(Nutritional adequacy therapeutic enhancement in the critically ill: A randomized double blind, placebo-controlled, active-compared trial of the motilin receptor agonist GSK962040.)
Background: Providing optimal delivery of enteral nutrition early in the clinical course of critically-ill patients is recognized as an integral component of high quality standard supportive care. In the critically ill, malnutrition and development of a negative energy balance results in impaired immunologic function, impaired ventilatory drive, prolonged ventilator dependence, increased infectious complications, and overall poor outcomes.
The prevalence of malnutrition is reported to be as high as 40% of intensive care unit (ICU) patients.
Gastric emptying is well documented to be impeded in 40-60% of ICU patients resulting in an inability to deliver adequate enteral nutrition (EN) (i.e., enteral feeding intolerance), leading to increased gastric residual volumes (GRV), and potential for aspiration of gastric contents. Normalization of gastric emptying by the use of prokinetic agents is a recommended strategy for optimizing delivery and minimizing risks of EN.
GSK962040 is an oral, small molecule, selective agonist of the motilin receptor in development for conditions in which delayed gastric emptying is thought to be part of the pathophysiology. GSK962040 has been investigated in a single center, randomized, double blind, placebo controlled, and single-dose study in mechanically ventilated ICU patients intolerant to enteral feeding. GSK962040 was well tolerated and, in most patients, well absorbed but with greater overall variability in exposures compared to healthy volunteers and diabetic subjects.
Objectives: The purpose of this study is to test the safety of GSK962040 and to see if it improves gastric emptying in patients in intensive care.
Study Population: A sufficient number of subjects will be enrolled such that approximately 150 subjects complete primary efficacy assessments. It is anticipated that the total number of randomized subjects will not exceed approximately 200.
Methods: This is a multi-center, parallel group, placebo-controlled and active-compared, randomized study of the ability of enterally administered GSK962040 to improve the delivery of enteral nutrition therapy in subjects who are likely to be predisposed to have slow gastric emptying. Male and female ICU subjects will be considered eligible if they are mechanically ventilated and receiving enteral nutrition. After meeting eligibility criteria, obtaining the appropriate consent, and at time of initiation of enteral feeding, subjects will be randomized to receive GSK962040 (50 mg) or placebo once daily via NG feeding tube. If subjects develop intolerance to enteral feeding at any point up to Dose 5 of study medication, subjects will be re-randomized to receive either a higher dose of GSK962040 (100 mg) or metoclopramide. Additionally, if subjects develop intolerance prior to randomization they will be re-randomized without receiving GSK962040 or placebo. All subjects will receive a standard feeding protocol which includes criteria for monitoring and adjusting feeding rates.
The study will consist of a screening/baseline assessment, an initial treatment period (up to 7 days in duration), a re-randomization period and a 4-day post treatment safety follow-up assessment. The duration of each subject's participation in the study from screening to follow-up safety assessment will be up to approximately 2 weeks. In addition, mortality will be assessed 60 days after admission to the ICU.