TAK-954 in Critically Ill Participants With Enteral Feeding Intolerance (EFI)

• Sponsor: Millennium Pharmaceuticals, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03477903
• Collaborator: (none)
• Enrollment: 1
• Locations: 44
• Arms: 4
• Actual Duration (Days): 4
• Patients Per Site: 0
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the treatment effect of intravenous TAK-954 in improving the average daily protein adequacy received through enteral nutrition in critically-ill participants developing EFI.

Condition or Disease	Intervention/Treatment	Phase
Critical Illness; Enteral Nutrition; Enteral Feeding Intolerance	Drug: TAK-954; Drug: Metoclopramide; Drug: Normal Saline	Phase 2

Detailed Description

The drug being tested in this study is called TAK-954. The study will assess the treatment effect of intravenous TAK-954 in improving average daily protein adequacy received through enteral nutrition in critically ill participants with EFI.

The study will enroll approximately 200 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the 4 treatment groups -which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

• Group A: TAK-954 0.1 mg

• Group B: TAK-954 0.3 mg

• Group C: TAK-954 1 mg

• Group D: Metoclopramide 10 mg

This multi-center trial will be conducted in the United States, United Kingdom, Australia and Canada. The overall duration of treatment in this study is maximum of 14 days while in hospital. Participants will be contacted by telephone 30 and 90 days after receiving their last dose of study drug for a follow-up assessment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2b, Randomized, Multi-Center, Double-Blind, Dose-Ranging Study to Assess the Efficacy, Safety and Pharmacokinetics of Intravenous TAK-954 in Critically Ill Patients With Enteral Feeding Intolerance
• Actual Study Start Date: Aug 25, 2018
• Actual Primary Completion Date: Aug 29, 2018
• Actual Study Completion Date: Aug 29, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group A: TAK-954 0.1 mg TAK-954 0.1 milligram (mg), intravenously, administered as 60 minute-infusion, once daily along with 2 milliliter (mL) normal saline injection, intravenously, three times a day for a minimum of 5 days up to a maximum of 14 days.	Drug: TAK-954; TAK-954 infusion; Drug: Normal Saline; 0.9% sodium chloride for injection
Experimental: Group B: TAK-954 0.3 mg TAK-954 0.3 mg, intravenously, administered as 60 minute-infusion, once daily along with 2 mL normal saline injection, intravenously, three times a day for a minimum of 5 days up to a maximum of 14 days.	Drug: TAK-954; TAK-954 infusion; Drug: Normal Saline; 0.9% sodium chloride for injection
Experimental: Group C: TAK-954 1.0 mg TAK-954 1.0 mg, intravenously, administered as 60 minute-infusion, once daily along with 2 mL normal saline injection, intravenously, three times a day for a minimum of 5 days up to a maximum of 14 days.	Drug: TAK-954; TAK-954 infusion; Drug: Normal Saline; 0.9% sodium chloride for injection
Active Comparator: Group D: Metoclopramide 10 mg Metoclopramide 10 mg, injection, intravenously, three times a day along with 100 mL normal saline 60-minute infusion, intravenously, once daily for a minimum of 5 days up to a maximum of 14 days.	Drug: Metoclopramide; Metoclopramide infusion; Drug: Normal Saline; 0.9% sodium chloride for injection

Outcome Measures

Primary Outcome Measures

1. Average Daily Protein Adequacy Over the First 5 Days of Treatment [Days 1 to 5]

   Average daily protein adequacy received through enteral nutrition is defined as the percentage of goal protein delivered per day, where percentage of goal protein delivered is calculated as the ratio of actual protein achievement to the total participant-specific target protein prescribed. The value for each of the 5 days was averaged.

Secondary Outcome Measures

1. Average Daily Protein Adequacy Over the Study Treatment Period [Days 1 to 14]

   Average daily protein adequacy received through enteral nutrition is defined as percentage of goal protein delivered per day, where percentage of protein goal delivered is calculated as the ratio of actual protein achievement to the total participant-specific target protein prescribed. The value for each of the 14 days was averaged.

2. Average Daily Change in 24-hour Gastric Residual Volume (GRV) Over the First 5 Days of Study Treatment [Days 1 to 5]

   GRV is defined as the volume of fluid remaining in the stomach at a point in time during enteral nutrition feeding. The value for each of the 5 days was averaged.

3. Average Daily Caloric Adequacy [Days 1 to 5 and Days 1 to 14]

   Average daily caloric adequacy received through enteral nutrition was defined by percentage of goal calories achieved per day (percentage calorie goal achieved=actual calorie achievement/total participant-specific target calories). The values in the 5-day period and the 14-day period were averaged.

4. Time to Resolution of Enteral Feeding Intolerance (EFI) [Days 1 to 14 or until resolution of EFI, whichever occurs first]

   Time to resolution of EFI is defined as the time needed to achieve GRV less than or equal to 250 ml in the absence of vomiting/retching.

5. Percentage of Participants Achieving at Least 80% of Daily Goal Calories [Days 1 to 14 or end of treatment]

6. Percentage of Participants Achieving at Least 80% of Daily Goal Protein [Days 1 to 14 or end of treatment]

7. Ctrough: Observed Concentration at the End of a Dosing Interval of TAK-954 [Day 5 pre-dose]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Has at least a size 12-(french size) Fr nasogastric or orogastric tube with its tip at least 10 centimeter (cm) below the esophagogastric junction confirmed radiologically (the tip of the tube must be in the body or the antrum of the stomach and not in the fundus).

2. Is intubated and mechanically ventilated in the ICU.

3. Is expected to remain alive, mechanically ventilated, and receive continuous enteral feeding for >=48 hours following randomization.

4. Have EFI, defined as a single GRV measurement of >=250 mL with vomiting/retching within the last 24 hours, or a single GRV measurement of >=500 mL with or without vomiting/retching within the last 24 hours.

Exclusion Criteria:

1. Is under consideration for withdrawal of life-sustaining treatments within the next 72 hours.

2. Has had major esophageal or gastric surgery or direct luminal trauma on this admission (participants with lower abdominal surgery are not excluded unless enteral feeding is contraindicated).

3. Has mechanical bowel obstruction, short bowel syndrome, or the presence of an active gastric pacemaker.

4. Have pre-existing hepatic disease that meets Child-Pugh Class B (moderate; total score 7 to 9 points) or C (severe; total score 10 to 15 points).

5. Has been admitted primarily for treatment of a drug overdose.

6. Has a presence of a post-pyloric tube in place at Randomization that may be used for enteral nutrition.

7. Is receiving parenteral nutrition (PN) at Screening.

8. Is in diabetic ketoacidosis or non-ketotic hyperosmolar coma.

9. Has a different nutrient requirement than allowed in feeding protocol.(outside a range of 1.2 to 2 gram per kilogram per day [g/kg/day] of proteins and up to 1.5 kilocalorie per milliliter [kcal/mL]).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Joseph M Still Burn Centers	Augusta	Georgia	United States	30909
2	Eastern Idaho Medical Consultants	Idaho Falls	Idaho	United States	83404
3	Illinois Lung & Critical Care Institute	Peoria	Illinois	United States	61606
4	University of Kentucky Health Care	Lexington	Kentucky	United States	40536
5	Anne Arundel Medical Center	Annapolis	Maryland	United States	21401
6	Truman Medical Center Hospital Hill	Kansas City	Missouri	United States	64108
7	Creighton University	Omaha	Nebraska	United States	68124
8	Englewood Hospital and Medical Center	Englewood	New Jersey	United States	07631
9	New York-Presbyterian Columbia University Medical Center	New York	New York	United States	10032
10	Duke University Medical Center	Durham	North Carolina	United States	27705
11	Cleveland Clinic	Cleveland	Ohio	United States	44195
12	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
13	The University of Texas Health Science Center at Houston	Houston	Texas	United States	77030
14	Froedtert Hospital	Wauwatosa	Wisconsin	United States	53226
15	Royal North Shore Hospital	St. Leonards	New South Wales	Australia	2065
16	Royal Brisbane and Women's Hospital	Brisbane	Queensland	Australia	4029
17	Logan Hospital	Meadowbrook	Queensland	Australia	4131
18	Mater Hospital Brisbane	South Brisbane	Queensland	Australia	4101
19	Royal Adelaide Hospital	Adelaide	South Australia	Australia	5000
20	Flinders Medical Centre	Bedford Park	South Australia	Australia	5042
21	Monash Medical Centre	Clayton	Victoria	Australia	3168
22	The Northern Hospital	Epping	Victoria	Australia	3076
23	Frankston Hospital	Frankston	Victoria	Australia	3199
24	The Royal Melbourne Hospital	Parkville	Victoria	Australia	3050
25	Royal Columbian Hospital	New Westminster	British Columbia	Canada	V3L 3W4
26	St. Paul's Hospital	Vancouver	British Columbia	Canada	V6Z 1Y6
27	Kingston General Hospital	Kingston	Ontario	Canada	K7L 2V7
28	Hopital Charles-LeMoyne	Greenfield Park	Quebec	Canada	J4V 2H1
29	Hopital du Sacre-Coeur de Montreal	Monteal	Quebec	Canada	H4J 1C5
30	McGill University Health Centre	Montreal	Quebec	Canada	H4A 3J1
31	Centre Hospitalier Universitaire de Quebec Hospital Centre Hospitalier de IUniversite Laval	Quebec		Canada	G1V 4G5
32	University Hospitals Birmingham NHS Foundation Trust	Birmingham	England	United Kingdom	B15 2GW
33	Royal Sussex County Hospital	Brighton	England	United Kingdom	BN2 5BE
34	University Hospitals Bristol NHS Foundation Trust	Bristol	England	United Kingdom	BS2 8HW
35	The Leeds Teaching Hospitals NHS Trust	Leeds	England	United Kingdom	LS9 7TF
36	The Royal London Hospital	London	England	United Kingdom	E1 1BB
37	Royal Free London NHS Foundation Trust	London	England	United Kingdom	NW3 2QG
38	Guy's and Saint Thomas' NHS Foundation Trust	London	England	United Kingdom	SE1 7EH
39	King's College Hospital NHS Foundation Trust	London	England	United Kingdom	SE5 9RS
40	NHS Lothian	Edinburgh	Scotland	United Kingdom	EH16 4SB
41	NHS Greater Glasgow and Clyde	Glasgow	Scotland	United Kingdom	G42 9TY
42	Cardiff and Vale University Health Board	Cardiff	Wales	United Kingdom	CF14 4XN
43	Aneurin Bevan University Health Board	Newport	Wales	United Kingdom	NP20 2UB
44	Royal Liverpool University Hospital NHS Trust	Liverpool		United Kingdom

Sponsors and Collaborators

• Millennium Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Director, Millennium Pharmaceuticals, Inc.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 28, 2018

More Information

Publications

None provided.

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT03477903
• Other Study ID Numbers: TAK-954-2002; U1111-1208-1831; 2017-003206-41; 18/NE/0139
• First Posted: Mar 27, 2018
• Last Update Posted: Sep 24, 2019
• Last Verified: Sep 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Millennium Pharmaceuticals, Inc.: Drug therapy
• Additional relevant MeSH terms: Critical Illness; Metoclopramide

Study Results

Participant Flow

Recruitment Details	One participant took part in the study at an investigative site in the United States from 25-Aug-2018 to 29-Aug-2018.
Pre-assignment Detail	One participant with a diagnosis of Enteral Feeding Intolerance (EFI) was enrolled and received 0.1 mg of TAK-954. No participants were enrolled in the other 3 planned arms of the study.

Arm/Group Title	TAK-954 0.1 mg
Arm/Group Description	TAK-954 0.1 milligrams (mg), intravenously, administered as 60 minute-infusion, once daily along with 2 milliliters (mL) normal saline injection, intravenously, three times a day for a minimum of 5 days up to a maximum of 14 days.
Period Title: Overall Study
STARTED	1
COMPLETED	0
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	TAK-954 0.1 mg
Arm/Group Description	TAK-954 0.1 milligrams (mg), intravenously, administered as 60 minute-infusion, once daily along with 2 milliliters (mL) normal saline injection, intravenously, three times a day for a minimum of 5 days up to a maximum of 14 days.
Overall Participants	1
Age (years) [Mean (Standard Deviation) ]
Sex: Female, Male (Count of Participants)
Female
Male
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino
Not Hispanic or Latino
Unknown or Not Reported
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
Asian
Native Hawaiian or Other Pacific Islander
Black or African American
White
More than one race
Unknown or Not Reported
Region of Enrollment (Count of Participants)
United States	1 100%

Outcome Measures

1. Primary Outcome

Title	Average Daily Protein Adequacy Over the First 5 Days of Treatment
Description	Average daily protein adequacy received through enteral nutrition is defined as the percentage of goal protein delivered per day, where percentage of goal protein delivered is calculated as the ratio of actual protein achievement to the total participant-specific target protein prescribed. The value for each of the 5 days was averaged.
Time Frame	Days 1 to 5

Outcome Measure Data

Analysis Population Description

Due to the low number of participants enrolled at only 1 site, 0 participants are reported due to the risk of identification of a person.

Arm/Group Title	TAK-954 0.1 mg
Arm/Group Description	TAK-954 0.1 milligrams (mg), intravenously, administered as 60 minute-infusion, once daily along with 2 milliliters (mL) normal saline injection, intravenously, three times a day for a minimum of 5 days up to a maximum of 14 days.
Measure Participants	0

2. Secondary Outcome

Title	Average Daily Protein Adequacy Over the Study Treatment Period
Description	Average daily protein adequacy received through enteral nutrition is defined as percentage of goal protein delivered per day, where percentage of protein goal delivered is calculated as the ratio of actual protein achievement to the total participant-specific target protein prescribed. The value for each of the 14 days was averaged.
Time Frame	Days 1 to 14

Outcome Measure Data

Analysis Population Description

Due to the low number of participants enrolled at only 1 site, 0 participants are reported due to the risk of identification of a person.

Arm/Group Title	TAK-954 0.1 mg
Arm/Group Description	TAK-954 0.1 milligrams (mg), intravenously, administered as 60 minute-infusion, once daily along with 2 milliliters (mL) normal saline injection, intravenously, three times a day for a minimum of 5 days up to a maximum of 14 days.
Measure Participants	0

3. Secondary Outcome

Title	Average Daily Change in 24-hour Gastric Residual Volume (GRV) Over the First 5 Days of Study Treatment
Description	GRV is defined as the volume of fluid remaining in the stomach at a point in time during enteral nutrition feeding. The value for each of the 5 days was averaged.
Time Frame	Days 1 to 5

Outcome Measure Data

Analysis Population Description

Due to the low number of participants enrolled at only 1 site, 0 participants are reported due to the risk of identification of a person.

Arm/Group Title	TAK-954 0.1 mg
Arm/Group Description	TAK-954 0.1 milligrams (mg), intravenously, administered as 60 minute-infusion, once daily along with 2 milliliters (mL) normal saline injection, intravenously, three times a day for a minimum of 5 days up to a maximum of 14 days.
Measure Participants	0

4. Secondary Outcome

Title	Average Daily Caloric Adequacy
Description	Average daily caloric adequacy received through enteral nutrition was defined by percentage of goal calories achieved per day (percentage calorie goal achieved=actual calorie achievement/total participant-specific target calories). The values in the 5-day period and the 14-day period were averaged.
Time Frame	Days 1 to 5 and Days 1 to 14

Outcome Measure Data

Analysis Population Description

Due to the low number of participants enrolled at only 1 site, 0 participants are reported due to the risk of identification of a person.

Arm/Group Title	TAK-954 0.1 mg
Arm/Group Description	TAK-954 0.1 milligrams (mg), intravenously, administered as 60 minute-infusion, once daily along with 2 milliliters (mL) normal saline injection, intravenously, three times a day for a minimum of 5 days up to a maximum of 14 days.
Measure Participants	0

5. Secondary Outcome

Title	Time to Resolution of Enteral Feeding Intolerance (EFI)
Description	Time to resolution of EFI is defined as the time needed to achieve GRV less than or equal to 250 ml in the absence of vomiting/retching.
Time Frame	Days 1 to 14 or until resolution of EFI, whichever occurs first

Outcome Measure Data

Analysis Population Description

Due to the low number of participants enrolled at only 1 site, 0 participants are reported due to the risk of identification of a person.

Arm/Group Title	TAK-954 0.1 mg
Arm/Group Description	TAK-954 0.1 milligrams (mg), intravenously, administered as 60 minute-infusion, once daily along with 2 milliliters (mL) normal saline injection, intravenously, three times a day for a minimum of 5 days up to a maximum of 14 days.
Measure Participants	0

6. Secondary Outcome

Title	Percentage of Participants Achieving at Least 80% of Daily Goal Calories
Time Frame	Days 1 to 14 or end of treatment

Outcome Measure Data

Analysis Population Description

Due to the low number of participants enrolled at only 1 site, 0 participants are reported due to the risk of identification of a person.

Arm/Group Title	TAK-954 0.1 mg
Arm/Group Description	TAK-954 0.1 milligrams (mg), intravenously, administered as 60 minute-infusion, once daily along with 2 milliliters (mL) normal saline injection, intravenously, three times a day for a minimum of 5 days up to a maximum of 14 days.
Measure Participants	0

7. Secondary Outcome

Title	Percentage of Participants Achieving at Least 80% of Daily Goal Protein
Time Frame	Days 1 to 14 or end of treatment

Outcome Measure Data

Analysis Population Description

Due to the low number of participants enrolled at only 1 site, 0 participants are reported due to the risk of identification of a person.

Arm/Group Title	TAK-954 0.1 mg
Arm/Group Description	TAK-954 0.1 milligrams (mg), intravenously, administered as 60 minute-infusion, once daily along with 2 milliliters (mL) normal saline injection, intravenously, three times a day for a minimum of 5 days up to a maximum of 14 days.
Measure Participants	0

8. Secondary Outcome

Title	Ctrough: Observed Concentration at the End of a Dosing Interval of TAK-954
Time Frame	Day 5 pre-dose

Outcome Measure Data

Analysis Population Description

Due to the low number of participants enrolled at only 1 site, 0 participants are reported due to the risk of identification of a person.

Arm/Group Title	TAK-954 0.1 mg
Arm/Group Description	TAK-954 0.1 milligrams (mg), intravenously, administered as 60 minute-infusion, once daily along with 2 milliliters (mL) normal saline injection, intravenously, three times a day for a minimum of 5 days up to a maximum of 14 days.
Measure Participants	0

Adverse Events

Time Frame	Up to 4 days
Adverse Event Reporting 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. Due to the low number of participants enrolled at only 1 site, 0 participants are reported due to the risk of identification of a person.
Arm/Group Title	TAK-954 0.1 mg
Arm/Group Description	TAK-954 0.1 milligrams (mg), intravenously, administered as 60 minute-infusion, once daily along with 2 milliliters (mL) normal saline injection, intravenously, three times a day for a minimum of 5 days up to a maximum of 14 days.
All Cause Mortality
	TAK-954 0.1 mg
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)
Serious Adverse Events
	TAK-954 0.1 mg
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)
Other (Not Including Serious) Adverse Events
	TAK-954 0.1 mg
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi-site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.