Not analyzed due to study termination

No statistical analyses for this end point

Secondary: Maximal change from Baseline in serum creatinine until Day 7 or until discharge from the hospital

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End point title

Maximal change from Baseline in serum creatinine until Day 7 or until discharge from the hospital ^[53]

End point description

End point type

Secondary

End point timeframe

Baseline to Day 7

Notes
[53] - 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: Efficacy endpoints were only assessed in Part 2 subjects

End point values	Part 2: Placebo	Part 2: 800 mcg/kg ABT-719	Part 2: 1600 mcg/kg ABT-719	Part 2: 2100 mcg/kg ABT-719
Number of subjects analysed	7 ^[54]	5 ^[55]	10 ^[56]	8 ^[57]
Units: mg/dL
least squares mean (standard error)	14.1 ± 22.9	9.2 ± 28.7	61.5 ± 19.6	22.4 ± 21.8

Notes
[54] - Per protocol analysis set
[55] - Per protocol analysis set
[56] - Per protocol analysis set
[57] - Per protocol analysis set

Comparison 1

Comparison groups

Part 2: Placebo v Part 2: 800 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.894 ^[58]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-4.9

Confidence interval

level

95%

sides

2-sided

lower limit

-78.8

upper limit

Variability estimate

Standard error of the mean

Dispersion value

36.6

Notes
[58] - ANCOVA model with treatment group as the factor and baseline as a covariate.

Comparison 2

Comparison groups

Part 2: Placebo v Part 2: 1600 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.119 ^[59]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

47.4

Confidence interval

level

95%

sides

2-sided

lower limit

-12.8

upper limit

107.5

Variability estimate

Standard error of the mean

Dispersion value

29.8

Notes
[59] - ANCOVA model with treatment group as the factor and baseline as a covariate.

Comparison 3

Comparison groups

Part 2: Placebo v Part 2: 2100 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.793 ^[60]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

8.3

Confidence interval

level

95%

sides

2-sided

lower limit

-55

upper limit

71.6

Variability estimate

Standard error of the mean

Dispersion value

31.4

Notes
[60] - ANCOVA model with treatment group as the factor and baseline as a covariate.

Secondary: Maximal change from Baseline in S-Cystatin C until Day 7 or until discharge from the hospital

Top of page

End point title

Maximal change from Baseline in S-Cystatin C until Day 7 or until discharge from the hospital ^[61]

End point description

End point type

Secondary

End point timeframe

Baseline to Day 7

Notes
[61] - 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: Efficacy endpoints were only assessed in Part 2 subjects

End point values	Part 2: Placebo	Part 2: 800 mcg/kg ABT-719	Part 2: 1600 mcg/kg ABT-719	Part 2: 2100 mcg/kg ABT-719
Number of subjects analysed	7 ^[62]	5 ^[63]	10 ^[64]	8 ^[65]
Units: mg/L
least squares mean (standard error)	2 ± 13.4	5.7 ± 16.1	38.1 ± 11.3	25.1 ± 12.8

Notes
[62] - Per protocol analysis set
[63] - Per protocol analysis set
[64] - Per protocol analysis set
[65] - Per protocol analysis set

Comparison 1

Comparison groups

Part 2: Placebo v Part 2: 800 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.863 ^[66]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

3.6

Confidence interval

level

95%

sides

2-sided

lower limit

-38.5

upper limit

45.8

Variability estimate

Standard error of the mean

Dispersion value

20.9

Notes
[66] - ANCOVA model with treatment group as the factor and baseline as a covariate.

Comparison 2

Comparison groups

Part 2: Placebo v Part 2: 1600 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.044 ^[67]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

36.1

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

71.1

Variability estimate

Standard error of the mean

Dispersion value

17.4

Notes
[67] - ANCOVA model with treatment group as the factor and baseline as a covariate.

Comparison 3

Comparison groups

Part 2: Placebo v Part 2: 2100 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.211 ^[68]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

23.1

Confidence interval

level

95%

sides

2-sided

lower limit

-13.6

upper limit

59.8

Variability estimate

Standard error of the mean

Dispersion value

18.2

Notes
[68] - ANCOVA model with treatment group as the factor and baseline as a covariate.

Secondary: Change from Baseline in SCr based eGFR, S-Cystatin C based eGFR and measured GFR at all study visits from Day 0 to Day 90

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End point title

Change from Baseline in SCr based eGFR, S-Cystatin C based eGFR and measured GFR at all study visits from Day 0 to Day 90 ^[69]

End point description

End point type

Secondary

End point timeframe

Baseline and Day 90

Notes
[69] - 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: Efficacy endpoints were only assessed in Part 2 subjects

End point values	Part 2: Placebo	Part 2: 800 mcg/kg ABT-719	Part 2: 1600 mcg/kg ABT-719	Part 2: 2100 mcg/kg ABT-719
Number of subjects analysed	0 ^[70]	0 ^[71]	0 ^[72]	0 ^[73]
Units: mL/min/1.73 m²
arithmetic mean (standard deviation)	±	±	±	±

Notes
[70] - Not analyzed due to study termination
[71] - Not analyzed due to study termination
[72] - Not analyzed due to study termination
[73] - Not analyzed due to study termination

No statistical analyses for this end point

Secondary: Changes from Baseline in AKI Biomarkers (urine and serum) at all study visits from Day 0 to Day 90

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End point title

Changes from Baseline in AKI Biomarkers (urine and serum) at all study visits from Day 0 to Day 90 ^[74]

End point description

End point type

Secondary

End point timeframe

Baseline to Day 90

Notes
[74] - 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: Efficacy endpoints were only assessed in Part 2 subjects

End point values	Part 2: Placebo	Part 2: 800 mcg/kg ABT-719	Part 2: 1600 mcg/kg ABT-719	Part 2: 2100 mcg/kg ABT-719
Number of subjects analysed	0 ^[75]	0 ^[76]	0 ^[77]	0 ^[78]
Units: mg/dL
arithmetic mean (standard deviation)	±	±	±	±

Notes
[75] - Not analyzed due to study termination
[76] - Not analyzed due to study termination
[77] - Not analyzed due to study termination
[78] - Not analyzed due to study termination

No statistical analyses for this end point

Secondary: Number of days hospitalized during the 90-day post-operative period

Top of page

End point title

Number of days hospitalized during the 90-day post-operative period ^[79]

End point description

End point type

Secondary

End point timeframe

90 days

Notes
[79] - 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: Efficacy endpoints were only assessed in Part 2 subjects

End point values	Part 2: Placebo	Part 2: 800 mcg/kg ABT-719	Part 2: 1600 mcg/kg ABT-719	Part 2: 2100 mcg/kg ABT-719
Number of subjects analysed	7 ^[80]	5 ^[81]	10 ^[82]	8 ^[83]
Units: days
least squares mean (standard error)	53.3 ± 12	36.4 ± 14.2	50.5 ± 10.1	43.4 ± 11.2

Notes
[80] - Per protocol analysis set
[81] - Per protocol analysis set
[82] - Per protocol analysis set
[83] - Per protocol analysis set

Comparison 1

Comparison groups

Part 2: Placebo v Part 2: 800 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.369 ^[84]

Method

ANOVA

Parameter type

LS Mean Difference

Point estimate

-16.9

Confidence interval

level

90%

sides

2-sided

lower limit

-48.1

upper limit

14.3

Variability estimate

Standard error of the mean

Dispersion value

18.6

Notes
[84] - ANOVA model with treatment as the factor.

Comparison 2

Comparison groups

Part 2: Placebo v Part 2: 1600 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.86 ^[85]

Method

ANOVA

Parameter type

LS Mean Difference

Point estimate

-2.8

Confidence interval

level

90%

sides

2-sided

lower limit

-29.1

upper limit

23.5

Variability estimate

Standard error of the mean

Dispersion value

15.7

Notes
[85] - ANOVA model with treatment as the factor.

Comparison 3

Comparison groups

Part 2: Placebo v Part 2: 2100 mcg/kg ABT-719

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.55 ^[86]

Method

ANOVA

Parameter type

LS Mean Difference

Point estimate

-9.9

Confidence interval

level

90%

sides

2-sided

lower limit

-37.5

upper limit

17.7

Variability estimate

Standard error of the mean

Dispersion value

16.5

Notes
[86] - ANOVA model with treatment as the factor.

Secondary: Change from Baseline in Euroqol 5 Dimensions (EQ-5D) index score

Top of page

End point title

Change from Baseline in Euroqol 5 Dimensions (EQ-5D) index score ^[87]

End point description

The EQ-5D consists of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. There are 3 levels to each dimension: no problems, some problems, and extreme problems. The scores of the 5 dimensions were converted into a single summary index by utilizing country specific value sets, from 0 to 1 where 1 represents perfect health.

End point type

Secondary

End point timeframe

Baseline, day of discharge and 90 days post surgery

Notes
[87] - 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: Efficacy endpoints were only assessed in Part 2 subjects

End point values	Part 2: Placebo	Part 2: 800 mcg/kg ABT-719	Part 2: 1600 mcg/kg ABT-719	Part 2: 2100 mcg/kg ABT-719
Number of subjects analysed	7 ^[88]	5 ^[89]	10 ^[90]	8 ^[91]
Units: units on a scale
arithmetic mean (standard deviation)
Change to Day of Discharge (n=4, 2, 3, 2)	-0.017 ± 0.051	0.021 ± 0.03	-0.055 ± 0.056	-0.065 ± 0.067
Change to Day 90 (n=2, 2, 3, 3)	-0.031 ± 0.065	0.156 ± 0.025	-0.078 ± 0.071	0.07 ± 0.132

Notes
[88] - Per protocol analysis set; subjects with available data at each time point is indicated by "n".
[89] - Per protocol analysis set; subjects with available data at each time point is indicated by "n".
[90] - Per protocol analysis set; subjects with available data at each time point is indicated by "n".
[91] - Per protocol analysis set; subjects with available data at each time point is indicated by "n".

No statistical analyses for this end point

Secondary: Change from Baseline in for EQ-5D visual analog scale (VAS) Score

Top of page

End point title

Change from Baseline in for EQ-5D visual analog scale (VAS) Score ^[92]

End point description

The EQ-5D is a patient-completed, multidimensional measure of health related quality of life. The EQ-5D VAS records the respondent’s self-rated health status on a vertical graduated (0-100) visual analogue scale. Higher EQ-5D VAS scores represent better health status.

End point type

Secondary

End point timeframe

Baseline, day of discharge and 90 days post-surgery

Notes
[92] - 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: Efficacy endpoints were only assessed in Part 2 subjects

End point values	Part 2: Placebo	Part 2: 800 mcg/kg ABT-719	Part 2: 1600 mcg/kg ABT-719	Part 2: 2100 mcg/kg ABT-719
Number of subjects analysed	7 ^[93]	5 ^[94]	10 ^[95]	8 ^[96]
Units: units on a scale
arithmetic mean (standard deviation)
Change to Day of Discharge (n=4, 2, 3, 2)	7.5 ± 17.08	7.5 ± 3.54	-6 ± 10.39	9 ± 1.41
Change to Day 90 (n=2, 2, 3, 3)	15 ± 21.21	-42.5 ± 67.18	13 ± 12.12	40.7 ± 22.9

Notes
[93] - Per protocol analysis set; subjects with available data at each time point is indicated by "n".
[94] - Per protocol analysis set; subjects with available data at each time point is indicated by "n".
[95] - Per protocol analysis set; subjects with available data at each time point is indicated by "n".
[96] - Per protocol analysis set; subjects with available data at each time point is indicated by "n".

No statistical analyses for this end point

Secondary: Number of subjects with 'no problem' and 'problems' in 5 dimensions of EQ-5D

Top of page

End point title

Number of subjects with 'no problem' and 'problems' in 5 dimensions of EQ-5D ^[97]

End point description

Number of subjects who experience 'no problem' (level 1) and 'problems' (level 2 and 3) in 5 dimensions of EQ-5D. The EQ-5D-3L consists of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. There are 3 levels to each dimension: no problems (level 1), some problems (level 2), and extreme problems (level 3).

End point type

Secondary

End point timeframe

Day of discharge

Notes
[97] - 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: Efficacy endpoints were only assessed in Part 2 subjects

End point values	Part 2: Placebo	Part 2: 800 mcg/kg ABT-719	Part 2: 1600 mcg/kg ABT-719	Part 2: 2100 mcg/kg ABT-719
Number of subjects analysed	4 ^[98]	2 ^[99]	3 ^[100]	2 ^[101]
Units: subjects
Mobility - No Problems	1	2	0	1
Mobility - Problems	3	0	3	1
Self-care - No Problems	4	2	0	1
Self-care - Problems	0	0	3	1
Usual Activities - No Problems	0	2	1	0
Usual Activities - Problems	4	0	2	2
Pain/Discomfort - No problems	1	0	0	1
Pain/Discomfort - Problems	3	2	3	1
Anxiety/Depression - No Problems	4	2	1	2
Anxiety/Depression - Problems	0	0	2	0

Notes
[98] - Per protocol analysis set with available data
[99] - Per protocol analysis set with available data
[100] - Per protocol analysis set with available data
[101] - Per protocol analysis set with available data

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

From the first dose of study drug until 30 days after last dose.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Part 1: 800 mcg/kg ABT-719

Reporting group description

Subjects received 800 mcg/kg ABT-719 divided in 3 doses given as 10 minute infusions of 200 mcg/kg, 400 mcg/kg, and 200 mcg/kg on Day 0 (the day of surgery).

Reporting group title

Part 2: Placebo

Reporting group description

Subjects received 6 infusions of placebo beginning on Day 0 (the day of surgery) and at 2 hours after the first dose and 6, 12, 24 and 48 hours after the second dose.

Reporting group title

Part 2: 800 mcg/kg ABT-719

Reporting group description

Reporting group title

Part 2: 1600 mcg/kg ABT-719

Reporting group description

Reporting group title

Part 2: 2100 mcg/kg ABT-719

Reporting group description

Serious adverse events	Part 1: 800 mcg/kg ABT-719	Part 2: Placebo	Part 2: 800 mcg/kg ABT-719	Part 2: 1600 mcg/kg ABT-719	Part 2: 2100 mcg/kg ABT-719
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 4 (50.00%)	3 / 7 (42.86%)	3 / 9 (33.33%)	2 / 10 (20.00%)	1 / 10 (10.00%)
number of deaths (all causes)	0	0	0	1	0
number of deaths resulting from adverse events
Investigations
Oxygen Saturation Decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular Accident
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diplegia
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Diaphragmatic Hernia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric Ulcer
subjects affected / exposed	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis Erosive
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal Haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal Ischaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal Perforation
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mechanical Ileus
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Diabetic Ulcer
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal Ischaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Septic Shock
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Wound Infection
subjects affected / exposed	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Part 1: 800 mcg/kg ABT-719	Part 2: Placebo	Part 2: 800 mcg/kg ABT-719	Part 2: 1600 mcg/kg ABT-719	Part 2: 2100 mcg/kg ABT-719
Total subjects affected by non serious adverse events
subjects affected / exposed	4 / 4 (100.00%)	5 / 7 (71.43%)	8 / 9 (88.89%)	9 / 10 (90.00%)	9 / 10 (90.00%)
Vascular disorders
Hypertension
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	3 / 10 (30.00%)
occurrences all number	0	0	0	1	3
Hypotension
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	0	2	0	2
Pallor
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Surgical and medical procedures
Prophylaxis Against Gastrointestinal Ulcer
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
General disorders and administration site conditions
Chest Pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Fatigue
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0
Malaise
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Medical Device Complication
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0
Pyrexia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0
Respiratory, thoracic and mediastinal disorders
Atelectasis
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1	0	0	1
Chronic Obstructive Pulmonary Disease
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Cough
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 9 (11.11%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0
Dyspnoea
subjects affected / exposed	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	1	0
Oropharyngeal Pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Pleural Effusion
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	1 / 9 (11.11%)	2 / 10 (20.00%)	1 / 10 (10.00%)
occurrences all number	0	1	1	2	1
Pneumothorax
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0
Respiratory Acidosis
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Respiratory Failure
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	0	0
Wheezing
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Psychiatric disorders
Confusional State
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0
Delirium
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0
Insomnia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	2 / 10 (20.00%)
occurrences all number	0	0	0	1	2
Mental Status Changes
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0
Investigations
Activated Partial Thromboplastin Time Prolonged
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Blood Bilirubin Increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0
Blood Creatine Phosphokinase Increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0
Blood Creatinine Increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Blood Pressure Increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Blood Pressure Systolic Increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Body Temperature Increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Cystatin C Increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Haemoglobin Decreased
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	0	0
International Normalised Ratio Increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0
Red Blood Cells Urine
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Troponin Increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0
Urinary Sediment Present
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Urine Albumin/Creatinine Ratio Increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Urine Analysis Abnormal
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Urine Output Decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
White Blood Cells Urine Positive
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Injury, poisoning and procedural complications
Arterial Injury
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0
Incision Site Pain
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 9 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)
occurrences all number	0	1	0	1	1
Laceration
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Post Procedural Constipation
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0
Postoperative Ileus
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Procedural Hypotension
subjects affected / exposed	0 / 4 (0.00%)	2 / 7 (28.57%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	0	0
Procedural Nausea
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 9 (0.00%)	3 / 10 (30.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	3	0
Procedural Pain
subjects affected / exposed	2 / 4 (50.00%)	2 / 7 (28.57%)	7 / 9 (77.78%)	3 / 10 (30.00%)	5 / 10 (50.00%)
occurrences all number	2	2	7	3	5
Procedural Vomiting
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0
Scrotal Haematoma
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0
Wound
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Wound Complication
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Cardiac disorders
Atrial Fibrillation
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Bradycardia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0
Tachycardia
subjects affected / exposed	1 / 4 (25.00%)	1 / 7 (14.29%)	1 / 9 (11.11%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	1	1	1	0	1
Nervous system disorders
Headache
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	2 / 9 (22.22%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	2	0	0
Hypoaesthesia
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Neuropathy Peripheral
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Syncope
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 4 (25.00%)	1 / 7 (14.29%)	1 / 9 (11.11%)	4 / 10 (40.00%)	3 / 10 (30.00%)
occurrences all number	1	1	1	4	3
Leukocytosis
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1	0	0	1
Thrombocytopenia
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	1 / 9 (11.11%)	0 / 10 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	1	1	0	2
Eye disorders
Visual Impairment
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Gastrointestinal disorders
Colitis Ischaemic
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0
Constipation
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	3 / 9 (33.33%)	2 / 10 (20.00%)	1 / 10 (10.00%)
occurrences all number	0	1	3	2	1
Diarrhoea
subjects affected / exposed	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	1	0
Haematemesis
subjects affected / exposed	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0
Ileus
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Nausea
subjects affected / exposed	3 / 4 (75.00%)	0 / 7 (0.00%)	1 / 9 (11.11%)	2 / 10 (20.00%)	4 / 10 (40.00%)
occurrences all number	3	0	1	2	4
Vomiting
subjects affected / exposed	3 / 4 (75.00%)	0 / 7 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	3	0	1	0	1
Hepatobiliary disorders
Hypertransaminasaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Skin and subcutaneous tissue disorders
Ecchymosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Pruritus
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	3 / 10 (30.00%)
occurrences all number	0	0	0	0	3
Rash
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1	0	1
Renal and urinary disorders
Renal Failure Acute
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 9 (0.00%)	2 / 10 (20.00%)	1 / 10 (10.00%)
occurrences all number	0	1	0	2	1
Renal Impairment
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0
Urinary Retention
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Musculoskeletal and connective tissue disorders
Groin Pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Muscle Spasms
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Muscular Weakness
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Musculoskeletal Stiffness
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Pain In Extremity
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Infections and infestations
Eye Infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Gangrene
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0
Gastroenteritis
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Lung Infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0
Urinary Tract Infection
subjects affected / exposed	1 / 4 (25.00%)	0 / 7 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	1	0	1	0	1
Metabolism and nutrition disorders
Acidosis
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Dehydration
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Fluid Overload
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 9 (11.11%)	1 / 10 (10.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1	1	1
Hyperglycaemia
subjects affected / exposed	1 / 4 (25.00%)	1 / 7 (14.29%)	1 / 9 (11.11%)	2 / 10 (20.00%)	1 / 10 (10.00%)
occurrences all number	1	1	1	2	1
Hyperkalaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Hypernatraemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Hypoalbuminaemia
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1	0	0	1
Hypocalcaemia
subjects affected / exposed	0 / 4 (0.00%)	2 / 7 (28.57%)	1 / 9 (11.11%)	1 / 10 (10.00%)	2 / 10 (20.00%)
occurrences all number	0	2	1	1	2
Hypoglycaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0
Hypokalaemia
subjects affected / exposed	2 / 4 (50.00%)	1 / 7 (14.29%)	0 / 9 (0.00%)	2 / 10 (20.00%)	2 / 10 (20.00%)
occurrences all number	3	1	0	2	2
Hypomagnesaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	2 / 10 (20.00%)	2 / 10 (20.00%)
occurrences all number	0	0	0	2	2
Hyponatraemia
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Hypophosphataemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0
Malnutrition
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0
Metabolic Acidosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0
Vitamin D Deficiency
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0

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Were there any global substantial amendments to the protocol? Yes

04 Feb 2013

The purpose of this amendment was to: ● Revise benefits and risks section to clarify the proper medical terminology of gastric fundus rather than ventricular fundus. ● Revise study procedures sections to note that a urine pregnancy test was to be performed rather than a serum pregnancy test at Baseline for Part 1 and Part 2 to meet exclusion criterion number 15. ● Revise throughout that the unblinded pharmacist could designate pharmacy procedures to an unblinded non-pharmacist staff member. ● Revise exclusion criteria section to add that subjects who required intravascular (IV) iodinated contrast within 5 days of the day of surgery (Day 0) and experienced a known SCr change of ≥ 0.3 mg on repeat testing 24 hours apart post-contrast were to be excluded. ● Revise exclusion criteria section to add that subjects who were scheduled to have a total or partial nephrectomy were to be excluded. ● Revise study procedures table to clarify that study drug administration was to only take place on Day 0 (Surgery Day) for Part 1 and that study drug administration was not to take place on Day 3 for Part 2. ● Clarify that blood pressure (BP) was to be taken in the sitting position when possible, as it cannot be taken while the subject is in surgery on Day 0 (Surgery Day). ● Clarify that pregnancy tests were to be conducted only on females of childbearing potential. ● Clarify the stratification variables for surgical procedures from 'Vascular or Other' to 'Endovascular or Other.' ● Revise Independent Data Monitoring Committee (IDMC) sections to remove external Data Monitoring Committee (DMC) members and add that unblinded AbbVie statisticians and medical doctors(s) not associated with the conduct of the study were to be part of the DMC. Rationale for Change: An external IDMC committee was no longer included in the protocol. ● Clarify randomization methods section to differentiate between low, mid and high doses of ABT-719.

15 Jan 2014

The purpose of this amendment was to: ● Revise definition for High Risk Major Surgery. ● Clarify the patient population was to include subjects that were undergoing high risk major surgeries including: cardiac (non-CPB), TAVR, endovascular surgery or vascular surgery. ● Clarify that subjects who failed Screening on laboratory criteria at this visit, or had their surgery delayed for > 28 days could be re-screened once, at the discretion of the principal investigator and study designated physician. ● Clarify that up to approximately 180 additional subjects may have been randomized to placebo and/or to the ABT-719 dose groups selected for further study based on the results of the interim analysis, as appropriate. ● Remove requirement for a Day 7 visit if subject was discharged prior to Day 5. ● Revisions to exclusion criteria ● Revise prior and concomitant therapy section to add the following: Nephrotoxic medications such as non-steroidal anti-inflammatory drugs (daily prophylactic aspirin use was acceptable) and aminoglycosides were to be minimized or avoided. ● Clarify that subjects who were discontinued from study drug after receiving at least 1 dose were to be followed for safety for 30 days. For subjects who were randomized but never received study drug or did not undergo surgery, additional enrollment may have occurred to maintain the power of the study. ● Revise randomization sections to delete: and ≤ 59 mL/min/1.73 m² from eGFR stratification arm and clarify that subjects were to be stratified in the IVRS based on screening eGFR (between 16 – 45 mL/min/1.73 m², and eGFR greater than 45 mL/min/1.73 m²).

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: A Phase 2b, Randomized, Double-Blind, Placebo Controlled, Safety and Efficacy Trial of Multiple Dosing Regimens of ABT-719 for the Prevention of Acute Kidney Injury in Subjects Undergoing High Risk Major Surgery

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Maximal change from Baseline in urine neutrophil gelatinase-associated lipocalin (NGAL) until Day 7 or discharge

Primary: Maximal change from Baseline in urine neutrophil gelatinase-associated lipocalin (NGAL) until Day 7 or discharge

Secondary: Maximal change from Baseline in serum NGAL until Day 7 or discharge

Secondary: Maximal change from Baseline in serum NGAL until Day 7 or discharge

Secondary: Maximal change from baseline in urine interleukin-18 until Day 7 or discharge

Secondary: Maximal change from baseline in urine interleukin-18 until Day 7 or discharge

Secondary: Maximal change from Baseline in urine kidney injury molecule (KIM-1) until Day 7 or discharge

Secondary: Maximal change from Baseline in urine kidney injury molecule (KIM-1) until Day 7 or discharge

Secondary: Number of subjects developing acute kidney injury (AKI) as defined by the AKIN scoring criteria

Secondary: Number of subjects developing acute kidney injury (AKI) as defined by the AKIN scoring criteria

Secondary: Number of subjects developing one of the composite events: death, renal replacement therapy (RRT), or ≥ 25% reduction in serum creatinine based estimated glomerular filtration rate (eGFR) at Day 90

Secondary: Number of subjects developing one of the composite events: death, renal replacement therapy (RRT), or ≥ 25% reduction in serum creatinine based estimated glomerular filtration rate (eGFR) at Day 90

Secondary: Number of subjects developing one of the composite events: death, RRT or ≥ 25% reduction in SCr based GFR at Day 60

Secondary: Number of subjects developing one of the composite events: death, RRT or ≥ 25% reduction in SCr based GFR at Day 60

Secondary: Number of subjects developing one of the composite events: death, RRT, or ≥ 25% reduction in S-Cystatin C based eGFR at Day 90

Secondary: Number of subjects developing one of the composite events: death, RRT, or ≥ 25% reduction in S-Cystatin C based eGFR at Day 90

Secondary: Number of subjects developing one of the composite events: death, or ≥ 25% reduction in S-Cystatin C based eGFR at Day 60

Secondary: Number of subjects developing one of the composite events: death, or ≥ 25% reduction in S-Cystatin C based eGFR at Day 60

Secondary: Number of subjects developing AKI as defined by the RIFLE scoring criteria

Secondary: Number of subjects developing AKI as defined by the RIFLE scoring criteria

Secondary: Number of subjects who developed AKI as determined by the Kidney Disease Improving Global Outcomes (KDIGO) Scoring criteria

Secondary: Number of subjects who developed AKI as determined by the Kidney Disease Improving Global Outcomes (KDIGO) Scoring criteria

Secondary: Changes from Baseline in serum creatinine (SCr) and S-Cystatin C at all study visits from Day 0 to Day 90

Secondary: Changes from Baseline in serum creatinine (SCr) and S-Cystatin C at all study visits from Day 0 to Day 90

Secondary: Maximal change from Baseline in serum creatinine until Day 7 or until discharge from the hospital

Secondary: Maximal change from Baseline in serum creatinine until Day 7 or until discharge from the hospital

Secondary: Maximal change from Baseline in S-Cystatin C until Day 7 or until discharge from the hospital

Secondary: Maximal change from Baseline in S-Cystatin C until Day 7 or until discharge from the hospital

Secondary: Change from Baseline in SCr based eGFR, S-Cystatin C based eGFR and measured GFR at all study visits from Day 0 to Day 90

Secondary: Change from Baseline in SCr based eGFR, S-Cystatin C based eGFR and measured GFR at all study visits from Day 0 to Day 90

Secondary: Changes from Baseline in AKI Biomarkers (urine and serum) at all study visits from Day 0 to Day 90

Secondary: Changes from Baseline in AKI Biomarkers (urine and serum) at all study visits from Day 0 to Day 90

Secondary: Number of days hospitalized during the 90-day post-operative period

Secondary: Number of days hospitalized during the 90-day post-operative period

Secondary: Change from Baseline in Euroqol 5 Dimensions (EQ-5D) index score

Secondary: Change from Baseline in Euroqol 5 Dimensions (EQ-5D) index score

Secondary: Change from Baseline in for EQ-5D visual analog scale (VAS) Score

Secondary: Change from Baseline in for EQ-5D visual analog scale (VAS) Score

Secondary: Number of subjects with 'no problem' and 'problems' in 5 dimensions of EQ-5D

Secondary: Number of subjects with 'no problem' and 'problems' in 5 dimensions of EQ-5D

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase 2b, Randomized, Double-Blind, Placebo Controlled, Safety and Efficacy Trial of Multiple Dosing Regimens of ABT-719 for the Prevention of Acute Kidney Injury in Subjects Undergoing High Risk Major Surgery