GSK1399686

An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition, associated with liver injury and impaired liver function defined as alanine aminotransferase \>=3 x upper limit of normal (ULN), and total bilirubin \>=2 x ULN or international normalized ratio \>1.5.

Normal reference range for clinical chemistry parameters include: alanine amino transferase (ALT) 0-41 international units per liter (IU/L); aspartate amino transferase (AST) 10 - 38 IU/L; alkaline phosphatase 40 - 129 IU/L; gamma glutamyl transferase (GGT) 10 - 66 IU/L; albumin 39 - 48 gram per liter (g/L); total protein 66 - 87 g/L; direct bilirubin 0 - 5.13 micromole per liter (µmol/L); total bilirubin 0 - 17.1 µmol/L; creatinine 61.88 - 106.08 µmol/L; uric acid 202.232 - 416.36 µmol/L; calcium 2.0958 - 2.42015 millimole per liter (mmol/L); cholesterol 2.8446 - 5.9478 mmol/L; chloride 98 - 106 mmol/L; glucose 2.2204 - 11.102 mmol/L; potassium 3.4 - 4.5 mmol/L; magnesium 0.6576 - 1.0686 mmol/L; sodium 0 - 2.26 mmol/L; urea/ blood urea nitrogen (BUN) 0 - 17.85 mmol/L. Number of participants with high and low values compared to the reference range is presented. Only those parameters for which at least one value outside the reference range was reported at any visit are summarized.

Normal reference range for clinical chemistry parameters include: basophils 0 - 0.2 giga cells (GI)/L; eosinophils 0 - 0.4 GI/L; lymphocytes 1 - 4.8 GI/L; monocyte 0 - 0.8 GI/L; total neutrophils (total absolute neutrophils count) 1.8 - 7.7 GI/L; platelet count 150 - 400 GI/L; red blood cell count 4.5 - 5.9 GI/L; white blood cell count 3.9 - 10.6 GI/L; hemoglobin 135 - 175 g/L; hematocrit 0.41 - 0.53 ratio; mean corpuscle hemoglobin concentration 310 - 370 g/L; mean corpuscle hemoglobin 26 - 34 picogram (PG); mean corpuscle volume 80 - 100 femtoliter (FL); reticulocytes 0.05 - 0.1 trillion cells (TI)/L. Number of participants with high and low values compared to the reference range is presented. Only those parameters for which at least one value outside the reference range was reported at any visit are summarized.

The urinalysis parameters included urine occult blood, urine general, glucose, ketones and protein by dipstick analysis. The assessments were done on screening, Week 2, Week 4 and Week 6.The number of participants with results of 0, 0.3, 1, 1+, 1.5, 10, 2+, 3+, 30, 4+, 5+, 55, not rated (NR), positive (pos) and trace is presented.

Vital signs assessment included systolic blood pressure (SBP), Diastolic blood pressure (DBP) and heart rate (HR). Criteria for vital sign values meeting PCI included: SBP \< 85 and \> 160 millimeter of mercury (mmHg); DBP \< 45 and \> 100 mmHg and HR \< 40 and \> 110 beats per minute (bpm). The assessments were done on screening, Week 2, Week 4 and Week 6. The participants with values higher and lower than the PCI range is presented. Only those parameters for which at least one value of PCI was reported at any visit are summarized.

Single 12-lead ECGs were obtained at each timepoint during the study using an ECG machine that automatically calculated the HR and measured PR, QRS, QT, and QTc intervals. Criteria for ECG parameter values meeting PCI included absolute QTc interval \>500 millisecond (msec); increase from Baseline QTc \>60 msec; PR interval \<110 and \>220 msec; QRS interval \<75 and \>110 msec. Only those participants for whom at least one value of abnormal clinically significant or abnormal not clinically significant ECG findings were reported at any visit are summarized.

Treatment effects was assessed using a low-dose ACTH stimulation test which was performed on Day 1 pre dose (Baseline) and at Week 4 visit. A blood sample for plasma cortisol was taken immediately, before and 30 minutes after an intravenous injection of 1 microgram (μg). tetracosactide acetate, a synthetic peptide displaying the same physiological properties as ACTH. The change from morning basal cortisol was calculated for Day 1 pre-dose (ACTH1) and Week 4 (ACTH2) using the equation: ACTH1 = Day 1 post ACTH - Day 1 pre ACTH; ACTH2 = Week 4 post ACTH - Week 4 pre ACTH. The change from morning basal cortisol between Week 4 and Day 1 (ACTH effect) was calculated as : ACTH effect = ACTH2 - ACTH1. The difference in morning basal cortisol between Week 4 and Day 1 (ACTH morning) was calculated as:- ACTH morning = Week 4 pre ACTH - Day 1 pre ACTH. Adrenocorticol function was classed as normal if the change from post ACTH to pre ACTH (using ACTH1 and ACTH2) was \>= 200 nanomoles per liter.

The assessment was done on the samples collected from the sigmoid colon and from the rectum obtained within 24 hour after the last dose on Week 4 visit after endoscopic evaluation of respective area for determination of GSK1399686 concentration. Non-quantifiable (NQ) concentration values were imputed as 0.