Safety, Tolerability, Efficacy and Dose-response of GSK2831781 in Ulcerative Colitis

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect or other important medical events that may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed before.

Vital signs were measured in a seated or semi-supine position after 5 minutes rest. The clinical concern range for vital signs were: SBP (lower: <85 and upper: > 160 mmHg); DBP (lower: <45 mmHg and upper: >100 mmHg); PR (lower: <40 and upper: >110 bpm) and Temp (lower: <35 and upper: >38 degree Celsius). Participants were counted in the worst-case category that their value changed to (low, within range or no change, or high), unless there was no change in their category. Participants whose value category was unchanged (e.g. High to High), or whose value became within range, were recorded in the "To w/in Range or No Change category". Participants were counted twice if the participant had values that changed "To Low" and "To High", so the percentages may not add to 100%.

Blood samples were collected for the assessment of hematology parameters. The clinical concern range for the parameters were: Hct (low: 0.201 and high: >0.599 proportion of red blood cells in blood); Hgb (low: <80 and high: >180 g/L), Lymph (low: <0.8x10^9 cells/L); Neut count (low: <1.5x10^9 cells/L); plat count (low: <100x10^9 cells/L and high: >550x10^9 cells/L); leuko (low: <3x10^9 cells/L and high: >20x10^9cells/L) and Eos (high: >=1x10^9 cells/L). Participants were counted in the worst-case category that their value changed to (low, within range or no change, or high), unless there was no change in their category. Participants whose value category was unchanged (e.g. High to High), or whose value became within range, were recorded in the "To w/in Range or No Change category". Participants were counted twice if the participant had values that changed "To Low" and "To High", so the percentages may not add to 100%.

Blood samples were collected for the assessment of clinical chemistry parameters. The clinical concern range for the parameters were: Alb (low: <30 and high: >55 g/L), C) (low: 2 and high: 2.75 mmol/L), urea (high: >10.5 mmol/L); Creat (high: change from Baseline >26 µmol/L), Glu (low: <3.5 and high: >7.9 mmol/L); eGFR (low: <60 mL/min/1.73m^2]; Pot low: <3 and high: >5.5 mmol/L); Sod (low: <130 and high: >150 mmol/L); Pro (low: <50 and high: >85 g/L) and CRP (high: >30 milligrams/L). Participants were counted in the worst-case category that their value changed to (low, within range or no change, or high), unless there was no change in their category. Participants whose value category was unchanged (e.g. High to High), or whose value became within range, were recorded in the "To w/in Range or No Change category". Participants were counted twice if the participant had values that changed "To Low" and "To High", so the percentages may not add to 100%.

Blood samples were collected for the assessment of liver function parameters. The clinical concern range for liver function parameters were: ALT (high: >=2 times ULN); AST (high: >=2 times ULN); ALP (high: >=2 times ULN) and Bil (high: >=1.5 times ULN). Participants were counted in the worst-case category that their value changed to (low, within range or no change, or high), unless there was no change in their category. Participants whose value category was unchanged (e.g. High to High), or whose value became within range, were recorded in the "To w/in Range or No Change category".

Urine samples were collected for the assessment of urine parameters by dipstick and microscopy. The dipstick test gives results in a semi-quantitative manner, and results can be read as Trace, 1+, 2+ indicating proportional concentrations in the urine sample. The clinical concern range for urine parameters were: Bil (high: >1+), glu (high: >1+); ket (high: >2+); leuko (high: >1+); LE; nit (high: positive); OB (high: >1+); pH (low: <4.6 and high: >8); prot (high:>1+); erythro (high: >3 cells per hpf); sp gra (low: <1.001 and high: >1.035) and uro (high: >1 mg/deciliter).

Twelve lead ECGs were obtained using an ECG machine that automatically calculated the QTcB and QTcF intervals. The clinical concern range for the QTcB and QTcF intervals was upper: >450 milliseconds.

The adapted Mayo clinical score consists of three components: stool frequency, rectal bleeding, and endoscopic appearance. The score for each component ranges from 0 (normal/none) to 3 (severe). The adapted Mayo endoscopic score of 0 indicates normal or inactive disease and 1 indicates mild disease (erythema, decreased vascular pattern).

The adapted Mayo clinical score is based on the complete 4-domain Mayo clinical score, but without the PGA. It consists of three components: stool frequency, rectal bleeding, and mucosal endoscopic appearance. The score for each component ranges from 0 (normal/none) to 3 (severe). The total adapted Mayo score is calculated as the sum of all three components and ranges from 0 to 9. Higher scores indicate greater disease severity. Clinical remission is defined as adapted Mayo Clinical Score of <=2 with no individual sub-score >1 and a rectal bleeding sub score of 0 with stool frequency sub score not greater than Baseline.

The adapted Mayo clinical score is based on the complete 4-domain Mayo clinical score, but without the PGA. It consists of three components: stool frequency, rectal bleeding, and mucosal endoscopic appearance. The score for each component ranges from 0 (normal/none) to 3 (severe). The total adapted Mayo score is calculated as the sum of all three components and ranges from 0 to 9. Higher scores indicate greater disease severity. Clinical response is defined as reduction in adapted Mayo clinical score >=3 points from Baseline and >=30% from Baseline and decrease in the rectal bleeding sub-score of >=1 point from Baseline (or a score of 0 or 1).

The Complete 4-domain Mayo Score is a 12-point scoring system where disease is evaluated based on the four components: stool frequency, rectal bleeding, PGA and endoscopic appearance (with mild friability associated with an endoscopic score of 1). Symptomatic remission is defined as a rectal bleeding subscore of 0, and a stool frequency subscore of <=1, with no worsening from Baseline.

The partial Mayo clinical score is based on the complete 4-domain Mayo clinical score but without the endoscopy sub-score. It consists of three components: stool frequency, rectal bleeding, and PGA. The score for each component ranges from 0 (normal/none) to 3 (severe). The total partial Mayo score is calculated as the sum of all three components and ranges from 0 to 9. Higher scores indicate greater disease severity. Baseline value was the latest pre-dose assessment with a non-missing value from Double-Blind Induction study phase. Change from Baseline was calculated as value at specified time point minus Baseline value.

The adapted Mayo clinical score is based on the complete 4-domain Mayo clinical score, but without the PGA. It consists of three components: stool frequency, rectal bleeding, and mucosal endoscopic appearance. The total adapted Mayo endoscopy score ranges from 0 (normal or inactive disease) to 3 (severe disease [spontaneous bleeding, ulceration]). Baseline value was the latest pre-dose assessment with a non-missing value from Double-Blind Induction study phase. Change from Baseline was calculated as value at specified time point minus Baseline value.

UCEIS was used as an additional tool to assess disease activity based on 3 sub-scales: endoscopic vascular pattern, bleeding, erosions and ulcerations. Individual sub-scale scores were vascular pattern (0=Normal, 1=Patchy loss, 2=Obliterated); bleeding (0=None, 1=Mucosal, 2=Luminal mild, 3=Luminal severe); erosions and ulcerations (0=None, 1=Erosions, 2=Superficial ulcer, 3=Deep ulcer). UCEIS total score was calculated as the sum of all 3 sub-scale scores and ranges from 0 to 8, with higher scores indicating more severe disease. Baseline value was the latest pre-dose assessment with a non-missing value from Double-Blind Induction study phase. Change from Baseline was calculated as value at specified time point minus Baseline value.

RHI was assessed by central reading of gut pinch biopsies. The RHI Score is a continuous score, ranging from 0-33 with higher scores indicating more severe disease. RHI Remission is defined as an RHI score <=6. Responders were defined as number of participants with RHI score <=6.

Nancy Histological Index was assessed by central reading of gut pinch biopsies. Key domains for scoring of the indices include chronic inflammatory infiltrate, neutrophils in the epithelium, lamina propria neutrophils, erosion and ulceration scored from 0 to 3 and multiplied by a weighting factor. The total Nancy Histological Index score is calculated by summing the weighted scores of the histological items, with total scores ranging from 0 (no disease activity) to 33 (severe disease activity). Nancy Index Remission was defined as a grade of 0 or 1. Responders were defined as number of participants with Nancy Index score of 0 or 1.

The Geboes Index is divided in 6 grades: architectural changes [grade 0], chronic inflammatory infiltrate [grade 1], lamina propria neutrophils and eosinophils [grade 2], neutrophils in epithelium [grade 3], crypt destruction [grade 4] and erosions or ulcerations [grade 5]. The subscores for grade 0 to 4 ranges from 0 (none/no abnormality) to 3 (marked increase/severe abnormality) and for grade 5 ranges from 0 (No erosion, ulceration, or granulation tissue) to 4 (Ulcer or granulation tissue). The overall Geboes score is derived by summing the subscores of the grades and ranges from 0 to 22, with higher scores indicating greater disease severity. Geboes Histological Remission was defined as a Geboes score <2. Responders were defined as number of participants with Geboes score <2.

Serum samples were collected at indicated time points to measure CRP levels. Baseline value was the latest pre-dose assessment with a non-missing value from Double-Blind Induction study phase. Change from Baseline was calculated as value at specified time point minus Baseline value.

Fecal samples were collected at indicated time points to measure fecal calprotectin. Baseline value was the latest pre-dose assessment with a non-missing value from Double-Blind Induction study phase. Ratio to Baseline is the value at specified time point divided by Baseline value

Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of GSK2831781. PK parameters were calculated using standard non-compartmental analysis.

Blood samples were collected at indicated time points for PK analysis of GSK2831781. PK parameters were calculated using standard non-compartmental analysis.

Blood samples were collected at indicated time points for PK analysis of GSK2831781. PK parameters were calculated using standard non-compartmental analysis.

Serum samples were assessed for the presence of anti-drug antibodies using a tiered approach. The assay involved screening, confirmation and titration steps. If serum samples tested positive in the screening assay, they were considered 'potentially positive' and were further analyzed for the specificity using the confirmation assay. Samples that confirmed positive in the confirmation assay were reported as 'confirmed positive'.