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

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.

Enteral Feeding Intolerance: Updates in Definitions and Pathophysiology

“…Even though a motilin‐agonist erythromycin is frequently administered, and also supported by recent guidelines, 34 its effect and usefulness for patient‐centered outcomes is not uniformly confirmed 35,36 . Other treatment modalities targeting hormonal pathways to accelerate gastric emptying were unable to inaugurate a new, efficient, and safe drug for clinical practice 37–39 . The limited efficacy of the pharmacological approach designed to manipulate hormonal pathways highlights the complexity and time‐varying pattern of EFI.…”

Randomised study: effects of the 5‐HT4 receptor agonist felcisetrag vs placebo on gut transit in patients with gastroparesis

“…On the other hand, we know from the literature that an improvement of the magnitude observed in this study was >20.4 minutes in GE T 1/2 that correlated well with a clinically meaningful improvement in upper gastrointestinal symptoms. The clinical relevance of the short‐lived acceleration of gastric emptying has been previously shown in critically ill patients requiring enteral feeding, where felcisetrag was beneficial in its effects on normalising gastric emptying compared to metoclopramide 16 . A third minor limitation is that the results of the current study are only applicable to patients with idiopathic or diabetic gastroparesis.…”

“…Felcisetrag is a highly selective and potent 5‐HT 4 receptor agonist with prokinetic activity throughout the gastrointestinal tract in experimental models 11,14,15 . After intravenous administration in healthy volunteers and in treatment of enteral feeding intolerance in critically ill patients, felcisetrag demonstrated prokinetic activity when administered over a short term 16 . As an intravenously administered drug, felcisetrag may be useful in treating acute gastrointestinal motility disorders such as post‐operative gastrointestinal dysfunction, acute exacerbations of gastroparesis (which may result in hospitalization) 6,17 and enteral feeding intolerance in critically ill patients.…”

Post-Operative Ileus: a Pharmacological Perspective

“…The study group with TAK-954 administration was compared to a control group treated with metoclopramide. There was no difference in adverse events and TAK-954 improved the gastric emptying rate compared to metoclopramide (Chapman et al, 2021). A clinical trial is currently underway to test its efficacy on POI (NCT03827655).…”