A Study of TAK-954 to Treat Gastrointestinal Dysfunction in Adults After Surgery

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

The main aim of this study is to check for side effects from TAK-954 and whether it speeds up the recovery of gastrointestinal function after small-bowel or large-bowel resection surgery.

Participants will be treated with TAK-954 before surgery and up to 10 days after surgery.

Study Overview

• Status: Completed
• Conditions: Postoperative Gastrointestinal Dysfunction
• Intervention / Treatment: Drug: TAK-954 Placebo; Drug: TAK-954

Detailed Description

The drug being tested in this study is called TAK-954. In this study TAK-954 is being administered presurgery to evaluate if it can enhance the recovery of GI function postsurgery in participants undergoing open or laparoscopic-assisted partial small- or large-bowel resection. In addition, some participants will also receive TAK-954 postoperatively to evaluate if there is an additional benefit when this drug is administered both pre and post-surgery.

The study will enroll approximately 180 participants. Participants will be equally randomized into one of the three remaining parallel treatment arms- which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need).

All participants will be given intravenous infusion preoperation and daily postoperation until return of upper and lower GI function or for up to 10 days.

This multi-center trial will be conducted in the United States and Germany. The overall time to participate in this study is up to 100 days. Participants will be treated with the study drug for up to 10 days after surgery or until return of GI function post-surgery (whichever occurs first).

• Study Type: Interventional
• Enrollment (Actual): 209
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Hamburg, Germany, 20246
    • Universitaetsklinikum Hamburg-Eppendorf
  • Baden-wuerttemberg
    • Freiburg, Baden-wuerttemberg, Germany, 79106
      • Universitätsklinikum Freiburg
    • Mannheim, Baden-wuerttemberg, Germany, 68167
      • Universitätsklinikum Mannheim
  • Bavaria
    • Regensburg, Bavaria, Germany, 93053
      • Universitaetsklinikum Regensburg
  • Bayern
    • Munchen, Bayern, Germany, 81675
      • Klinikum rechts der Isar der Technischen Universität München
  • Nordrhein-westfalen
    • Bochum, Nordrhein-westfalen, Germany, 44791
      • Sankt Josef-Hospital
• United States
  • Alabama
    • Mobile, Alabama, United States, 30617
      • University of South Alabama Medical Center
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Los Angeles, California, United States, 90007
      • Keck School of Medicine
    • Orange, California, United States, 92868
      • University Of California Irvine Medical Center
    • Riverside, California, United States, 92504
      • Parkview Community Hospital Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Leonard M. Miller School of Medicine
    • Orlando, Florida, United States, 32804
      • Center for Colon & Rectal Surgery - Altamonte Springs
    • Weston, Florida, United States, 33331
      • Cleveland Clinic Florida
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Melvin and Bren Simon Cancer Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University Of Kentucky
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Medical Center
  • Massachusetts
    • Worcester, Massachusetts, United States, 01605
      • University of Massachusetts Memorial Medical Center
  • New York
    • Stony Brook, New York, United States, 11794
      • Stony Brook University Hospital
  • Ohio
    • Cleveland, Ohio, United States, 44111
      • Fairview Hospital
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Wexner Medical Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Health Milton S. Hershey Medical Center
  • Texas
    • Houston, Texas, United States, 77024
      • HD Research Corp.
    • Houston, Texas, United States, 77089
      • North Star Medical

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Participant is scheduled to undergo a laparoscopic-assisted or open partial small- or large-bowel resection.
2. Participant's American Society of Anesthesiologists (ASA) physical status classification is ASA 1 to 3.

Exclusion Criteria:

1. Has significant mechanical bowel obstruction that is not expected to resolve after the surgery, short bowel syndrome, pre-existing clinically significant GI motility disorder (example, gastroparesis, scleroderma, chronic intestinal pseudo-obstruction), uncontrolled diabetes (glycosylated hemoglobin [HbA1c] greater than [>] 10 percent [%]), has an active gastric pacemaker, or requires parenteral nutrition.
2. Had previous major abdominal surgery (example, gastrectomy, gastric bypass, gastric sleeve, lap banding, Whipple, pancreatic resection, total/subtotal colectomy, hemicolectomy, extensive bowel resection).
3. Had a history of radiation therapy to the abdomen or pelvis.
4. Scheduled to undergo any of the following surgeries: low anterior resection, total or subtotal colectomy, colostomy, ileostomy or reversal of stoma, or has a diagnosis that requires rectal resection (eg, tumors in the anorectum) and will likely require lower anterior resection surgery. Participants with planned surgery for which there is no anticipated significant rectal resection and is, therefore, likely to preserve anorectal function and continence postsurgery, will likely be eligible for inclusion in the study if they meet all the study inclusion/exclusion criteria (eg, participants with lesions not involving the rectum [sigmoid colon and above]).
5. Has 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).
6. Has received alvimopan, erythromycin, prucalopride, metoclopramide, domperidone, cisapride, mosapride, renzapride, or azithromycin in the 24 hours prior to starting study drug.
7. Participant has known COVID-19 infection, or suspected COVID-19 infection.
8. Scheduled for abdominal surgery that is classified as emergency.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; TAK-954 placebo-matching, 60-minute infusion, intravenously (IV), once presurgery on Day 1 and once daily postsurgery until return of upper and lower GI function or for up to 10 days.	Drug: TAK-954 Placebo; TAK-954 placebo-matching intravenous infusion.
Experimental: TAK-954 0.1 mg/100 mL; 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.	Drug: TAK-954; TAK-954 intravenous infusion.
Experimental: TAK-954 0.5 mg/100 mL; 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.	Drug: TAK-954; TAK-954 intravenous infusion.
Experimental: TAK-954 0.1 mg/100 mL + Placebo; 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.	Drug: TAK-954 Placebo; TAK-954 placebo-matching intravenous infusion.; Drug: TAK-954; TAK-954 intravenous infusion.
Experimental: TAK-954 0.5 mg/100 mL + Placebo; 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.	Drug: TAK-954 Placebo; TAK-954 placebo-matching intravenous infusion.; Drug: TAK-954; TAK-954 intravenous infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time From End of the Surgery to Resolution of Upper and Lower Gastrointestinal (GI) Function Postsurgery as Assessed by the Investigator	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.	Day 1 (surgery) up to Day 10 postsurgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time From the End of the Surgery (Time the Incision is Closed) Until Ready for Discharge as Assessed by the Investigator	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.	Day 1 (surgery) up to Day 24
Time From the End of Surgery Until the Discharge Order is Written	Kaplan-Meier survival analysis method was used.	Day 1 (surgery) up to Day 24
Time From the End of Surgery to Discharge From Hospital	Kaplan-Meier survival analysis method was used.	Day 1 (surgery) up to Day 24
Time From End of Surgery to Tolerance of Solid Food as Assessed by the Investigator	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.	Day 1 (surgery) up to Day 10 postsurgery
Time From End of Surgery to First Spontaneous Bowel Movement as Assessed by the Investigator	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.	Day 1 (surgery) up to Day 10 postsurgery
Percentage of Participants With Postoperative Gastrointestinal Dysfunction (POGD) >= 5 Days as Assessed by the Investigator	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.	Day 1 (surgery) up to Day 10
Percentage of Participants Requiring Insertion of Nasogastric (NG) Tube Postsurgery	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.	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)
Time From End of Surgery to First Flatus	Kaplan-Meier survival analysis method was used.	Day 1 (surgery) up to first flatus (up to Day 10 postsurgery)
Observed Plasma Concentration of TAK-954 at the End of Infusion on Day 1		Day 1 (surgery): postinfusion

Collaborators and Investigators

• Sponsor: Takeda
• Collaborators: Takeda Development Center Americas, Inc.
• Investigators: Study Director: Medical Director, Takeda

Publications and helpful links

Helpful Links

• To obtain more information on the study, click here/on this link.

Study record dates

Study Major Dates

• Study Start (Actual): March 7, 2019
• Primary Completion (Actual): May 27, 2022
• Study Completion (Actual): May 27, 2022

Study Registration Dates

• First Submitted: January 30, 2019
• First Submitted That Met QC Criteria: January 30, 2019
• First Posted (Actual): February 1, 2019

Study Record Updates

• Last Update Posted (Actual): June 23, 2023
• Last Update Submitted That Met QC Criteria: May 26, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Drug Therapy
• Other Study ID Numbers: TAK-954-2004; 2018-003318-42 (EudraCT Number); U1111-1222-4784 (Registry Identifier: WHO)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

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