Nutritional Adequacy Therapeutic Enhancement in the Critically Ill. The NUTRIATE Study

Gastroparesis Clinical Trial

Official title:

NUTRItional Adequacy Therapeutic Enhancement in the Critically Ill: A Randomized Double Blind, Placebo-controlled Trial of the Motilin Receptor Agonist GSK962040. The NUTRIATE Study

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01934192
• Other study ID #: 113445
• Status: Terminated
• Phase: Phase 2
• First received: August 29, 2013
• Last updated: November 9, 2017
• Start date: April 4, 2014
• Est. completion date: July 8, 2016

Study information

• Verified date: October 2017
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a multi-center, parallel group, placebo-controlled and active-compared, randomized study to assess the ability of GSK962040 to enhance the delivery of enteral feed to critically ill subjects that are predisposed to developing feeding intolerance (e.g., percentage of goal volume); enhance gastric emptying in this population; and provide preliminary evidence of the drug's effect on outcomes of therapy (length of stay in the Intensive Care Unit [ICU], time on ventilator, ICU acquired infections, and 60-day mortality). Other aims are evaluation of GSK962040 safety, tolerability and pharmacokinetics upon repeat dosing in a critically ill population.

After meeting eligibility criteria, male and female subjects will be randomized to either receive GSK962040 (50 milligram [mg]) once daily (OD) via naso-gastric (NG) or orogastric (OG) feeding tube (oral solution), or placebo by the same route. If subjects develop intolerance to enteral feeding at any point up to Dose 5 of study medication (inclusive), study treatments will switch such that those originally receiving GSK962040 will receive metoclopramide (10 mg, intravenous [iv], every 6 hours) and those subjects originally randomized to receive placebo will receive GSK962040 (50 mg, via NG, OD). Additionally, if subjects develop intolerance prior to any treatment, they will be randomized to receive either GSK962040 (50 mg, via NG, OD) or metoclopramide (10 mg, iv, every 6 hours).

The study will consist of a screening/baseline assessment, a treatment period (up to 7 days in duration), 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 91
• Est. completion date: July 8, 2016
• Est. primary completion date: July 8, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

Inclusion Criteria:

• Age & Gender: Male or female between 18 and 85 years of age inclusive, at the time of obtaining the informed consent.

• First admitted to participating ICU within the previous 48 hours.

• Intubated and invasively mechanically ventilated

• Indicated to receive early EN or are already receiving EN (subject must be on EN prior to receiving study treatment)

• Have at least one of the following

• Clinical evidence of cardiovascular dysfunction defined as the need for vasopressor agents (e.g. norepinephrine, epinephrine, vasopressin), >5 microgram/kg/min of dopamine, or >/= 50 microgram/min phenylephrine) for greater than or equal to 2 hours;

• Poly-trauma with an injury severity score (ISS) >=15 points

• Acute traumatic or non-traumatic brain injury Glasgow Coma Scale (GCS) <=12, prior to the initiation of sedation.

Exclusion Criteria:

• Subjects who are not expected to be in the ICU and alive for at least 48 hrs from point of screening.

• Subjects with acute hepatitis (e.g. acute hepatitis B or C) or severe chronic liver disease (e.g. Child Pugh class C cirrhosis) will be excluded

• Liver function tests: If Alanine aminotransferase (ALT) >=8x upper limit of normal (ULN); OR If ALT >5-8x ULN and bilirubin >2<=3 ULN or bilirubin >3x ULN (Include only if bilirubin <1.5xULN); OR If ALT <=5xULN and Bilirubin >3xULN (Include only if ALT <=3xULN and Bilirubin >2 <=3xULN)

• Subjects who have received a gastric prokinetic agent in the previous 12 hours (e.g., erythromycin, azithromycin, metoclopramide, domperidone).

• QT duration corrected for heart rate (QTc) >480 ms. QTcF is the recommended correction factor for all sites. If QT duration corrected for heart rate by Fridericia's formula (QTcF) is not possible to obtain or calculate, QT duration corrected for heart rate by Bazett's formula (QTcB) or machine or manual over read, may be obtained after consultation with the medical monitor. The QT correction formula used to determine inclusion and discontinuation should be the same throughout the study.

• Use of strong Cyp3A4 inhibitors

• Subjects who require renal replacement therapy or with an estimated glomerular filtration rate (GFR) of <30 mL/min byCockroft-Gault calculation).

• Subjects who have a history of or who have undergone major esophageal or gastric surgery on this admission (major lower abdominal surgery will not result in exclusion unless this carries a contraindication to enteral feeding).

• Subjects with an absolute contraindication to enteral nutrition e.g. subjects with ongoing bowel obstruction or perforation.

• Subject has a gastric pacemaker

• Pregnant or lactating females

• 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.

• Concurrent enrollment in other interventional study involving a novel (i.e.unapproved or experimental) chemical or biopharmaceutical entity.

• Previous randomization in this study

• Subjects for whom the reason for admission to ICU was an overdose (deliberate or accidental; medicinal product or not).

• Exclusion to re-randomization:

• Subjects with an untreated pheochromocytoma.

• Subjects with a past history of a seizure disorder (e.g., epilepsy) and is currently receiving anti-epileptic treatment for their seizure disorder, ongoing refractory, or sustained seizure disorder (prophylactic use for head injury/isolated new seizure maintained on anti-seizure meds in ICU acceptable).

• Subjects taking drugs likely to cause extrapyramidal reactions.

Related Conditions & MeSH terms

• Critical Illness
• Gastroparesis

Intervention

Drug:
• GSK962040 50 mg
GSK962040 50 mg will be administered once daily enteral dose through NG tube up to 7 days.
• Metoclopramide 10 mg
Metoclopramide will be administered IV every 6 h
• Placebo NG
Matching placebo once daily enteral dose will be administered through NG tube up to 7 days
• Placebo IV
Placebo will be administered IV every 6 hours

Locations

Country	Name	City	State
Australia	GSK Investigational Site	Adelaide	South Australia
Australia	GSK Investigational Site	Randwick	New South Wales
Australia	GSK Investigational Site	Southport	Queensland
Australia	GSK Investigational Site	Woodville	South Australia
Canada	GSK Investigational Site	Calgary	Alberta
Canada	GSK Investigational Site	Calgary	Alberta
Canada	GSK Investigational Site	Hamilton	Ontario
Canada	GSK Investigational Site	Kingston	Ontario
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Ottawa	Ontario
Canada	GSK Investigational Site	Ottawa	Ontario
Canada	GSK Investigational Site	Quebec
Canada	GSK Investigational Site	Sainte-Foy	Quebec
Canada	GSK Investigational Site	Sherbrooke	Quebec
Canada	GSK Investigational Site	Toronto	Ontario
United States	GSK Investigational Site	Augusta	Georgia
United States	GSK Investigational Site	Aurora	Colorado
United States	GSK Investigational Site	Louisville	Kentucky
United States	GSK Investigational Site	Philadelphia	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Australia,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Average Percentage Goal Volume Delivered Prior to Development of Intolerance for ITT Population	The average percentage goal volume received via EN was defined as the percent of goal volume received via EN from the first study dose up to permanent discontinuation of EN. It is calculated as 100 multiplied by total volume received via EN during the on treatment period prior to intolerance divided by total prescribed volume. 'Prior to intolerance' means 'prior to start of intolerance treatment. One participant was missing for prior to start of intolerance treatment. The average percentage goal volume received via EN was assessed and comparison between Camicinal 50mg and placebo arm was performed. Adjusted mean and its 95% confidence interval (CI) were estimated and Analysis of Covariance (ANCOVA) model was used for analysis.	Up to Day 7
Primary	Average Percentage Goal Volume Delivered Prior to Development of Intolerance for PP Population	The average percentage goal volume received via EN was defined as the percent of goal volume received via EN from the first study dose up to permanent discontinuation of EN. It is calculated as 100 multiplied by total volume received via EN during the on treatment period prior to intolerance divided by total prescribed volume. 'Prior to intolerance' means 'prior to start of intolerance treatment. One participant was missing for prior to start of intolerance treatment. The average percentage goal volume received via EN was assessed and comparison between Camicinal 50mg and placebo arm was performed. Adjusted mean and its 95% CI were estimated and ANCOVA model was used for analysis.	Up to Day 7
Secondary	Average Percentage Goal Calories Delivered Prior to Development of Intolerance	The average percentage goal calories received via EN was defined as the percent of goal calories received via EN from the first study dose up to permanent discontinuation of EN. It is calculated as 100 multiplied by total calories received via EN during the on treatment period prior to intolerance divided by total prescribed calories. 'Prior to intolerance' means 'prior to start of intolerance treatment. The average percentage goal calories received via EN was assessed and comparison between Camicinal 50mg and placebo arm was performed. Adjusted mean and its 95% CI were estimated and ANCOVA model was used for analysis.	Up to Day 7
Secondary	Average Percentage Goal Protein Delivered Prior to Development of Intolerance	The average percentage goal protein received via EN was defined as the percent of goal protein received via EN from the first study dose up to permanent discontinuation of EN. It is calculated as 100 multiplied by total protein received via EN during the on treatment period prior to intolerance divided by total prescribed protein. 'Prior to intolerance' means 'prior to start of intolerance treatment. One participant was missing for prior to start of intolerance treatment. The average percentage goal protein received via EN was assessed and comparison between Camicinal 50mg and placebo arm was performed. Adjusted mean and its 95% CI were estimated and ANCOVA model was used for analysis.	Up to Day 7
Secondary	Time to Delivery of 80 Percent Prescribed Calories Prior to Intolerance	Time required for the delivery of 80 percent prescribed calories prior to intolerance was calculated using Kaplan-Meier estimates for time variable. Prior to intolerance was defined as prior to start of intolerance treatment. Participants who did not reach delivery of 80 percent prescribed calories were censored at the last day on which they received randomized treatment and with available nutritional data.	Up to Day 7
Secondary	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or all events of possible drug-induced liver injury with hyperbilirubinaemia were categorized as SAE.	up to 23 days
Secondary	Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)	SBP and DBP were measured at Baseline, Day 1, up to 6 hrs pre-dose on Day 2-7 and at follow-up (till 23 days). The Baseline value was considered to be the participant's last available assessment prior to randomized treatment. Change from Baseline was defined as post dose visit value minus Baseline value. For participants who developed intolerance, SBP and DBP were measured at Day 1 to Day 7 post-intolerance. NA indicates that data were not available. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles). If n < 3 the standard deviation (SD) was set to missing.	Up to 23 days
Secondary	Change From Baseline in Heart Rate (HR)	HR was measured at Baseline, Day 1, up to 6 hrs pre-dose on Day 2-7 and at follow-up (till Day 23). The Baseline value was considered to be the participant's last available assessment prior to randomized treatment. Change from Baseline was defined as post dose visit value minus Baseline value. For participants who developed intolerance, HR was measured at Day 1 to Day 7 post-intolerance. NA indicates that data were not available. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles). If n < 3 the SD was set to missing.	Up to 23 days
Secondary	Number of Participants With Maximum Increase From Baseline in Electrocardiogram (ECG) Values	12-lead ECGs was done at Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7 and at follow up (till Day 23) that automatically calculates corrected QT (QTc), QTcF (QT duration corrected for heart rate by Fridericia's formula) and QTcB (QT duration corrected for heart rate by Bazett's formula) intervals. Three ECGs approximately 5 min apart were collected prior to dose 1and single recordings were made at other time points. On Day 1ECGs were collected at pre-dose (up to 6 hrs) and 2 hr post treatment. Number of participants with maximum increase from Baseline were collected and participants showed increase in 3 parameters namely QTc, QTcB and QTcF. Only those participants available at the specified time points were analyzed (represented by n=x in the category titles).	Up to 23 days
Secondary	Change From Baseline in Albumin and Total Protein Levels	Blood samples were collected to evaluate change from Baseline in albumin and total protein values at Baseline, Day 2-7 and follow-up (till Day 23). Blood samples were also collected on Day 9 for those participants who completed 7 days of dosing. Change from Baseline was defined as post dose visit value minus Baseline value. For participants who developed intolerance, blood samples were taken for Day 1 to Day 7 up to 6 hrs prior to dosing. NA indicates that data were not available. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). If n < 3 the SD was set to missing.	Up to 23 days
Secondary	Change From Baseline in Alkaline Phosphatase (Alk. Phosph.), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma Glutamyl Transferase (GGT) Levels	Blood samples were collected to evaluate change from Baseline in alk.phosp., ALT, AST and GGT values at Baseline, Day 1- Day 7 and follow up (till Day 23). Blood samples were also collected on Day 9 for those participants who completed 7 days of dosing. Change from Baseline was defined as post dose visit value minus Baseline value. For participants who developed intolerance, blood samples were taken for Day 1 to Day 7 up to 6 hrs prior to dosing. NA indicates that data were not available. Only those participants available at the specified time points were analyzed (represented by n=x in the category titles). If n < 3 the SD was set to missing.	Up to 23 days
Secondary	Change From Baseline in Total and Direct Bilirubin, Creatinine and Uric Acid Levels	Blood samples were collected to evaluate change from Baseline in total and direct bilirubin, creatinine and uric acid values at Baseline, Day 2- Day 7 and at follow up (Till Day 23). Blood samples were also collected on Day 9 for those participants who completed 7 days of dosing. Change from Baseline was defined as post dose visit value minus Baseline value. For participants who developed intolerance, blood samples were taken for Day 1 to Day 7 up to 6 hrs prior to dosing. NA indicates that data were not available. Only those participants available at the specified time points were analyzed (represented by n=x in the category titles). If n < 3 the SD was set to missing.	Up to 23 days
Secondary	Change From Baseline in Calcium, Chloride, Carbon Dioxide, Glucose, Potassium, Sodium, Blood Urea Nitrogen (BUN) Values	Blood samples were collected to evaluate change from Baseline in calcium, chloride, carbon dioxide, glucose, potassium, sodium, BUN values at Baseline, up to Day 7 and follow up (till Day 23). Blood samples were also collected on Day 9 for those participants who completed 7 days of dosing. Change from Baseline was defined as post dose visit value minus Baseline value. For participants who developed intolerance, blood samples were taken for Day 1 to Day 7 up to 6 hrs prior to dosing. NA indicates that data were not available. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles). If n < 3 the SD was set to missing.	Up to 23 days
Secondary	Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet and White Blood Cell (WBC) Levels	Blood samples were collected to evaluate change from Baseline in basophils, eosinophils, lymphocytes, monocytes, total neutrophils, platelet and WBC values at Baseline up to Day 7 and follow up (till Day 23). Blood samples were also collected on Day 9 for those participants who completed 7 days of dosing. Change from Baseline was defined as post dose visit value minus Baseline value. For participants who developed intolerance, blood samples were taken for Day 1 to Day 7 up to 6 hrs prior to dosing. NA indicates that data were not available. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles). If n < 3 the SD was set to missing.	Up to 23 days
Secondary	Change From Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) Levels	Blood samples were collected to evaluate change from Baseline in hemoglobin and MCHC values at Baseline up to Day 7 and follow up (till Day 23). Blood samples were also collected on Day 9 for those participants who completed 7 days of dosing. Change from Baseline was defined as post dose visit value minus Baseline value. For participants who developed intolerance, blood samples were taken for Day 1 to Day 7 up to 6 hrs prior to dosing. NA indicates that data were not available. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles). If n < 3 the SD was set to missing.	Up to 23 days
Secondary	Change From Baseline in Hematocrit Level	Blood samples were collected to evaluate change from Baseline in hematocrit values at Baseline up to Day 7 and follow up (till day 23). Blood samples were also collected on Day 9 for those participants who completed 7 days of dosing. Change from Baseline was defined as post dose visit value minus Baseline value. For participants who developed intolerance, blood samples were taken for Day 1 to Day 7 up to 6 hrs prior to dosing. NA indicates that data were not available. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles). If n < 3 the SD was set to missing.	Up to 23 days
Secondary	Change From Baseline in Mean Corpuscle Volume (MCV) Levels	Blood samples were collected to evaluate change from Baseline in MCV values at Baseline up to Day 7 and follow up (till Day 23). Blood samples were also collected on Day 9 for those participants who completed 7 days of dosing. Change from Baseline was defined as post dose visit value minus Baseline value. For participants who developed intolerance, blood samples were taken for Day 1 to Day 7 up to 6 hrs prior to dosing. NA indicates that data were not available. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles). If n < 3 the SD was set to missing.	Up to 23 days
Secondary	Change From Baseline in Red Blood Cell (RBC) and Reticulocyte Count	Blood samples were collected to evaluate change from Baseline in RBC and reticulocytes values at Baseline up to Day 7 and follow up (till Day 23). Blood samples were also collected on Day 9 for those participants who completed 7 days of dosing. Change from Baseline was defined as post dose visit value minus Baseline value. For participants who developed intolerance, blood samples were taken for Day 1 to Day 7 up to 6 hrs prior to dosing. NA indicates that data were not available. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles). If n < 3 the SD was set to missing.	Up to 23 days
Secondary	Change From Baseline in Mean Corpuscle Hemoglobin (MCH) Levels	Blood samples were collected to evaluate change from Baseline in MCH values at Baseline up to Day 7 and follow up (till Day 23). Blood samples were also collected on Day 9 for those participants who completed 7 days of dosing. Change from Baseline was defined as post dose visit value minus Baseline value. For participants who developed intolerance, blood samples were taken for Day 1 to Day 7 up to 6 hrs prior to dosing. NA indicates that data were not available. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles). If n < 3 the SD was set to missing.	Up to 23 days
Secondary	Log Transformed Concentration at 60 Minutes (Min) (C60) and Maximum Observed Concentration (Cmax) of Acetaminophen (Prior to Intolerance)	Blood samples for pharmacokinetic (PK) analysis were collected at Baseline, and at Day 2 or at Day 3 (OR very rarely Day 4 - only if Day 2 or Day 3 sample could not be obtained) prior to intolerance. Prior to intolerance was defined as prior to development of intolerance. C60 was defined as observed plasma concentration at 60 min after administration of enteral feed with acetaminophen and Cmax was defined as maximum observed plasma concentration of acetaminophen. The absorption profile of acetaminophen was used as an indirect measure of gastric emptying function. The analysis was performed on ITT (exposed) Population. Due to change in sampling schedule, samples were only obtained to 4 hours. Only those participants available at the specified time points were analyzed (represented by n= x in the category titles).	At Day 2
Secondary	Log Transformed AUC[0-60] of Acetaminophen	Blood samples for PK analysis were collected at Baseline, and at 60 min. at Day 2 or Day 3 (or very rarely Day 4 - only if Day 2 or Day 3 sample could not be obtained) prior to intolerance. Prior to intolerance was defined as prior to development of intolerance. AUC[0-60] of acetaminophen was defined as area under the concentration-time curve from time zero to 60 min. and it was calculated as Log trapezoidal rule from concentration-time data. The absorption profile of acetaminophen was used as an indirect measure of gastric emptying function. Only those participants available at the specified time points were analyzed (represented by n=x in the category titles)	At Day 2
Secondary	Log Transformed AUC[0-60] of 3-O-methylglucose (3- OMG)	Blood samples for PK analysis were collected at Baseline, and at Day 2 or Day 3 (or very rarely Day 4 - only if Day 2 or Day 3 sample could not be obtained) prior to intolerance. Prior to intolerance was defined as prior to development of intolerance. AUC[0-60] of 3-OMG was defined as area under the concentration-time curve from time zero to 60 min. and it was calculated as Log trapezoidal rule from concentration-time data. The absorption profile of 3-OMG was used as an indirect measure of gastric emptying function. Only those participants available at the specified time points were analyzed (represented by n=x in the category titles)	At Day 2
Secondary	Log Transformed C60 of 3-OMG	Blood samples for PK analysis were collected at Baseline and at Day 2 or Day 3 (or very rarely at Day 4 - only if Day 2 or Day 3 sample could not be obtained)prior to intolerance. Prior to intolerance was defined as prior to development of intolerance. C60 was defined as observed plasma concentration at 60 min after administration of enteral feed with 3-OMG. The absorption profile of 3-OMG was used as an indirect measure of gastric emptying function. The analysis was performed on ITT (exposed) Population. Cmax was not analyzed. Only those participants available at the specified time points were analyzed (represented by n=x in the category titles).	At Day 2
Secondary	Derived Tmax of 3-OMG Post Intolerance	Blood samples for PK analysis were collected at Day 2 or Day 3 (or very rarely at Day 4 - only if Day 2 or Day 3 sample could not be obtained) post development of intolerance. Tmax was defined as time to maximum observed plasma concentration of 3-OMG.	At Day 2
Secondary	Percentage of Participants That Became Intolerant	Percentage of participants that became intolerant was calculated. Those participants who developed intolerance were assessed to characterize gastric emptying (GE). Participants who did not develop intolerance were censored at the time of the last available Gastric Residual Volume (GRV) measurement.	Up to Day 7
Secondary	Time to Development of Feeding Intolerance	Time required for the development of feeding intolerance was calculated using Kaplan-Meier estimates for time variable. Median and quartiles were not calculable due to the small number of participants developing EN intolerance and mean and standard error of mean were presented.	Up to Day 7
Secondary	GE Assessment as AUC (0-60) Within 24 Hrs of Developing Intolerance and Prior to Change of Treatment Using Acetaminophen	GE assessment within 24 hrs of developing intolerance and prior to change of treatment was analyzed using acetaminophen absorption method. AUC (0-60) was calculated and data was presented for pre-dose Visit (day prior to change of treatment). Geometric mean and 95 percent CI was analyzed.	Day 2
Secondary	GE Assessment as Cmax Within 24 Hrs of Developing Intolerance and Prior to Change of Treatment Using Acetaminophen	GE assessment within 24 hrs of developing intolerance and prior to change of treatment was analyzed using acetaminophen absorption method. Cmax was calculated and data was presented for pre-dose Visit(day prior to change of treatment). Geometric mean and 95 percent CI was analyzed.	Baseline, Day 2, Day 3, Day 4
Secondary	GE Assessment as AUC (0-60) and AUC (0-240) Within 24 Hrs of Developing Intolerance and Prior to Change of Treatment Using 3-OMG	GE assessment within 24 hrs of developing intolerance and prior to change of treatment was analyzed using 3-OMG absorption method. AUC(0-60) and AUC (0-240) was calculated and data was presented for pre-dose Visit (day prior to change of treatment). Geometric mean and 95 percent CI was analyzed.	Baseline, Day 2, Day 3, Day 4
Secondary	GE Assessment as C60 Within 24 Hrs of Developing Intolerance and Prior to Change of Treatment Using 3-OMG	GE assessment within 24 hrs of developing intolerance and prior to change of treatment was analyzed using 3-OMG absorption method. C60 was calculated and data was presented for pre-dose Visit (day prior to change of treatment). Geometric mean and 95 percent CI was analyzed.	Baseline, Day 2, Day 3, Day 4
Secondary	Number of Participants With Occurrences of Vomiting, Regurgitation and Macroaspiration Episodes	The total number of vomiting, regurgitation and macroaspiration episodes were categorized separately for prior to and post intolerance. Intolerance was considered as start of intolerance treatment. Only the records with non-zero counts were listed.	up to 23 days
Secondary	Total GRV for 24 hr Period	Total GRV for each 24 hr period up to 7 days were assessed to determine the effect of GSK962040 vs. Placebo upon the daily GRV. Intolerance was defined as start of the intolerance treatment. The total GRV for each 24hr period was the sum of all available GRV measurements during the period. The 24hr was counted using the same 24hr clock as for the collection of nutritional data.	Up to Day 7
Secondary	Log Transformed Derived Plasma Cmax of GSK962040 Prior to Intolerance	Blood samples for PK analysis were collected at Day 2, Day 3, Day 4, Day 7 prior to intolerance. Prior to intolerance was defined as prior to development of intolerance. Cmax was defined as maximum observed plasma concentration of Camicinal. The analysis was performed on PK Population. PK Population comprised of participants in the 'Safety' population for whom a PK sample of Camicinal was obtained and analyzed. Only those participants available at the specified time points were analyzed (represented by n=x in the category titles).	Day 2, Day 3, Day 4, Day 7
Secondary	Log Transformed Derived Plasma Cmax of GSK962040 Post Intolerance	Blood samples for PK analysis were collected at Day 2 and Day 4 post development of intolerance. Cmax was defined as maximum observed plasma concentration of Camicinal. The analysis was performed on PK Population. NA indicates that data were not available. SD was not provided if n < 3.	Day 2 and Day 4
Secondary	Derived Tmax of GSK962040 Post Intolerance	Blood samples for PK analysis were collected at Day 2 and Day 4 post development of intolerance. Tmax was defined as time to maximum observed plasma concentration of Camicinal.NA indicates that data were not available. SD was not provided if n<3.	Day 2 and Day 4
Secondary	Derived AUC Over the Dosing Period [AUC(0-tau)] of GSK962040 Post Intolerance	Blood samples for PK analysis were collected at Baseline, and at Day 2 and Day 4 post development of intolerance. AUC from time zero extrapolated to infinite time [AUC(0-inf)] was not analyzed.	Day 2 and Day 4
Secondary	Derived Accumulation Ratio (RO) of GSK962040 Post Intolerance	To estimate the extent of accumulation after repeat dosing, the observed accumulation ratio (Ro) was assessed.	Baseline, Day 2, Day 3, Day 4