This study is the first-time-in-patient trial of GSK1399686, a novel locally-acting anti-inflammatory compound, aimed at obtaining initial information on the tolerability, safety, pharmacokinetics (including concentrations in colon mucosa) and anti-inflammatory activity of GSK1399686 upon oral dosing in patients with active ulcerative colitis. The study is designed as a randomized, double-blind, double-dummy, placebo-controlled, sequential dose escalating trial, with an active control (ASACOL) group as internal control. Up to three cohorts (Cohorts 1-3), each consisting of approximately 20 patients with mild-moderately active ulcerative colitis not limited to the rectum, will be included, one for each dose level of GSK1399686 to be tested. Within a cohort, patients will be randomized in a 3:1:1 ratio to receive GSK1399686 (once daily over 4 weeks, followed by 2 weeks dosing with placebo), placebo, or ASACOL (t.i.d. for 6 weeks), respectively. An interim analysis of fecal markers and disease activity data will be performed by the end of Cohort 3. Based upon results, the study may be stopped or continued by recruiting either Cohort 4 (if data on an additional dose level would be warranted to establish or clarify a dose-response relationship) or, in the case of a robust efficacy signal at any dose level previously studied, Cohort 5 (to expand the sample size for given dose level in order to evaluate the efficacy of GSK1399686). The number of patients and randomization allocation ratio may be altered in Cohort 5 and it may not include an active control arm. If Cohort 4 is initiated upon interim analysis, then a second interim analysis may be performed at the end of Cohort 4, to assess whether progression into Cohort 5 (as defined above) would be justifiable.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
120
Each dose level of GSK1399686 will be subsequently tested in a cohort of approximately 20 patients, who will be randomized in a 3:1:1 ratio to receive GSK1399686 (once daily over 4 weeks, followed by 2 weeks dosing with placebo), placebo, or ASACOL (t.i.d. for 6 weeks), respectively.
GSK Investigational Site
Bonheiden, Belgium
GSK Investigational Site
Brussels, Belgium
GSK Investigational Site
Ghent, Belgium
GSK Investigational Site
Edmonton, Alberta, Canada
GSK Investigational Site
Kingston, Ontario, Canada
GSK Investigational Site
London, Ontario, Canada
GSK Investigational Site
Vaughan, Ontario, Canada
GSK Investigational Site
Québec, Quebec, Canada
GSK Investigational Site
Hanover, Lower Saxony, Germany
GSK Investigational Site
Münster, North Rhine-Westphalia, Germany
...and 16 more locations
Number of Participants With Any Adverse Events (AE) or Serious Adverse Events (SAE)
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.
Time frame: Up to Week 6
Number of Participants With Clinical Chemistry Data Outside the Reference Range
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.
Time frame: Screening (Day -7 to -1), Day 1, Week 1, 2, 3, 4 and 6
Number of Participants With Hematology Data Outside the Reference Range
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.
Time frame: Screening (Day -7 to -1), Day 1, Week 1, 2, 3, 4 and 6
Number of Participants of Abnormal Urinalysis Dipstick Results
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.
Time frame: Screening (Day -7 to -1), Week 2, 4 and 6
Number of Participants With Vital Sign Outside Range of Potential Clinical Importance (PCI)
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.
Time frame: Screening (Day -7 to -1), Week 2, 4 and 6
Number of Participants With Abnormal Electrocardiography (ECG) Findings
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.
Time frame: Screening (Day -7 to -1), Week 2, 4 and 6
Mean Treatment Effects on Basal Morning Cortisol and Adrenocorticotropic Hormone (ACTH) Stimulated Cortisol Levels at Week 4 in Comparison With Baseline
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.
Time frame: Baseline (Day 1, pre dose) and Week 4
Mean Concentration of GSK1399686 in Colon Biopsy Obtained Within 24 h After the Last Dose
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.
Time frame: Week 4
Mean Simple Clinical Colitis Activity Index (SCCAI) Score
SSCAI included composite score: bowel frequency during day on a scale of 0-3 defined as 0 was \<= 3, 1= 4 to 6, 2= 7 to 9 and 3 was \> 9, during night on a scale of 0-2 defined as 0= none, 1=1 to 3 and 2 was \>=4, defecation urgency on a scale of 0-3 defined as 0=none, 1=hurry, 2=immediately and 3=incontinence, blood in stool on a scale of 0-3 defined as 0= none, 1= trace, 2= occasionally frank and 3= usually frank, general well being on a scale of 0-4 defined as 0=very well, 1= slightly below par, 2= poor, 3 = very poor and 4= terrible, extracolonic features (arthritis, pyoderma gangrenosum, erythema nodosum, uveitis) on a scale of 0-1 defined as 0= absent, 1= present. The SCCAI score was calculated as a sum of scores for each individual component of the SCCAI. Minimum score 0, maximum score 19. Higher score implied worsening of symptoms. Participants were given a diary to score each component of SCCAI each morning. Average SCCAI scores over last 3 days were used for each Week.
Time frame: Up to Week 6
Number of Participants With Clinical Response and Clinical Remission at Week 4 and Week 6
Participants were defined as clinical responders if the average change from baseline total SCCAI score was \<-2. (i.e. the post dose total SCCAI score was decreased by \>2 points compared to the baseline total SCCAI score). Baseline was defined as the value on Day -1. The change from baseline total SCCAI score was derived by subtracting the baseline value (Day -1) from the individual post-dose values. Participants were defined as in clinical remission if the post dose total SCCAI score was \<3 and baseline SCCAI score was not \<3 (i.e . =\>3).
Time frame: Week 4 and Week 6
Median Time to Clinical Response and Clinical Remission
Time to clinical response was defined as the number of days between first dose of study medication and first day of at least 3 consecutive days with SCCAI score decreased for \>2 points in comparison with baseline (Day -1 value). Time to clinical remission was defined as the number of days between the first dose of study medication and the first day of at least 3 consecutive days with SCCAI score \< 3. Time to clinical response and remission was derived using daily diary data. Participants who did not meet the criteria for clinical response or clinical remission were censored at their last day on study medication.
Time frame: Up to Week 6
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Mean Fecal Calprotectin Levels Over Time
Fecal calprotectin, a non-invasive surrogate marker of inflammation in the small intestine, and levels of which was associated with mucosal healing. Calprotectin is a calcium and zinc-binding protein found in neutrophils, monocytes and macrophages. Calprotectin is produced in significant amounts by inflammatory cells. Fecal levels of this protein has been demonstrated to correlate with colorectal and intestinal inflammation. Calprotectin plays a regulatory role in the inflammatory process and used as a diagnostic biomarker. It was assessed from Week 1 to Week 6.
Time frame: Up to Week 6
Mean Fecal Lactoferrin Levels Over Time
Fecal lactoferrin, a non-invasive surrogate marker of inflammation in the small intestine, and levels of which was associated with mucosal healing. Lactoferrin is an iron binding glycoprotein that is the major component of the secondary granules of polymorphonuclear neutrophils (but not monocytes and lymphocytes). Lactoferrin is produced in significant amounts by inflammatory cells. Fecal levels of this protein has been demonstrated to correlate with colorectal and intestinal inflammation. Lactoferrin plays an important role in the innate immunity as a bactericidal and used as a diagnostic biomarker. It was assessed from Week 1 to Week 6.
Time frame: Up to Week 6
Mean Maximum Observed Concentration (Cmax) on Day 1 and Day 28 Derived From Observed Plasma Concentrations of GSK1399686 After Repeated Oral Dosing
Cmax was derived on Day 1 and Day 28 from observed plasma concentrations of GSK1399686 after repeated oral dosing. Blood samples were collected on Day 1 (1 hour, 2 hour, 3 hour post dose) and Day 28 (Week 4 at pre dose, 1 hour, 2 hour, 3 hour and 4 hour morning post dose).
Time frame: Day 1 (1 hour, 2 hour, 3 hour post dose) and Day 28 (Week 4 at pre dose, 1 hour, 2 hour, 3 hour and 4 hour morning post dose)
Pre-dose Trough Concentration at the End of the Dosing Interval (Cτ) on Day 28 Derived From Observed Plasma Concentrations of GSK1399686 After Repeated Oral Dosing
Cτ was derived on Day 28 from observed plasma concentrations of GSK1399686 after repeated oral dosing. Blood samples were collected on Day 28 (Week 4 at pre dose, 1 hour, 2 hour, 3 hour and 4 hour morning post dose).
Time frame: Day 28 (Week 4 at pre dose, 1 hour, 2 hour, 3 hour and 4 hour morning post dose)
Plasma Clearance Estimated Based on Population Pharmacokinetic Analysis of Healthy Volunteers (Historical Data) and Patient Data
Clearance derived from plasma concentration-time data was planned to be combined with data from healthy volunteers from Phase I study to characterize the population pharmacokinetics of GSK1399686. However data for this outcome measure was not collected.
Time frame: Day 1 (1 hour, 2 hour, 3 hour post dose), Week 1 (anytime relative to the last dose), Week 2 (anytime relative to the last dose) and Day 28 (Week 4 at pre dose, 1 hour, 2 hour, 3 hour and 4 hour morning post dose)
Volume of Distribution Estimated Based on Population Pharmacokinetic Analysis of Healthy Volunteers (Historical Data) and Patient Data
Volume of distribution derived from concentration-time data was planned to be combined with data from healthy volunteers from Phase I study to characterize the population pharmacokinetics of GSK1399686. However data for this outcome measure was not collected.
Time frame: Day 1 (1 hour, 2 hour, 3 hour post dose), Week 1 (anytime relative to the last dose), Week 2 (anytime relative to the last dose) and Day 28 (Week 4 at pre dose, 1 hour, 2 hour, 3 hour and 4 hour morning post dose)