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

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

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.

Study Overview

• Status: Terminated
• Conditions: Critical Illness; Enteral Nutrition; Enteral Feeding Intolerance
• Intervention / Treatment: Drug: TAK-954; Drug: Normal Saline; Drug: Metoclopramide

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 Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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]).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / 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: Normal Saline; 0.9% sodium chloride for injection; Drug: Metoclopramide; Metoclopramide infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average Daily Protein Adequacy Over the First 5 Days of Treatment	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.	Days 1 to 5

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average Daily Protein Adequacy Over the Study Treatment Period	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.	Days 1 to 14
Average Daily Change in 24-hour Gastric Residual Volume (GRV) Over the First 5 Days of Study Treatment	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.	Days 1 to 5
Average Daily Caloric Adequacy	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.	Days 1 to 5 and Days 1 to 14
Time to Resolution of Enteral Feeding Intolerance (EFI)	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.	Days 1 to 14 or until resolution of EFI, whichever occurs first
Percentage of Participants Achieving at Least 80% of Daily Goal Calories		Days 1 to 14 or end of treatment
Percentage of Participants Achieving at Least 80% of Daily Goal Protein		Days 1 to 14 or end of treatment
Ctrough: Observed Concentration at the End of a Dosing Interval of TAK-954		Day 5 pre-dose

Collaborators and Investigators

• Sponsor: Millennium Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): August 25, 2018
• Primary Completion (Actual): August 29, 2018
• Study Completion (Actual): August 29, 2018

Study Registration Dates

• First Submitted: March 19, 2018
• First Submitted That Met QC Criteria: March 19, 2018
• First Posted (Actual): March 27, 2018

Study Record Updates

• Last Update Posted (Actual): September 24, 2019
• Last Update Submitted That Met QC Criteria: September 23, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: Drug therapy
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Critical Illness; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Dopamine Agents; Dopamine D2 Receptor Antagonists; Dopamine Antagonists; Metoclopramide
• Other Study ID Numbers: TAK-954-2002; U1111-1208-1831 (Other Identifier: WHO); 2017-003206-41 (EudraCT Number); 18/NE/0139 (Registry Identifier: NRES)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Takeda makes patient-level, de-identified data sets and associated documents available after applicable marketing approvals and commercial availability have been received, an opportunity for the primary publication of the research has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com/Approach for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No