Part 1: Number of participants with Adverse Events (AE) and Serious adverse events (SAE)
An AE was defined as any untoward medical occurrence (MO) in a participant temporally associated with the use of a medicinal product (MP), whether or not considered related to the MP and can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with its use. The SAE was any untoward MO that, at any dose, results in death, life threatening, persistent or significant disability/incapacity, results in or prolongs inpatient hospitalization, congenital abnormality or birth defect, that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition. Refer to the general AE/SAE module for a list of AEs and SAEs.
Part 1: Mean values for urea, sodium, potassium, cholesterol, chloride, high density lipids-cholesterol (HDLC), and triglyceride
Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1 pre-dose and 24h post dose in Part 1 of study. All participants were present at the time of measurement.
Part 1: Mean values for creatinine and total bilirubin
Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1 pre-dose and 24h post dose in Part 1 of study. All participants were present at the time of measurement.
Part 1: Mean values for total protein and albumin
Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1 pre-dose and 24h post dose in Part 1 of study. All participants were present at the time of measurement.
Part 1: Mean values for aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), creatine kinase and gamma glutamyl transferase (GGT). All participants were present at the time of measurement.
Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1 pre-dose and 24h post dose in Part 1 of study. All participants were present at the time of measurement.
Part 1: Mean values for platelet and white blood cell (WBC)
Blood samples were collected for measurement of indicated hematology tests on D1 pre-dose and 24h post dose in Part 1 of study.
Part 1: Mean values for hemoglobin and mean corpuscle hemoglobin concentration (MCHC)
Blood samples were collected for measurement of indicated hematology tests on D1 pre-dose and 24h post dose in Part 1 of study.
Part 1: Mean values for hematocrit
Blood samples were collected for measurement of indicated hematology tests on D1 pre-dose and 24h post dose in Part 1 of study.
Part 1: Mean values for mean corpuscle volume (MCV)
Blood samples were collected for measurement of indicated hematology tests on D1 pre-dose and 24h post dose in Part 1 of study.
Part 1: Mean values for mean corpuscle hemoglobin (MCH)
Blood samples were collected for measurement of indicated hematology tests on D1 pre-dose and 24h post dose in Part 1 of study.
Part 1: Mean values for reticulocytes, total neutrophil, lymphocyte, monocyte, eosinophil and basophil
Blood samples were collected for measurement of indicated hematology tests on D1 pre-dose and 24h post dose in Part 1 of study.
Part 1: Mean values for red blood cells (RBC)
Blood samples were collected for measurement of indicated hematology tests on D1 pre-dose and 24h post dose in Part 1 of study.
Part 1: Summary of Results of Statistical Serial Time point Analysis of FEV1 Data-Treatment Differences
Lung function tests (FEV1) was recorded whilst the participant was in a sitting position (if taken whilst the participant was on the bed, their legs should be over the edge). All lung function tests was repeated, until three technically acceptable measurements were made. Each measurement should be done at least 1 M apart. Participants must be resting in the body box for at least 30 seconds prior to any assessments. FEV1 measurements were taken after sGaw measurements. The FEV1 was measured at 15, 1, 4, 12 and 24 h post dose of each treatment period on D1. Data for adjusted mean is presented as least square mean. All participants were present at the time of measurement.
Part 1: Change from Baseline derived Electrocardiogram (ECG) parameters- QT interval corrected according to Bazzet's formula (QTcF) and QT interval corrected according to Fridericia's formula (QTcB) Maximum value (0-4 h)
ECG measurements were made with the participants in a supine position having rested in this position for at least 10 M before each reading. Data is presented as maximum value 0-4 h of each treatment period on D1. The QTcB was derived automatically by the machine. The QTcF was manually derived by dividing QT interval with cube root of division of RR interval by 1000. Where, RR interval (milliseconds [msec]) was calculated as square of QT interval divided by QTcB, which was multiplied by 1000. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Baseline value was defined as the mean of the three pre-dose measurements on D1 for each treatment period. Data for adjusted mean is presented as least square mean.
Part 1: Change from Baseline derived ECG parameters-QTc(F) and QTc(B) Weighted mean (0-4 h)-Part
ECG measurements was made with the participants in a supine position having rested in this position for at least 10 M before each reading. The QTcB was derived automatically by the machine. The QTcF was manually derived by dividing QT interval with cube root of division of RR interval by 1000. Where, RR interval (msec) was calculated as square of QT interval divided by QTcB, which was multiplied by 1000. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Baseline value was defined as the mean of the three pre-dose measurements on D1 for each treatment period. All available data at the actual relative times were included in the derivation of the weighted mean with pre-dose measurements representing the time point zero, and all subsequent time points (0- 4 h) calculated relative to dosing in that period. Data for adjusted mean is presented as least square mean.
Part 1: Mean supine systolic blood pressure (SBP) maximum value (0-4 h)
Participants were required to rest in the supine position for at least 10 M before each reading. SBP was measured with an automatic measuring device. Data is presented as maximum value 0-4 h of each treatment period on D1.Three baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. Data for adjusted mean is presented as least square mean.
Part 1: Mean supine diastolic blood pressure (DBP) minimum change (0-4 h)
Participants were required to rest in the supine position for at least 10 M before each reading. DBP was measured with an automatic measuring device. Data is presented as minimum change 0-4 h of each treatment period on D1. The Baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. Data for adjusted mean is presented as least square mean. Data for adjusted mean is presented as least square mean.
Part 1: Mean supine SBP and supine DBP Weighted mean (0-4 h)
Participants were required to rest in the supine position for at least 10 M before each reading. SBP and DBP were measured with an automatic measuring device. It was measured at 0- 4 h post dose of each treatment period on D1. The baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. All available data at the actual relative times were included in the derivation of the weighted mean with pre-dose measurements representing the time point zero, and all subsequent time points calculated relative to dosing in that period. Data for adjusted mean is presented as least square mean.
Part 1: Change from Baseline supine heart rate maximum value (0-4 h)
Participants were required to rest in the supine position for at least 10 M before each reading. Heart rate was measured with an automatic measuring device. Data is presented as maximum value 0-4 h of each treatment period on D1. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. The baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. Data for adjusted mean is presented as least square mean.
Part 1: Change from Baseline supine heart rate Weighted mean (0-4 h)
Participants were required to rest in the supine position for at least 10 M before each reading. Heart rate was measured with an automatic measuring device. It was measured at 0-4 h post dose of each treatment period on D1. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. The Baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. All available data at the actual relative times were included in the derivation of the weighted mean with pre-dose measurements representing the time point zero, and all subsequent time points calculated relative to dosing in that period. Data for adjusted mean is presented as least square mean.
Part 1: Maximum change in postural SBP and DBP (0-4h)
Participants were required to rest in the supine position for at least 10 M before each reading. SBP and DBP were measured with an automatic measuring device. Data is presented as maximum value 0-4 h of each treatment period on D1. The Baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. Maximum change in postural SBP and DBP (0-4 h) was derived as post dose standing reading minus post dose supine reading. Data for adjusted mean is presented as least square mean.
Part 1: Maximum change from Baseline value (0-4h) for glucose
Data is presented as maximum value of glucose at 0-4 h of each treatment period on D1. Blood samples were collected for measurement of glucose at pre-dose (0.0), 30 M, 1, 2 and 4 h post dose of each treatment period on D1. The Baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Data for adjusted mean is presented as least square mean.
Part 1: Minimum change from Baseline value (0-4h) for potassium
Data is presented as minimum change for potassium at 0-4 h of each treatment period on D1. Blood samples were collected for measurement of potassium at pre-dose (0.0), 30 M, 1, 2 and 4 h post dose of each treatment period on D1. The Baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Data for adjusted mean is presented as least square mean.
Part 1: Maximum change from Baseline value (0-4h) for potassium
Blood samples were collected for measurement of glucose at pre-dose (0.0), 30 M, 1, 2 and 4 h post dose of each treatment period on D1. The data for maximum change from Baseline for potassium was not analyzed.
Part 1: Weighted mean change from baseline (0-4h) for glucose and potassium
Blood samples were collected for measurement of glucose and potassium at pre-dose (0.0), 30 M, 1, 2 and 4 h post dose of each treatment period on D1. The Baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. All available data at the actual relative times were included in the derivation of the weighted mean with pre-dose measurements representing the time point zero, and all subsequent time points calculated relative to dosing in that period. Data for adjusted mean is presented as least square mean.
Part 1: Number of participants with abnormal Holter ECG findings as a function of cardiac monitoring
Holter monitoring (24 h) was conducted at screening and after each dose during. Holter tapes were analyzed locally at site. A screening visit was taken place within 28 days of the first dosing occasion. Participants with abnormal (not clinically significant [NCS]), abnormal (clinically significant [CS]) and no result were presented.
Part 1: Number of participants with abnormal Lead II ECG findings as a function of cardiac monitoring
Lead II ECG monitoring (via telemetry) will be recorded from pre-dose until 6 h after the dose. Participants with abnormal (NCS), abnormal (CS) and no result were presented.
Part 2: Number of participants with AE and SAE
An AE was defined as any untoward MO in a participant temporally associated with the use of a MP, whether or not considered related to the MP and can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with its use. The SAE was any untoward MO that, at any dose, results in death, life threatening, persistent or significant disability/incapacity, results in or prolongs inpatient hospitalization, congenital abnormality or birth defect, that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition. Refer to the general AE/SAE module for a list of AEs and SAEs.
Part 2: Mean values for urea, sodium, potassium, cholesterol, chloride, high density lipids-cholesterol (HDLC), and triglyceride
Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1, 4, 7, 14 pre-dose and 24h post dose on D14 in Part 2 of study.
Part 2: Mean values for creatinine and total bilirubin
Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1, 4, 7, 14 pre-dose and 24h post dose on D14 in Part 2 of study.
Part 2: Mean values for total protein and albumin
Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1, 4, 7, 14 pre-dose and 24h post dose on D14 in Part 2 of study.
Part 2: Mean values for AST, ALT, ALP, creatine kinase and GGT
Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1, 4, 7, 14 pre-dose and 24h post dose on D14 in Part 2 of study.
Part 2: Mean values for hemoglobin and MCHC
Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1, 4, 7, 14 pre-dose and 24h post dose on D14 in Part 2 of study.
Part 2: Mean values for hematocrit
Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1, 4, 7, 14 pre-dose and 24h post dose on D14 in Part 2 of study.
Part 2: Mean values for MCV
Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1, 4, 7, 14 pre-dose and 24h post dose on D14 in Part 2 of study.
Part 2: Mean values for MCH
Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1, 4, 7, 14 pre-dose and 24h post dose on D14 in Part 2 of study.
Part 2: Mean values for total neutrophil, lymphocyte, monocyte, eosinophil and basophil
Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1, 4, 7 pre-dose and 24h post dose on D14 in Part 2 of study.
Part 2: Mean values for platelets and WBC
Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1, 4, 7, 14 pre-dose and 24h post dose on D14 in Part 2 of study.
Part 2: Mean values for RBC
Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1, 4, 7, 14 pre-dose and 24h post dose on D14 in Part 2 of study.
Part 2: Mean values for reticulocytes
Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1, 4, 7 pre-dose and 24h post dose on D14 in Part 2 of study.
Part 2: Change from Baseline derived ECG parameters- QTcF and QTcB Maximum value (0-4 h)
ECG measurements were made with the participants in a supine position having rested in this position for at least 10 M before each reading. Data is presented as maximum value of glucose at 0-4 h of each treatment period on D1 and D14. The QTcB was derived automatically by the machine. The QTcF was manually derived by dividing QT interval with cube root of division of RR interval by 1000. Where, RR interval (msec) was calculated as square of QT interval divided by QTcB, which was multiplied by 1000. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Baseline value was defined as the mean of the three pre-dose measurements on D1 for each treatment period. Data for adjusted mean is presented as least square mean.
Part 2: Change from Baseline derived ECG parameters-QTcF and QTcB Weighted mean (0-4 h)
ECG measurements was made with the participants in a supine position having rested for at least 10 M before reading. Data is presented as maximum value of glucose at 0-4 h of each treatment period on D1 and D14. The QTcB was derived automatically by the machine. The QTcF was manually derived by dividing QT interval with cube root of division of RR interval by 1000. Where RR interval (msec) was calculated as square of QT interval divided by QTcB, which was multiplied by 1000. The change from Baseline was calculated by subtracting the Baseline values from the post-randomization values. Baseline value was defined as the mean of three pre-dose measurements on D1 for each treatment period. All available data at the actual relative times were included in the derivation of the weighted mean with pre-dose measurements representing the time point zero, and all subsequent time points (0-4 h) calculated relative to dosing in that period. Data for adjusted mean is presented as least square mean.
Part 2: Maximum change from Baseline value (0-4h) for potassium
Blood samples were collected for measurement of glucose at pre-dose (0.0), 30 M, 1, 2 and 4 h post dose of each treatment period on D1 and D14. The data for maximum change from Baseline was not analyzed.
Part 2: Ambulatory blood pressure: maximum, minimum, time to maximum, time to minimum and weighted mean for systolic and diastolic blood pressure, and weighted mean arterial pressure over 0-8 and 8-24 h after dosing on Days 1 and 14
Ambulatory blood pressure was monitored over 0-8 h and 8-24 h after dosing of each treatment period on D1 and D14. The data for ambulatory blood pressure was not analyzed.
Part 2: Number of participants with abnormal Holter ECG findings as a function of cardiac monitoring
Holter monitoring (24 h) was conducted at screening and on D1 and 14 of each treatment period. Holter tapes were analyzed locally at site. A screening visit was taken place within 28 days of the first dosing occasion. Participants with abnormal (not clinically significant), abnormal (clinically significant) and no result were presented.
Part 2: Number of participants with abnormal Lead II ECG findings as a function of cardiac monitoring
Lead II ECG monitoring (via telemetry) will be recorded from pre-dose until 8 h after the dose on D1 and D14 of each treatment period. Participants with abnormal (not clinically significant), abnormal (CS) and no result were presented.
Part 2: Mean supine SBP maximum value (0-4 h)
Participants were required to rest in the supine position for at least 10 M before each reading. SBP was measured with an automatic measuring device. Data is presented as maximum value 0-4 h of each treatment period on D1 and D14. The baseline was defined as the mean of the three pre-dose measurements on D1 and D14 for each treatment period. Data for adjusted mean is presented as least square mean.
Part 2: Mean supine DBP minimum change (0-4 h)
Participants were required to rest in the supine position for at least 10 M before each reading. DBP was measured with an automatic measuring device. Data is presented as minimum change 0-4 h of each treatment period on D1 and D14. The baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. Data for adjusted mean is presented as least square mean. Data for adjusted mean is presented as least square mean.
Part 2: Mean supine SBP and supine DBP Weighted mean (0-4 h)
Participants were required to rest in the supine position for at least 10 M before each reading. SBP and DBP were measured with an automatic measuring device. It was measured at 0- 4 h post dose of each treatment period on D1 and D14. The baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. All available data at the actual relative times were included in the derivation of the weighted mean with pre-dose measurements representing the time point zero, and all subsequent time points calculated relative to dosing in that period. Data for adjusted mean is presented as least square mean.
Part 2: Change from Baseline supine heart rate maximum value (0-4 h)
Participants were required to rest in the supine position for at least 10 M before each reading. Heart rate was measured with an automatic measuring device. Data is presented as maximum value 0-4 h of each treatment period on D1 and D14. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. The baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. Data for adjusted mean is presented as least square mean.
Part 2: Change from Baseline supine heart rate Weighted mean (0-4 h)
Participants were required to rest in the supine position for at least 10 M before each reading. Heart rate was measured with an automatic measuring device. It was measured at 0-4 h post dose of each treatment period on D1 and D14. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. The Baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. All available data at the actual relative times were included in the derivation of the weighted mean with pre-dose measurements representing the time point zero, and all subsequent time points calculated relative to dosing in that period. Data for adjusted mean is presented as least square mean.
Part 2: Maximum change in postural SBP and DBP (0-4h)
Participants were required to rest in the supine position for at least 10 M before each reading. SBP and DBP were measured with an automatic measuring device. Data is presented as maximum value 0-4 h of each treatment period on D1 and D14. The Baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. Maximum change in postural SBP and DBP (0-4h) was derived as post dose standing reading minus post dose supine reading. Data for adjusted mean is presented as least square mean.
Part 2: Minimum change from Baseline value (0-4h) for potassium
Data is presented as minimum change for potassium at 0-4 h of each treatment period on D1 and D14. Blood samples were collected for measurement of potassium at pre-dose (0.0), 30 M, 1, 2 and 4 h post dose of each treatment period on D1 and D14. The Baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Data for adjusted mean is presented as least square mean.
Part 2: Weighted mean change from baseline (0-4h) for potassium
Blood samples were collected for measurement of glucose and potassium at pre-dose (0.0), 30 M, 1, 2 and 4 h post dose of each treatment period on D1 and D14. The Baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. All available data at the actual relative times were included in the derivation of the weighted mean with pre-dose measurements representing the time point zero, and all subsequent time points calculated relative to dosing in that period. Data for adjusted mean is presented as least square mean.
Part 2: Summary of AUC after a single dose
Plasma samples for PK analysis were drawn on D1, 7 and 14 at indicated time points of each treatment period. The AUC from time zero (0M) to 2h (AUC 0-2) was area under the plasma concentration-time curve over the 2h time period. AUC(0-6) was area under the plasma concentration-time curve from 0M to 6h. AUC(0-t) was area under the plasma concentration-time curve from 0M to last quantifiable concentration. The AUC extrapolated to inf (AUC[0-inf]) was calculated as the sum of AUC(0-t) and Ct/lambda z, where Ct is the observed GSK961081 concentration obtained from the log-linear regression analysis of the last quantifiable time-point and lambda z is the terminal phase rate constant estimated by linear regression analysis of the log transformed concentration-time data. The number of time points used in the estimation of lambda z.
Part 2: Summary of Cmax of GSK961081 after a single dose
Plasma samples for PK analysis were drawn on D1, 7 and 14 at indicated time points of each treatment period. The first occurrence of the maximum observed GSK961081 concentration determined directly from the raw concentration-time data after each single dose. All participants were present at the time of measurement.
Part 2: Summary of t-last, t-max and t-half
PK population. Only those participants available at the specified time points were analyzed (represented by n=x,x in the category titles). Different participants may have been analyzed at different time points; thus, the overall number of participants analyzed reflects everyone in the PK population.
Part 2: Serial sGaw measurement over 24 hours post-dose on D1 and 14
sGaw was assessed by whole body plethysmography at 30 M, 1, 4, 12 and 24 h post dose of each treatment period on D1 and D14. Participants must be resting in the body box for at least 30 seconds prior to any assessments. Data for adjusted