Blinded, Double-Dummy, Parallel-Group, Phase 2a Randomized Clinical Trial to Evaluate the Efficacy and Safety of a Highly Selective 5-Hydroxytryptamine Type 4 Receptor Agonist in Critically Ill Patients With Enteral Feeding Intolerance

Marianne J Chapman, Karen L Jones, Cristina Almansa, Chris N Barnes, Deanna Nguyen, Adam M Deane, Marianne J Chapman, Karen L Jones, Cristina Almansa, Chris N Barnes, Deanna Nguyen, Adam M Deane

Abstract

Background: Delayed gastric emptying is the leading cause of enteral feeding intolerance (EFI) in critical illness. This phase 2a study compared TAK-954, a selective agonist of 5-hydroxytryptamine type 4 receptors, with metoclopramide in critically ill patients with EFI (NCT01953081).

Methods: A blinded, double-dummy trial was conducted in mechanically ventilated patients with EFI (>200 mL gastric residual volume within 24 hours before randomization). Patients were randomized to receive either 0.5 mg intravenous TAK-954 over 1 hour then 0.9% saline injection 4 times/d (sham metoclopramide) or the active comparator 10 mg intravenous metoclopramide 4 times/d and a 1-hour 0.9% saline infusion. After initial dosing, participants received a radiolabeled meal of liquid nutrient (Ensure; 106 kcal), and gastric emptying was measured (scintigraphy). Adverse events (AEs) were recorded from the time of consent through to day 5; serious AEs were collected to day 30.

Results: Thirteen patients (TAK-954, n = 7; metoclopramide, n = 6) participated. Five patients in the TAK-954 group and 4 in the metoclopramide group experienced AEs (2 and 3, respectively, were serious). All AEs except 1 (diarrhea in the metoclopramide group) were considered unrelated to study drug. Following treatment, a greater proportion of patients receiving TAK-954 had normal gastric retention (<13% retention at 180 minutes) than those receiving metoclopramide (6/7 vs 3/6 patients, respectively).

Conclusion: A single dose of 0.5 mg intravenous TAK-954 appears to have at least similar efficacy in accelerating gastric emptying to multiple doses of 10 mg metoclopramide and was not associated with increased AEs.

Keywords: TAK-954 (td-8954); critically ill; enteral feeding intolerance; gastric emptying; metoclopramide; scintigraphy.

© 2020 The Authors. Journal of Parenteral and Enteral Nutrition published by Wiley Periodicals, Inc. on behalf of American Society for Parenteral and Enteral Nutrition.

Figures

Figure 1
Figure 1
Study design.
Figure 2
Figure 2
Consort‐style patient flow.a aThere were 27 patients who met two exclusion criteria, meaning there were 78 exclusion episodes in 51 patients. ECG, electrocardiogram; GI, gastrointestinal; QTc interval, corrected QT interval; SSRI, selective serotonin reuptake inhibitor.
Figure 3
Figure 3
Gastric retention assessed by individual scintigraphy in participants treated with (A) TAK‐954 0.5 mg (n = 7) and (B) metoclopramide 10 mg (n = 6). (C) Median gastric emptying at 180 minutes.a aEach cross in Figure 3C represents the gastric retention of a patient at 180 minutes. Each horizontal line is the median value of the patients' gastric retention in each group.

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