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

Phase 2

Terminated

Conditions: Gastroparesis

Interventions: Drug: GSK962040 50 mg
Drug: Placebo NG
Drug: Metoclopramide 10 mg
Drug: Placebo IV

Registration Number: NCT01934192

Lead Sponsor: GlaxoSmithKline

Brief 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 91

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Initial randomization: GSK962040 Arm	GSK962040 50 mg	Subjects in the GSK962040 Arm will receive 50 mg once daily enteral dose administered through NG tube up to 7 days.
Initial randomization: Placebo Arm	Placebo NG	Subjects in the placebo arm will receive once daily dose enteral dose administered through NG tube up to 7 days.
Treatment change due to intolerance: GSK962040 Arm	GSK962040 50 mg	Subjects that develop intolerance and that originally received Placebo will receive 50 mg once daily enteral dose administered through NG tube + placebo IV
Treatment change due to intolerance: GSK962040 Arm	Placebo IV	Subjects that develop intolerance and that originally received Placebo will receive 50 mg once daily enteral dose administered through NG tube + placebo IV
Treatment change due to intolerance: Metoclopramide Arm	Metoclopramide 10 mg	Subjects that develop intolerance and that originally received GSK962040 will receive metoclopramide 10 mg IV every 6 h + placebo NG
Treatment change due to intolerance: Metoclopramide Arm	Placebo NG	Subjects that develop intolerance and that originally received GSK962040 will receive metoclopramide 10 mg IV every 6 h + placebo NG

Primary Outcome Measures

Name	Time	Method
Average Percentage Goal Volume Delivered Prior to Development of Intolerance for ITT Population	Up to Day 7	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.
Average Percentage Goal Volume Delivered Prior to Development of Intolerance for PP Population	Up to Day 7	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.

Secondary Outcome Measures

Name	Time	Method
Average Percentage Goal Calories Delivered Prior to Development of Intolerance	Up to Day 7	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.
Average Percentage Goal Protein Delivered Prior to Development of Intolerance	Up to Day 7	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.
Time to Delivery of 80 Percent Prescribed Calories Prior to Intolerance	Up to Day 7	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.
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	up to 23 days	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.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)	Up to 23 days	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.
Change From Baseline in Heart Rate (HR)	Up to 23 days	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.
Number of Participants With Maximum Increase From Baseline in Electrocardiogram (ECG) Values	Up to 23 days	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).
Change From Baseline in Albumin and Total Protein Levels	Up to 23 days	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.
Change From Baseline in Alkaline Phosphatase (Alk. Phosph.), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma Glutamyl Transferase (GGT) Levels	Up to 23 days	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.
Change From Baseline in Total and Direct Bilirubin, Creatinine and Uric Acid Levels	Up to 23 days	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.
Change From Baseline in Calcium, Chloride, Carbon Dioxide, Glucose, Potassium, Sodium, Blood Urea Nitrogen (BUN) Values	Up to 23 days	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.
Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet and White Blood Cell (WBC) Levels	Up to 23 days	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.
Change From Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) Levels	Up to 23 days	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.
Change From Baseline in Hematocrit Level	Up to 23 days	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.
Change From Baseline in Mean Corpuscle Volume (MCV) Levels	Up to 23 days	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.
Change From Baseline in Red Blood Cell (RBC) and Reticulocyte Count	Up to 23 days	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.
Change From Baseline in Mean Corpuscle Hemoglobin (MCH) Levels	Up to 23 days	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.
Log Transformed Concentration at 60 Minutes (Min) (C60) and Maximum Observed Concentration (Cmax) of Acetaminophen (Prior to Intolerance)	At Day 2	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).
Log Transformed AUC[0-60] of Acetaminophen	At Day 2	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)
Log Transformed AUC[0-60] of 3-O-methylglucose (3- OMG)	At Day 2	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)
Log Transformed C60 of 3-OMG	At Day 2	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).
Derived Tmax of 3-OMG Post Intolerance	At Day 2	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.
Percentage of Participants That Became Intolerant	Up to Day 7	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.
Time to Development of Feeding Intolerance	Up to Day 7	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.
GE Assessment as AUC (0-60) Within 24 Hrs of Developing Intolerance and Prior to Change of Treatment Using Acetaminophen	Day 2	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.
GE Assessment as Cmax Within 24 Hrs of Developing Intolerance and Prior to Change of Treatment Using Acetaminophen	Baseline, Day 2, Day 3, Day 4	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.
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	Baseline, Day 2, Day 3, Day 4	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.
GE Assessment as C60 Within 24 Hrs of Developing Intolerance and Prior to Change of Treatment Using 3-OMG	Baseline, Day 2, Day 3, Day 4	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.
Derived Tmax of GSK962040 Post Intolerance	Day 2 and Day 4	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.
Number of Participants With Occurrences of Vomiting, Regurgitation and Macroaspiration Episodes	up to 23 days	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.
Total GRV for 24 hr Period	Up to Day 7	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.
Log Transformed Derived Plasma Cmax of GSK962040 Prior to Intolerance	Day 2, Day 3, Day 4, Day 7	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).
Log Transformed Derived Plasma Cmax of GSK962040 Post Intolerance	Day 2 and Day 4	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.
Derived AUC Over the Dosing Period [AUC(0-tau)] of GSK962040 Post Intolerance	Day 2 and Day 4	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.
Derived Accumulation Ratio (RO) of GSK962040 Post Intolerance	Baseline, Day 2, Day 3, Day 4	To estimate the extent of accumulation after repeat dosing, the observed accumulation ratio (Ro) was assessed.