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Clinical Trial Results:
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Dose Ranging Study to Evaluate the Efficacy and Safety of 2 Dose Regimens of Intravenous TAK-954 for the Prophylaxis and Treatment of Postoperative Gastrointestinal Dysfunction in Patients Undergoing Large- and Small-Bowel Resection

Summary
EudraCT number	2018-003318-42
Trial protocol	DE BE
Global end of trial date	27 May 2022

Results information
Results version number	v1(current)
This version publication date	11 Jun 2023
First version publication date	11 Jun 2023
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

TAK-954-2004

ISRCTN number

US NCT number

NCT03827655

WHO universal trial number (UTN)

U1111-1222-4784

Sponsor organisation name

Takeda

Sponsor organisation address

95 Hayden Avenue, Lexington, United States, MA 02421

Public contact

Study Director, Takeda, TrialDisclosures@takeda.com

Scientific contact

Study Director, Takeda, TrialDisclosures@takeda.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

27 May 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

27 May 2022

Was the trial ended prematurely?

Main objective of the trial

The main objective of this study was to assess the efficacy and safety of intravenous (IV) TAK-954 for accelerating the recovery of gastrointestinal (GI) function postsurgery in participants undergoing open or laparoscopic-assisted partial small- or large-bowel resection.

Protection of trial subjects

Study participants were required to read and sign an informed consent form.

Background therapy

Evidence for comparator

Actual start date of recruitment

07 Mar 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 36

Country: Number of subjects enrolled

United States: 173

Worldwide total number of subjects

209

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)

152

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants took part in the study at 20 investigative sites in Germany and the United States from 07 March 2019 to 27 May 2022.

Screening details

Participants with a diagnosis of postoperative gastrointestinal dysfunction were enrolled in a 1:1:1:1:1 ratio into one of the five treatment groups to receive TAK-954 and/or placebo before and after surgery.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Assessor, Carer, Investigator, Data analyst, Subject

Are arms mutually exclusive

Placebo

Arm description

TAK-954 placebo-matching, 60-minute infusion, intravenously (IV), once presurgery on Day 1 and once daily postsurgery until return of upper and lower gastrointestinal (GI) function or for up to 10 days.

Arm type

Placebo

Investigational medicinal product name

TAK-954 Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

TAK-954 placebo-matching intravenous infusion.

TAK-954 0.1 mg/100 mL

Arm description

TAK-954 0.1 milligrams per 100 milliliters (mg/100 mL), 60-minute infusion, IV, once presurgery on Day 1 and once daily postsurgery until return of upper and lower GI function or for up to 10 days.

Arm type

Experimental

Investigational medicinal product name

TAK-954

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

TAK-954 intravenous infusion.

TAK-954 0.5 mg/100 mL

Arm description

TAK-954 0.5 mg/100 mL, 60-minute infusion, IV, once presurgery on Day 1 and once daily postsurgery until return of upper and lower GI function or for up to 10 days.

Arm type

Experimental

Investigational medicinal product name

TAK-954

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

TAK-954 intravenous infusion.

TAK-954 0.1 mg/100 mL + Placebo

Arm description

TAK-954 0.1 mg/100 mL, 60-minute infusion, IV, once presurgery on Day 1 and once daily placebo infusions postsurgery up to Day 10 or until resolution of upper and lower GI function.

Arm type

Experimental

Investigational medicinal product name

TAK-954

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

TAK-954 intravenous infusion.

Investigational medicinal product name

TAK-954 Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

TAK-954 placebo-matching intravenous infusion.

TAK-954 0.5 mg/100 mL + Placebo

Arm description

TAK-954 0.5 mg/100 mL, 60-minute infusion, IV, once presurgery on Day 1 and once daily placebo infusions postsurgery up to Day 10 or until resolution of upper and lower GI function.

Arm type

Experimental

Investigational medicinal product name

TAK-954

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

TAK-954 intravenous infusion.

Investigational medicinal product name

TAK-954 Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

TAK-954 placebo-matching intravenous infusion.

Number of subjects in period 1	Placebo	TAK-954 0.1 mg/100 mL	TAK-954 0.5 mg/100 mL	TAK-954 0.1 mg/100 mL + Placebo	TAK-954 0.5 mg/100 mL + Placebo
Started	52	27	51	27	52
Safety Set	49	26	48	25	50
Full Analysis Set (FAS)	45	23 ^[1]	42 ^[2]	21 ^[3]	44 ^[4]
Pharmacokinetic (PK) Analysis Set	0 ^[5]	26	47	24 ^[6]	50
Completed	45	24	47	25	49
Not completed	7	3	4	2	3
Adverse event, serious fatal	-	-	-	-	1
Consent withdrawn by subject	3	2	2	-	1
Protocol Deviation	1	-	1	1	-
Reason not Specified	3	1	1	1	1

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Safety Set included all participants who were randomized and received at least 1 dose of double-blind study medication. FAS included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid postbaseline on-treatment primary efficacy evaluation (bowel movement or tolerating solid food). PK Analysis Set included all participants who were randomized, received at least 1 dose and had at least 1 measurable post-dose plasma for TAK-954.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Safety Set included all participants who were randomized and received at least 1 dose of double-blind study medication. FAS included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid postbaseline on-treatment primary efficacy evaluation (bowel movement or tolerating solid food). PK Analysis Set included all participants who were randomized, received at least 1 dose and had at least 1 measurable post-dose plasma for TAK-954.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Safety Set included all participants who were randomized and received at least 1 dose of double-blind study medication. FAS included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid postbaseline on-treatment primary efficacy evaluation (bowel movement or tolerating solid food). PK Analysis Set included all participants who were randomized, received at least 1 dose and had at least 1 measurable post-dose plasma for TAK-954.
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Safety Set included all participants who were randomized and received at least 1 dose of double-blind study medication. FAS included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid postbaseline on-treatment primary efficacy evaluation (bowel movement or tolerating solid food). PK Analysis Set included all participants who were randomized, received at least 1 dose and had at least 1 measurable post-dose plasma for TAK-954.
[5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Safety Set included all participants who were randomized and received at least 1 dose of double-blind study medication. FAS included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid postbaseline on-treatment primary efficacy evaluation (bowel movement or tolerating solid food). PK Analysis Set included all participants who were randomized, received at least 1 dose and had at least 1 measurable post-dose plasma for TAK-954.
[6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Safety Set included all participants who were randomized and received at least 1 dose of double-blind study medication. FAS included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid postbaseline on-treatment primary efficacy evaluation (bowel movement or tolerating solid food). PK Analysis Set included all participants who were randomized, received at least 1 dose and had at least 1 measurable post-dose plasma for TAK-954.

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Reporting group title

TAK-954 0.1 mg/100 mL

Reporting group description

TAK-954 0.1 milligrams per 100 milliliters (mg/100 mL), 60-minute infusion, IV, once presurgery on Day 1 and once daily postsurgery until return of upper and lower GI function or for up to 10 days.

Reporting group title

TAK-954 0.5 mg/100 mL

Reporting group description

TAK-954 0.5 mg/100 mL, 60-minute infusion, IV, once presurgery on Day 1 and once daily postsurgery until return of upper and lower GI function or for up to 10 days.

Reporting group title

TAK-954 0.1 mg/100 mL + Placebo

Reporting group description

TAK-954 0.1 mg/100 mL, 60-minute infusion, IV, once presurgery on Day 1 and once daily placebo infusions postsurgery up to Day 10 or until resolution of upper and lower GI function.

Reporting group title

TAK-954 0.5 mg/100 mL + Placebo

Reporting group description

TAK-954 0.5 mg/100 mL, 60-minute infusion, IV, once presurgery on Day 1 and once daily placebo infusions postsurgery up to Day 10 or until resolution of upper and lower GI function.

Reporting group values	Placebo	TAK-954 0.1 mg/100 mL	TAK-954 0.5 mg/100 mL	TAK-954 0.1 mg/100 mL + Placebo	TAK-954 0.5 mg/100 mL + Placebo	Total
Number of subjects	52	27	51	27	52
Age Categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	57.9 ( 11.99 )	55.9 ( 13.83 )	57.3 ( 14.10 )	53.7 ( 12.15 )	53.2 ( 15.28 )	-
Gender categorical
Units: Subjects
Female	32	10	21	12	26	101
Male	20	17	30	15	26	108
Ethnicity
Units: Subjects
Hispanic or Latino	1	1	3	2	3	10
Not Hispanic or Latino	43	21	37	21	39	161
Unknown or Not Reported	8	5	11	4	10	38
Race
Units: Subjects
American Indian or Alaska Native	1	0	0	0	0	1
Asian	1	1	0	0	0	2
Native Hawaiian or Other Pacific Islander	0	1	0	0	0	1
Black or African American	5	2	0	4	3	14
White	37	18	42	18	38	153
More than one race	0	0	0	0	0	0
Unknown or Not Reported	8	5	9	5	11	38
Region of Enrollment
Units: Subjects
Germany	8	5	9	4	10	36
United States	44	22	42	23	42	173
Height
Units: centimeters (cm)
arithmetic mean (standard deviation)	170.83 ( 10.991 )	173.01 ( 9.273 )	172.30 ( 9.335 )	172.23 ( 10.972 )	172.60 ( 9.603 )	-
Weight
Units: kilograms (kg)
arithmetic mean (standard deviation)	87.25 ( 19.317 )	82.92 ( 18.066 )	87.26 ( 15.995 )	82.84 ( 26.018 )	85.64 ( 20.416 )	-
Body Mass Index (BMI)
BMI=[weight(kg)]/[height(m^2)]
Units: kilograms per square meter (kg/m^2)
arithmetic mean (standard deviation)	29.84 ( 5.920 )	27.80 ( 6.492 )	29.45 ( 5.465 )	27.60 ( 6.904 )	28.76 ( 6.652 )	-

End points

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Reporting group title

Placebo

Reporting group description

Reporting group title

TAK-954 0.1 mg/100 mL

Reporting group description

TAK-954 0.1 milligrams per 100 milliliters (mg/100 mL), 60-minute infusion, IV, once presurgery on Day 1 and once daily postsurgery until return of upper and lower GI function or for up to 10 days.

Reporting group title

TAK-954 0.5 mg/100 mL

Reporting group description

TAK-954 0.5 mg/100 mL, 60-minute infusion, IV, once presurgery on Day 1 and once daily postsurgery until return of upper and lower GI function or for up to 10 days.

Reporting group title

TAK-954 0.1 mg/100 mL + Placebo

Reporting group description

TAK-954 0.1 mg/100 mL, 60-minute infusion, IV, once presurgery on Day 1 and once daily placebo infusions postsurgery up to Day 10 or until resolution of upper and lower GI function.

Reporting group title

TAK-954 0.5 mg/100 mL + Placebo

Reporting group description

TAK-954 0.5 mg/100 mL, 60-minute infusion, IV, once presurgery on Day 1 and once daily placebo infusions postsurgery up to Day 10 or until resolution of upper and lower GI function.

Primary: Time From End of the Surgery to Resolution of Upper and Lower Gastrointestinal (GI) Function Postsurgery as Assessed by the Investigator

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End point title

Time From End of the Surgery to Resolution of Upper and Lower Gastrointestinal (GI) Function Postsurgery as Assessed by the Investigator

End point description

The time from end of surgery to tolerance of solid food, without first occurrence of vomiting or clinically significant nausea for 1 calendar day after a solid meal (upper GI function) and first spontaneous bowel movement (lower GI function), whichever occurred later up to 10 days postsurgery was observed. Kaplan-Meier survival analysis method was used. FAS included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid postbaseline on-treatment primary efficacy evaluation (bowel movement or tolerating solid food).

End point type

Primary

End point timeframe

Day 1 (surgery) up to Day 10 postsurgery

End point values	Placebo	TAK-954 0.1 mg/100 mL	TAK-954 0.5 mg/100 mL	TAK-954 0.1 mg/100 mL + Placebo	TAK-954 0.5 mg/100 mL + Placebo
Number of subjects analysed	45	23	42	21	44
Units: days
median (full range (min-max))	1.89 (1.41 to 5.79)	2.76 (1.51 to 7.85)	2.59 (0.85 to 4.97)	2.62 (1.13 to 7.59)	2.58 (1.46 to 7.74)

Statistical Analysis 1

Statistical analysis description

Hazard ratios, 90% CIs and associated Wald Chi-square p-values between TAK-954 dose levels and placebo are obtained using a stratified Cox proportional hazard model with treatment as the only independent variable.

Comparison groups

Placebo v TAK-954 0.5 mg/100 mL

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.649 ^[1]

Method

Wald chi-square test

Parameter type

Hazard ratio (HR)

Point estimate

0.92

Confidence interval

level

90%

sides

2-sided

lower limit

0.63

upper limit

1.33

Notes
[1] - P-values were derived using a one-sided test with alternative hypothesis (Ha): Hazard Ratio>1.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v TAK-954 0.5 mg/100 mL + Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.505 ^[2]

Method

Wald chi-square test

Parameter type

Hazard ratio (HR)

Point estimate

Confidence interval

level

90%

sides

2-sided

lower limit

0.69

upper limit

1.43

Notes
[2] - P-values were derived using a one-sided test with alternative hypothesis (Ha): Hazard Ratio>1.

Secondary: Time From the End of the Surgery (Time the Incision is Closed) Until Ready for Discharge as Assessed by the Investigator

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End point title

Time From the End of the Surgery (Time the Incision is Closed) Until Ready for Discharge as Assessed by the Investigator

End point description

The time from the end of surgery (time the incision is closed) until ready for discharge was defined as time from end of surgery until the participant presented effective intestinal transit (spontaneous bowel movement), tolerated solids without vomiting or clinically significant nausea for 1 calendar day after a solid meal, had satisfactory pain control with oral analgesics, and was medically stable/free of complications. Kaplan-Meier survival analysis method was used. FAS included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid postbaseline on-treatment primary efficacy evaluation (bowel movement or tolerating solid food).

End point type

Secondary

End point timeframe

Day 1 (surgery) up to Day 24

End point values	Placebo	TAK-954 0.1 mg/100 mL	TAK-954 0.5 mg/100 mL	TAK-954 0.1 mg/100 mL + Placebo	TAK-954 0.5 mg/100 mL + Placebo
Number of subjects analysed	45	23	42	21	44
Units: days
median (full range (min-max))	2.03 (1.41 to 16.83)	2.82 (1.51 to 9.68)	2.69 (0.85 to 8.79)	2.94 (1.47 to 7.73)	2.77 (1.51 to 7.74)

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo v TAK-954 0.5 mg/100 mL

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.449 ^[3]

Method

Wald chi-square test

Parameter type

Hazard ratio (HR)

Point estimate

1.03

Confidence interval

level

90%

sides

2-sided

lower limit

0.71

upper limit

1.49

Notes
[3] - P-values were derived using a one-sided test with alternative hypothesis (Ha): Hazard Ratio>1.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v TAK-954 0.5 mg/100 mL + Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.507 ^[4]

Method

Wald chi-square test

Parameter type

Hazard ratio (HR)

Point estimate

Confidence interval

level

90%

sides

2-sided

lower limit

0.69

upper limit

1.44

Notes
[4] - P-values were derived using a one-sided test with alternative hypothesis (Ha): Hazard Ratio>1.

Secondary: Time From the End of Surgery Until the Discharge Order is Written

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End point title

Time From the End of Surgery Until the Discharge Order is Written

End point description

Kaplan-Meier survival analysis method was used. FAS included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid postbaseline on-treatment primary efficacy evaluation (bowel movement or tolerating solid food).

End point type

Secondary

End point timeframe

Day 1 (surgery) up to Day 24

End point values	Placebo	TAK-954 0.1 mg/100 mL	TAK-954 0.5 mg/100 mL	TAK-954 0.1 mg/100 mL + Placebo	TAK-954 0.5 mg/100 mL + Placebo
Number of subjects analysed	45	23	42	21	44
Units: days
median (full range (min-max))	2.86 (1.62 to 16.72)	3.95 (1.88 to 10.89)	2.81 (0.89 to 11.09)	2.94 (1.47 to 7.81)	3.33 (1.56 to 14.74)

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo v TAK-954 0.5 mg/100 mL

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.406 ^[5]

Method

Wald chi-square test

Parameter type

Hazard ratio (HR)

Point estimate

1.05

Confidence interval

level

90%

sides

2-sided

lower limit

0.73

upper limit

1.52

Notes
[5] - P-values were derived using a one-sided test with alternative hypothesis (Ha): Hazard Ratio>1.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v TAK-954 0.5 mg/100 mL + Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.88 ^[6]

Method

Wald chi-square test

Parameter type

Hazard ratio (HR)

Point estimate

0.77

Confidence interval

level

90%

sides

2-sided

lower limit

0.54

upper limit

1.11

Notes
[6] - P-values were derived using a one-sided test with alternative hypothesis (Ha): Hazard Ratio>1.

Secondary: Time From the End of Surgery to Discharge From Hospital

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End point title

Time From the End of Surgery to Discharge From Hospital

End point description

End point type

Secondary

End point timeframe

Day 1 (surgery) up to Day 24

End point values	Placebo	TAK-954 0.1 mg/100 mL	TAK-954 0.5 mg/100 mL	TAK-954 0.1 mg/100 mL + Placebo	TAK-954 0.5 mg/100 mL + Placebo
Number of subjects analysed	45	23	42	21	44
Units: days
median (full range (min-max))	2.96 (1.72 to 16.76)	4.06 (1.97 to 10.89)	2.89 (1.00 to 11.11)	3.05 (1.58 to 7.83)	3.39 (1.70 to 14.77)

Satistical Analysis 1

Statistical analysis description

Comparison groups

Placebo v TAK-954 0.5 mg/100 mL

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.446 ^[7]

Method

Wald chi-square test

Parameter type

Hazard ratio (HR)

Point estimate

1.03

Confidence interval

level

90%

sides

2-sided

lower limit

0.72

upper limit

1.48

Notes
[7] - P-values were derived using a one-sided test with alternative hypothesis (Ha): Hazard Ratio>1.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v TAK-954 0.5 mg/100 mL + Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.892 ^[8]

Method

Wald chi-square test

Parameter type

Hazard ratio (HR)

Point estimate

0.76

Confidence interval

level

90%

sides

2-sided

lower limit

0.53

upper limit

1.09

Notes
[8] - P-values were derived using a one-sided test with alternative hypothesis (Ha): Hazard Ratio>1.

Secondary: Time From End of Surgery to Tolerance of Solid Food as Assessed by the Investigator

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End point title

Time From End of Surgery to Tolerance of Solid Food as Assessed by the Investigator

End point description

The time from end of surgery to tolerance of solid food was defined as intake of solids without vomiting or clinically significant nausea for 1 calendar day after a solid meal. Kaplan-Meier survival analysis method was used. FAS included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid postbaseline on-treatment primary efficacy evaluation (bowel movement or tolerating solid food).

End point type

Secondary

End point timeframe

Day 1 (surgery) up to Day 10 postsurgery

End point values	Placebo	TAK-954 0.1 mg/100 mL	TAK-954 0.5 mg/100 mL	TAK-954 0.1 mg/100 mL + Placebo	TAK-954 0.5 mg/100 mL + Placebo
Number of subjects analysed	45	23	42	21	44
Units: days
median (full range (min-max))	1.82 (1.41 to 5.79)	2.76 (1.51 to 7.85)	2.36 (0.74 to 4.97)	2.15 (1.13 to 7.59)	2.55 (1.32 to 7.74)

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo v TAK-954 0.5 mg/100 mL

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.76 ^[9]

Method

Wald chi-square test

Parameter type

Hazard ratio (HR)

Point estimate

0.86

Confidence interval

level

90%

sides

2-sided

lower limit

0.6

upper limit

1.23

Notes
[9] - P-values were derived using a one-sided test with alternative hypothesis (Ha): Hazard Ratio>1.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v TAK-954 0.5 mg/100 mL + Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.81 ^[10]

Method

Wald chi-square test

Parameter type

Hazard ratio (HR)

Point estimate

0.83

Confidence interval

level

90%

sides

2-sided

lower limit

0.58

upper limit

1.18

Notes
[10] - P-values were derived using a one-sided test with alternative hypothesis (Ha): Hazard Ratio>1.

Secondary: Time From End of Surgery to First Spontaneous Bowel Movement as Assessed by the Investigator

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End point title

Time From End of Surgery to First Spontaneous Bowel Movement as Assessed by the Investigator

End point description

The time from end of surgery to first spontaneous bowel movement was defined as a stool not induced by the use of enemas or laxatives. Kaplan-Meier survival analysis method was used. FAS included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid postbaseline on-treatment primary efficacy evaluation (bowel movement or tolerating solid food).

End point type

Secondary

End point timeframe

Day 1 (surgery) up to Day 10 postsurgery

End point values	Placebo	TAK-954 0.1 mg/100 mL	TAK-954 0.5 mg/100 mL	TAK-954 0.1 mg/100 mL + Placebo	TAK-954 0.5 mg/100 mL + Placebo
Number of subjects analysed	45	23	42	21	44
Units: days
median (full range (min-max))	1.56 (0.16 to 7.89)	1.73 (0.11 to 3.81)	1.11 (0.08 to 4.82)	1.72 (0.20 to 3.23)	1.74 (0.53 to 4.94)

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v TAK-954 0.5 mg/100 mL + Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.453 ^[11]

Method

Wald chi-square test

Parameter type

Hazard ratio (HR)

Point estimate

1.03

Confidence interval

level

90%

sides

2-sided

lower limit

0.72

upper limit

1.47

Notes
[11] - P-values were derived using a one-sided test with alternative hypothesis (Ha): Hazard Ratio>1.

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo v TAK-954 0.5 mg/100 mL

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.288 ^[12]

Method

Wald chi-square test

Parameter type

Hazard ratio (HR)

Point estimate

1.13

Confidence interval

level

90%

sides

2-sided

lower limit

0.78

upper limit

1.64

Notes
[12] - P-values were derived using a one-sided test with alternative hypothesis (Ha): Hazard Ratio>1.

Secondary: Percentage of Participants with Postoperative Gastrointestinal Dysfunction (POGD) >= 5 Days as Assessed by the Investigator

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End point title

Percentage of Participants with Postoperative Gastrointestinal Dysfunction (POGD) >= 5 Days as Assessed by the Investigator

End point description

Participants unable to tolerate solid foods, take anything by mouth, or requiring insertion or reinsertion of nasogastric (NG) tube at or after 5 days post-surgery. Percentages are rounded off to whole number at the nearest single decimal. Stratified Miettinen and Nurminen approach was used for analysis. FAS included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid postbaseline on-treatment primary efficacy evaluation (bowel movement or tolerating solid food).

End point type

Secondary

End point timeframe

Day 1 (surgery) up to Day 10

End point values	Placebo	TAK-954 0.1 mg/100 mL	TAK-954 0.5 mg/100 mL	TAK-954 0.1 mg/100 mL + Placebo	TAK-954 0.5 mg/100 mL + Placebo
Number of subjects analysed	45	23	42	21	44
Units: percentage of participants
number (not applicable)	8.9	8.7	2.4	4.8	9.1

Statistical Analysis 2

Statistical analysis description

The p-values, risk differences and corresponding 90% CIs were obtained using a stratified Miettinen and Nurminen approach with strata weighting by sample size.

Comparison groups

Placebo v TAK-954 0.5 mg/100 mL + Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.516 ^[13]

Method

Stratified Miettinen and Nurminen

Parameter type

Risk difference (RD)

Point estimate

Confidence interval

level

90%

sides

2-sided

lower limit

-0.11

upper limit

0.11

Notes
[13] - P-value was derived using a one-sided test with Ha: Risk Difference<0.

Statistical Analysis 1

Statistical analysis description

The p-values, risk differences and corresponding 90% CIs were obtained using a stratified Miettinen and Nurminen approach with strata weighting by sample size.

Comparison groups

Placebo v TAK-954 0.5 mg/100 mL

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.046 ^[14]

Method

Stratified Miettinen and Nurminen

Parameter type

Risk difference (RD)

Point estimate

-0.09

Confidence interval

level

90%

sides

2-sided

lower limit

-0.17

upper limit

Notes
[14] - P-value was derived using a one-sided test with Ha: Risk Difference<0.

Secondary: Percentage of Participants Requiring Insertion of Nasogastric (NG) Tube Postsurgery

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End point title

Percentage of Participants Requiring Insertion of Nasogastric (NG) Tube Postsurgery

End point description

Participants who required insertion of NG tube postsurgery for drainage and symptom relief in case of persistent nausea and vomiting postsurgery were observed. Percentages are rounded off to whole number at the nearest single decimal. Stratified Miettinen and Nurminen approach was used for analysis. FAS included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid postbaseline on-treatment primary efficacy evaluation (bowel movement or tolerating solid food).

End point type

Secondary

End point timeframe

Day 1 (surgery) up to Day 24 postsurgery (10 days of treatment period postsurgery plus 14-day observation period post last dose for recurrence of symptoms)

End point values	Placebo	TAK-954 0.1 mg/100 mL	TAK-954 0.5 mg/100 mL	TAK-954 0.1 mg/100 mL + Placebo	TAK-954 0.5 mg/100 mL + Placebo
Number of subjects analysed	45	23	42	21	44
Units: percentage of participants
number (not applicable)	8.9	0.0	4.8	4.8	11.4

Statistical Analysis 2

Statistical analysis description

The p-values, risk differences and corresponding 90% CIs were obtained using a stratified Miettinen and Nurminen approach with strata weighting by sample size.

Comparison groups

Placebo v TAK-954 0.5 mg/100 mL + Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.677 ^[15]

Method

Stratified Miettinen and Nurminen

Parameter type

Risk difference (RD)

Point estimate

0.03

Confidence interval

level

90%

sides

2-sided

lower limit

-0.07

upper limit

0.13

Notes
[15] - P-value was derived using a one-sided test with Ha: Risk Difference<0.

Statistical Analysis 1

Statistical analysis description

The p-values, risk differences and corresponding 90% CIs were obtained using a stratified Miettinen and Nurminen approach with strata weighting by sample size.

Comparison groups

Placebo v TAK-954 0.5 mg/100 mL

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.296 ^[16]

Method

Stratified Miettinen and Nurminen

Parameter type

Risk difference (RD)

Point estimate

-0.03

Confidence interval

level

90%

sides

2-sided

lower limit

-0.12

upper limit

0.06

Notes
[16] - P-value was derived using a one-sided test with Ha: Risk Difference<0.

Secondary: Time From End of Surgery to First Flatus

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End point title

Time From End of Surgery to First Flatus

End point description

End point type

Secondary

End point timeframe

Day 1 (surgery) up to first flatus (up to Day 10 postsurgery)

End point values	Placebo	TAK-954 0.1 mg/100 mL	TAK-954 0.5 mg/100 mL	TAK-954 0.1 mg/100 mL + Placebo	TAK-954 0.5 mg/100 mL + Placebo
Number of subjects analysed	45	23	42	21	44
Units: days
median (full range (min-max))	1.21 (0.06 to 6.22)	1.26 (0.28 to 7.62)	0.96 (0.08 to 3.04)	1.18 (0.20 to 2.82)	1.12 (0.02 to 3.88)

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo v TAK-954 0.5 mg/100 mL

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.338 ^[17]

Method

Wald chi-square test

Parameter type

Hazard ratio (HR)

Point estimate

1.1

Confidence interval

level

90%

sides

2-sided

lower limit

0.76

upper limit

1.57

Notes
[17] - P-values were derived using a one-sided test with alternative hypothesis (Ha): Hazard Ratio>1.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v TAK-954 0.5 mg/100 mL + Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.422 ^[18]

Method

Wald chi-square test

Parameter type

Hazard ratio (HR)

Point estimate

1.04

Confidence interval

level

90%

sides

2-sided

lower limit

0.73

upper limit

1.49

Notes
[18] - P-values were derived using a one-sided test with alternative hypothesis (Ha): Hazard Ratio>1.

Secondary: Observed Plasma Concentration of TAK-954 at the End of Infusion on Day 1

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End point title

Observed Plasma Concentration of TAK-954 at the End of Infusion on Day 1 ^[19]

End point description

PK Analysis Set included all participants who were randomized, received at least 1 dose and had at least 1 measurable post-dose plasma for TAK-954. Overall number analyzed is the number of participants with data available for analyses.

End point type

Secondary

End point timeframe

Day 1 (surgery): postinfusion

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: As pre-specified in the statistical analysis plan, only drug-treated arms were to be analysed in this endpoint.

End point values	TAK-954 0.1 mg/100 mL	TAK-954 0.5 mg/100 mL	TAK-954 0.1 mg/100 mL + Placebo	TAK-954 0.5 mg/100 mL + Placebo
Number of subjects analysed	20	33	20	35
Units: picograms per milliliter (pg/mL)
arithmetic mean (standard deviation)	1190 ( 480 )	5220 ( 1810 )	2500 ( 4140 )	12000 ( 28500 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose of study drug up to Day 100

Adverse event reporting additional description

At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

Placebo

Reporting group description

Reporting group title

TAK-954 0.1 mg/100 mL

Reporting group description

TAK-954 0.1 milligrams per 100 milliliters (mg/100 mL), 60-minute infusion, IV, once presurgery on Day 1 and once daily postsurgery until return of upper and lower GI function or for up to 10 days.

Reporting group title

TAK-954 0.5 mg/100 mL + Placebo

Reporting group description

TAK-954 0.5 mg/100 mL, 60-minute infusion, IV, once presurgery on Day 1 and once daily placebo infusions postsurgery up to Day 10 or until resolution of upper and lower GI function.

Reporting group title

TAK-954 0.1 mg/100 mL + Placebo

Reporting group description

TAK-954 0.1 mg/100 mL, 60-minute infusion, IV, once presurgery on Day 1 and once daily placebo infusions postsurgery up to Day 10 or until resolution of upper and lower GI function.

Reporting group title

TAK-954 0.5 mg/100 mL

Reporting group description

TAK-954 0.5 mg/100 mL, 60-minute infusion, IV, once presurgery on Day 1 and once daily postsurgery until return of upper and lower GI function or for up to 10 days.

Serious adverse events	Placebo	TAK-954 0.1 mg/100 mL	TAK-954 0.5 mg/100 mL + Placebo	TAK-954 0.1 mg/100 mL + Placebo	TAK-954 0.5 mg/100 mL
Total subjects affected by serious adverse events
subjects affected / exposed	8 / 49 (16.33%)	9 / 26 (34.62%)	11 / 50 (22.00%)	2 / 25 (8.00%)	8 / 48 (16.67%)
number of deaths (all causes)	0	0	1	0	0
number of deaths resulting from adverse events	0	0	0	0	0
Injury, poisoning and procedural complications
Gastrointestinal stoma complication
subjects affected / exposed	1 / 49 (2.04%)	0 / 26 (0.00%)	0 / 50 (0.00%)	0 / 25 (0.00%)	0 / 48 (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
Anastomotic leak
subjects affected / exposed	2 / 49 (4.08%)	1 / 26 (3.85%)	1 / 50 (2.00%)	0 / 25 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	0 / 49 (0.00%)	0 / 26 (0.00%)	0 / 50 (0.00%)	1 / 25 (4.00%)	0 / 48 (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
Wound evisceration
subjects affected / exposed	0 / 49 (0.00%)	0 / 26 (0.00%)	1 / 50 (2.00%)	0 / 25 (0.00%)	0 / 48 (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
Postoperative ileus
subjects affected / exposed	1 / 49 (2.04%)	1 / 26 (3.85%)	5 / 50 (10.00%)	0 / 25 (0.00%)	2 / 48 (4.17%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 5	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative delirium
subjects affected / exposed	0 / 49 (0.00%)	0 / 26 (0.00%)	0 / 50 (0.00%)	0 / 25 (0.00%)	1 / 48 (2.08%)
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
Cardiac disorders
Cardiac arrest
subjects affected / exposed	0 / 49 (0.00%)	0 / 26 (0.00%)	0 / 50 (0.00%)	0 / 25 (0.00%)	1 / 48 (2.08%)
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
General disorders and administration site conditions
Dehiscence
subjects affected / exposed	1 / 49 (2.04%)	0 / 26 (0.00%)	0 / 50 (0.00%)	0 / 25 (0.00%)	0 / 48 (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
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 49 (0.00%)	0 / 26 (0.00%)	1 / 50 (2.00%)	0 / 25 (0.00%)	0 / 48 (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
Colitis
subjects affected / exposed	0 / 49 (0.00%)	0 / 26 (0.00%)	1 / 50 (2.00%)	0 / 25 (0.00%)	0 / 48 (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
Crohn's disease
subjects affected / exposed	1 / 49 (2.04%)	0 / 26 (0.00%)	0 / 50 (0.00%)	0 / 25 (0.00%)	0 / 48 (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
Diarrhoea
subjects affected / exposed	0 / 49 (0.00%)	0 / 26 (0.00%)	1 / 50 (2.00%)	0 / 25 (0.00%)	0 / 48 (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
Duodenitis
subjects affected / exposed	1 / 49 (2.04%)	0 / 26 (0.00%)	0 / 50 (0.00%)	0 / 25 (0.00%)	0 / 48 (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
Haematochezia
subjects affected / exposed	1 / 49 (2.04%)	0 / 26 (0.00%)	1 / 50 (2.00%)	0 / 25 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intra-abdominal fluid collection
subjects affected / exposed	0 / 49 (0.00%)	0 / 26 (0.00%)	1 / 50 (2.00%)	0 / 25 (0.00%)	0 / 48 (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
Ileus
subjects affected / exposed	0 / 49 (0.00%)	1 / 26 (3.85%)	0 / 50 (0.00%)	0 / 25 (0.00%)	0 / 48 (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
Intra-abdominal haemorrhage
subjects affected / exposed	0 / 49 (0.00%)	1 / 26 (3.85%)	0 / 50 (0.00%)	0 / 25 (0.00%)	0 / 48 (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
Rectal haemorrhage
subjects affected / exposed	0 / 49 (0.00%)	0 / 26 (0.00%)	1 / 50 (2.00%)	0 / 25 (0.00%)	0 / 48 (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
Mechanical ileus
subjects affected / exposed	0 / 49 (0.00%)	1 / 26 (3.85%)	0 / 50 (0.00%)	0 / 25 (0.00%)	0 / 48 (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
Small intestinal perforation
subjects affected / exposed	0 / 49 (0.00%)	1 / 26 (3.85%)	0 / 50 (0.00%)	0 / 25 (0.00%)	0 / 48 (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
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	0 / 49 (0.00%)	1 / 26 (3.85%)	0 / 50 (0.00%)	0 / 25 (0.00%)	0 / 48 (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
Pleural effusion
subjects affected / exposed	0 / 49 (0.00%)	0 / 26 (0.00%)	0 / 50 (0.00%)	0 / 25 (0.00%)	1 / 48 (2.08%)
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
Pulmonary embolism
subjects affected / exposed	0 / 49 (0.00%)	0 / 26 (0.00%)	0 / 50 (0.00%)	0 / 25 (0.00%)	1 / 48 (2.08%)
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
Skin and subcutaneous tissue disorders
Drug reaction with eosinophilia and systemic symptoms
subjects affected / exposed	0 / 49 (0.00%)	1 / 26 (3.85%)	0 / 50 (0.00%)	0 / 25 (0.00%)	0 / 48 (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
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 49 (0.00%)	0 / 26 (0.00%)	0 / 50 (0.00%)	1 / 25 (4.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prerenal failure
subjects affected / exposed	1 / 49 (2.04%)	0 / 26 (0.00%)	0 / 50 (0.00%)	0 / 25 (0.00%)	0 / 48 (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
Urinoma
subjects affected / exposed	0 / 49 (0.00%)	0 / 26 (0.00%)	0 / 50 (0.00%)	0 / 25 (0.00%)	1 / 48 (2.08%)
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
Infections and infestations
Abdominal abscess
subjects affected / exposed	1 / 49 (2.04%)	0 / 26 (0.00%)	0 / 50 (0.00%)	0 / 25 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 49 (0.00%)	0 / 26 (0.00%)	0 / 50 (0.00%)	0 / 25 (0.00%)	1 / 48 (2.08%)
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
Postoperative wound infection
subjects affected / exposed	0 / 49 (0.00%)	0 / 26 (0.00%)	1 / 50 (2.00%)	0 / 25 (0.00%)	0 / 48 (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
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	0 / 49 (0.00%)	1 / 26 (3.85%)	0 / 50 (0.00%)	0 / 25 (0.00%)	0 / 48 (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	Placebo	TAK-954 0.1 mg/100 mL	TAK-954 0.5 mg/100 mL + Placebo	TAK-954 0.1 mg/100 mL + Placebo	TAK-954 0.5 mg/100 mL
Total subjects affected by non serious adverse events
subjects affected / exposed	46 / 49 (93.88%)	23 / 26 (88.46%)	41 / 50 (82.00%)	21 / 25 (84.00%)	39 / 48 (81.25%)
Investigations
Electrocardiogram QT prolonged
subjects affected / exposed	1 / 49 (2.04%)	1 / 26 (3.85%)	4 / 50 (8.00%)	1 / 25 (4.00%)	1 / 48 (2.08%)
occurrences all number	1	1	4	1	1
Urine output decreased
subjects affected / exposed	1 / 49 (2.04%)	0 / 26 (0.00%)	3 / 50 (6.00%)	0 / 25 (0.00%)	2 / 48 (4.17%)
occurrences all number	1	0	3	0	2
Injury, poisoning and procedural complications
Anaemia postoperative
subjects affected / exposed	6 / 49 (12.24%)	1 / 26 (3.85%)	5 / 50 (10.00%)	2 / 25 (8.00%)	9 / 48 (18.75%)
occurrences all number	6	1	5	2	9
Postoperative ileus
subjects affected / exposed	3 / 49 (6.12%)	1 / 26 (3.85%)	1 / 50 (2.00%)	1 / 25 (4.00%)	0 / 48 (0.00%)
occurrences all number	3	1	1	1	0
Procedural complication
subjects affected / exposed	3 / 49 (6.12%)	1 / 26 (3.85%)	0 / 50 (0.00%)	0 / 25 (0.00%)	1 / 48 (2.08%)
occurrences all number	3	1	0	0	1
Procedural hypotension
subjects affected / exposed	15 / 49 (30.61%)	0 / 26 (0.00%)	10 / 50 (20.00%)	0 / 25 (0.00%)	9 / 48 (18.75%)
occurrences all number	16	0	10	0	9
Procedural hypertension
subjects affected / exposed	5 / 49 (10.20%)	0 / 26 (0.00%)	1 / 50 (2.00%)	0 / 25 (0.00%)	4 / 48 (8.33%)
occurrences all number	5	0	1	0	4
Procedural nausea
subjects affected / exposed	3 / 49 (6.12%)	1 / 26 (3.85%)	2 / 50 (4.00%)	1 / 25 (4.00%)	1 / 48 (2.08%)
occurrences all number	3	1	2	1	1
Procedural pain
subjects affected / exposed	4 / 49 (8.16%)	5 / 26 (19.23%)	4 / 50 (8.00%)	4 / 25 (16.00%)	2 / 48 (4.17%)
occurrences all number	4	5	4	4	2
Vascular disorders
Hypertension
subjects affected / exposed	6 / 49 (12.24%)	1 / 26 (3.85%)	7 / 50 (14.00%)	0 / 25 (0.00%)	7 / 48 (14.58%)
occurrences all number	7	1	7	0	7
Hypotension
subjects affected / exposed	3 / 49 (6.12%)	0 / 26 (0.00%)	4 / 50 (8.00%)	0 / 25 (0.00%)	4 / 48 (8.33%)
occurrences all number	3	0	4	0	4
Cardiac disorders
Bradycardia
subjects affected / exposed	3 / 49 (6.12%)	0 / 26 (0.00%)	2 / 50 (4.00%)	0 / 25 (0.00%)	3 / 48 (6.25%)
occurrences all number	4	0	3	0	3
Tachycardia
subjects affected / exposed	5 / 49 (10.20%)	1 / 26 (3.85%)	3 / 50 (6.00%)	0 / 25 (0.00%)	2 / 48 (4.17%)
occurrences all number	7	1	3	0	2
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	7 / 49 (14.29%)	1 / 26 (3.85%)	4 / 50 (8.00%)	2 / 25 (8.00%)	6 / 48 (12.50%)
occurrences all number	7	1	4	2	6
Leukocytosis
subjects affected / exposed	6 / 49 (12.24%)	1 / 26 (3.85%)	4 / 50 (8.00%)	0 / 25 (0.00%)	4 / 48 (8.33%)
occurrences all number	6	1	5	0	4
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	3 / 49 (6.12%)	3 / 26 (11.54%)	0 / 50 (0.00%)	0 / 25 (0.00%)	2 / 48 (4.17%)
occurrences all number	4	3	0	0	2
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	2 / 49 (4.08%)	0 / 26 (0.00%)	1 / 50 (2.00%)	2 / 25 (8.00%)	2 / 48 (4.17%)
occurrences all number	3	0	1	2	2
Abdominal distension
subjects affected / exposed	5 / 49 (10.20%)	1 / 26 (3.85%)	5 / 50 (10.00%)	1 / 25 (4.00%)	5 / 48 (10.42%)
occurrences all number	5	1	5	1	6
Constipation
subjects affected / exposed	1 / 49 (2.04%)	2 / 26 (7.69%)	1 / 50 (2.00%)	1 / 25 (4.00%)	0 / 48 (0.00%)
occurrences all number	1	2	1	1	0
Diarrhoea
subjects affected / exposed	7 / 49 (14.29%)	3 / 26 (11.54%)	7 / 50 (14.00%)	2 / 25 (8.00%)	11 / 48 (22.92%)
occurrences all number	7	3	7	3	11
Dyspepsia
subjects affected / exposed	0 / 49 (0.00%)	4 / 26 (15.38%)	1 / 50 (2.00%)	0 / 25 (0.00%)	2 / 48 (4.17%)
occurrences all number	0	4	1	0	2
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 49 (4.08%)	0 / 26 (0.00%)	2 / 50 (4.00%)	3 / 25 (12.00%)	0 / 48 (0.00%)
occurrences all number	2	0	2	3	0
Nausea
subjects affected / exposed	22 / 49 (44.90%)	14 / 26 (53.85%)	19 / 50 (38.00%)	12 / 25 (48.00%)	20 / 48 (41.67%)
occurrences all number	35	16	24	15	23
Vomiting
subjects affected / exposed	14 / 49 (28.57%)	8 / 26 (30.77%)	11 / 50 (22.00%)	9 / 25 (36.00%)	8 / 48 (16.67%)
occurrences all number	20	9	11	10	9
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
subjects affected / exposed	2 / 49 (4.08%)	1 / 26 (3.85%)	3 / 50 (6.00%)	0 / 25 (0.00%)	1 / 48 (2.08%)
occurrences all number	2	1	3	0	1
Renal and urinary disorders
Urinary retention
subjects affected / exposed	4 / 49 (8.16%)	3 / 26 (11.54%)	1 / 50 (2.00%)	2 / 25 (8.00%)	0 / 48 (0.00%)
occurrences all number	4	3	1	2	0
Infections and infestations
Urinary tract infection
subjects affected / exposed	0 / 49 (0.00%)	0 / 26 (0.00%)	3 / 50 (6.00%)	1 / 25 (4.00%)	0 / 48 (0.00%)
occurrences all number	0	0	3	1	0
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	4 / 49 (8.16%)	0 / 26 (0.00%)	3 / 50 (6.00%)	0 / 25 (0.00%)	3 / 48 (6.25%)
occurrences all number	4	0	3	0	3
Hypocalcaemia
subjects affected / exposed	10 / 49 (20.41%)	1 / 26 (3.85%)	7 / 50 (14.00%)	1 / 25 (4.00%)	10 / 48 (20.83%)
occurrences all number	10	1	7	1	10
Hypophosphataemia
subjects affected / exposed	3 / 49 (6.12%)	5 / 26 (19.23%)	4 / 50 (8.00%)	1 / 25 (4.00%)	3 / 48 (6.25%)
occurrences all number	3	5	4	1	3
Hypomagnesaemia
subjects affected / exposed	2 / 49 (4.08%)	4 / 26 (15.38%)	7 / 50 (14.00%)	1 / 25 (4.00%)	3 / 48 (6.25%)
occurrences all number	2	4	7	1	3
Hypokalaemia
subjects affected / exposed	6 / 49 (12.24%)	5 / 26 (19.23%)	5 / 50 (10.00%)	4 / 25 (16.00%)	2 / 48 (4.17%)
occurrences all number	6	5	5	4	2

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Were there any global substantial amendments to the protocol? Yes

09 Jul 2019

Following changes were implemented with Protocol Amendment 4: -Incorporated individual country amendments (Germany’s Bundesinstitut für Arzneimittel und Medizinprodukte [BfArM] and Belgium’s Federal Agency for Medicines and Health Products) containing responses to their regulatory reviews. -Added changes to address operational issues and an updated list of prohibited medicines as a consequence of new data supporting the absence of direct evidence suggesting a relationship between selective 5-hydroxytryptamine receptor 4 (5-HT4) agonist and serotonin syndrome. -Clarified end of the surgery. -Corrected of the collection of a peak nausea severity score. -Clarified the maximum dose that will be used for this study. -Added the justification for a maximum dose of 1.0 mg TAK-954. -Added definition for the end of the study. -Deleted “subject’s legally acceptable representative”. -Clarified who can review an electrocardiogram (ECG) for inclusion into the study. -Revised the timeframe for excluded medications. -Clarified laxative use. -Removed medications associated with serotonin syndrome. -Clarified drug dosing in relation to surgery delays. -Clarified the use of the interactive response technology (IRT). -Clarified the procedure for clinically significant physical examination changes. -Added collection of approximate length of bowel removed during surgery. -Clarified the clinical assessments.

22 Mar 2021

Following changes were implemented with Protocol Amendment 5: -Revised to reflect the total sample size for the study. -Added new figure to indicate study design. -Clarified the secondary objective. -Specified time window for study drug dosing for the secondary objective. -Refined the definition of the primary efficacy endpoint time. -Clarified the timing for participants requiring NG tubes postsurgery and clarified plasma TAK-954 concentrations will be measured. -Removed minimum percentage of participants required for each surgery type. -Revised sample size of remaining arms based on blinded assessments. -Revised the language. -Modified protocol for impact of coronavirus disease-19 (COVID-19). -Defined time assessment windows for the follow-up visit. -Revised inclusion and exclusion criteria. -Revised study withdrawal. -Revised liver function tests to liver tests. -Added the possibility that the participant may withdraw from the study or study drug. -Updated wording. - Added definitions. -Clarified primary and secondary efficacy analyses. -Added clarification and specification that sites should make every effort to conduct follow-up assessments. -Revised to clarify that all medications are to be collected and not just excluded medications. -Clarified timing of assessments. -Defined timing of study procedure. -Clarified study procedures.

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Time From End of the Surgery to Resolution of Upper and Lower Gastrointestinal (GI) Function Postsurgery as Assessed by the Investigator

Primary: Time From End of the Surgery to Resolution of Upper and Lower Gastrointestinal (GI) Function Postsurgery as Assessed by the Investigator

Secondary: Time From the End of the Surgery (Time the Incision is Closed) Until Ready for Discharge as Assessed by the Investigator

Secondary: Time From the End of the Surgery (Time the Incision is Closed) Until Ready for Discharge as Assessed by the Investigator

Secondary: Time From the End of Surgery Until the Discharge Order is Written

Secondary: Time From the End of Surgery Until the Discharge Order is Written

Secondary: Time From the End of Surgery to Discharge From Hospital

Secondary: Time From the End of Surgery to Discharge From Hospital

Secondary: Time From End of Surgery to Tolerance of Solid Food as Assessed by the Investigator

Secondary: Time From End of Surgery to Tolerance of Solid Food as Assessed by the Investigator

Secondary: Time From End of Surgery to First Spontaneous Bowel Movement as Assessed by the Investigator

Secondary: Time From End of Surgery to First Spontaneous Bowel Movement as Assessed by the Investigator

Secondary: Percentage of Participants with Postoperative Gastrointestinal Dysfunction (POGD) >= 5 Days as Assessed by the Investigator

Secondary: Percentage of Participants with Postoperative Gastrointestinal Dysfunction (POGD) >= 5 Days as Assessed by the Investigator

Secondary: Percentage of Participants Requiring Insertion of Nasogastric (NG) Tube Postsurgery

Secondary: Percentage of Participants Requiring Insertion of Nasogastric (NG) Tube Postsurgery

Secondary: Time From End of Surgery to First Flatus

Secondary: Time From End of Surgery to First Flatus

Secondary: Observed Plasma Concentration of TAK-954 at the End of Infusion on Day 1

Secondary: Observed Plasma Concentration of TAK-954 at the End of Infusion on Day 1

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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