Evaluation of Single Doses of GSK962040 in Critically Ill Patients With Enteral Feed Intolerance

Study Overview
=================
Brief Summary
-----------------
The aims of MOT112571 are to assess the pharmacodynamic effects, safety, tolerability, pharmacokinetics, and potential therapeutic benefit of single doses of GSK962040 in critically ill patients with delayed gastric emptying and who are intolerant to enteral feeding.

Official Title
-----------------
A Double-blind, Randomized, Placebo Controlled Phase II Study to Evaluate the Pharmacodynamics, Safety, Tolerability, and Pharmacokinetics of Single Doses of the Oral Motilin Receptor Agonist GSK962040, in Critically Ill Male and Female Patients With Enteral Feed Intolerance

Conditions
-----------------
Gastroparesis

Intervention / Treatment
-----------------
* Drug: GSK962040 (50 mg)
* Drug: Placebo
* Drug: GSK962040 (75 mg)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female between 18-85 years of age, at the time consent is obtained. Mechanically ventilated on the Intensive Care Unit who has become intolerant of nasogastric enteral feeding. intolerance of nasogastric tube feeding is defined as a gastric aspirate volume (GRV) >250 mL at least 6 hours after commencing feeding at >40 mL/hr. Expected to remain mechanically ventilated for at least 48 hours after enrollment and expected to survive for at least 24 hours post dose of study medication. Subject has a nasogastric tube for enteral feeding. Body weight > or = 50 kg Written informed consent may be obtained from a legally acceptable representative, which includes compliance with the requirements and restrictions listed in the consent form. In most cases, consent will be sought from next of kin as the subject will not be competent to give their own consent. Average QTcB or QTcF < 450 msec; or QTc < 480 msec in subjects with Bundle Branch Block. AST and ALT < 3xULN; alkaline phosphatase and bilirubin < or = 2xULN. Subjects who have rapidly rising aminotransferases or for whem there is not a plausible explanation for the observed elevation will not be enrolled LFTs will be checked for eligibility on screening and again prior to dosing with GSK962040. Exclusion Criteria: Subjects that have received a gastric prokinetic agent in the previous 24 h (e.g., erythromycin, azithromycin, metoclopramide). These agents are prohibited for the duration of the study. Subjects whose clinical condition is deteriorating rapidly or any subject for whom the investigator does not consider there is a reasonable expectation that they will be able to complete the study. Subjects who are known to be infected with Hepatitis B, Hepatitis C, or HIV viruses. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). Exposure to more than four new chemical entities within 12 months prior to the first dosing day. Use of prohibited medications listed in Section 9.2 within the restricted timeframe relative to dosing of study medication. Subjects with renal failure requiring replacement therapy (dialysis or filtration). Subjects for whom the reason for admission to ICU was an overdose (deliberate or accidental; medicinal product or not). Subjects with altered upper gastrointestinal tract anatomy and subjects who have undergone upper gastrointestinal tract surgery on this admission to ICU. Subjects with bowel obstruction or perforation. Subject has a gastric pacemaker Subject is receiving parenteral feeding History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation. Pregnant females as determined by positive serum or urine hCG test at screening or prior to dosing. Lactating females.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Subjects randomized to either GSK962040 (50 mg) or placebo | Drug: GSK962040 (50 mg)<br>* Cohort 1 = 50 mg<br>Drug: Placebo<br>* matching placebo<br>|
| Experimental: Cohort 2<br>Subjects randomized to either GSK962040 (75 mg) or placebo | Drug: Placebo<br>* matching placebo<br>Drug: GSK962040 (75 mg)<br>* Cohort 2 = 75 mg<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gastric emptying |  | 3 days | 
| Safety and tolerability of GSK962040 |  | 5 days | 
| Pharmacokinetic parameters of GSK962040: Cmax, Tmax, AUC(0-inf), AUC(0-t), CL/F, V/F, and half-life |  | 3 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pre and post GSK962040 dose Gastric Residual Volume (GRV) |  | Duration of dosing | 
| Pharmacokinetic parameters of paracetamol |  | duration of dosing | 
| Pharmacokinetic parameters of 3OMG |  | duration of dosing | 
| Plasma concentrations of motilin |  | duration of dosing | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
GSK962040, 13C octanoic acid breath test, pharmacokinetics, critically ill patients, gut motility, pharmacodynamics, tolerability, single dose, gastric emtpying