Effect of GSK1399686 in Patients With Mild to Moderately Active Ulcerative Colitis

Study Overview
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Brief Summary
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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.

Official Title
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A Double-Blind, Double-Dummy, Placebo- and Active-Controlled Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Anti-Inflammatory Effects of GSK1399686 in Patients With Mild to Moderately Active Ulcerative Colitis

Conditions
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Colitis, Ulcerative

Intervention / Treatment
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* Drug: GSK1399686


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female of non-childbearing potential between 18 and 65 years of age inclusive. Presence of mild-to-moderately active ulcerative colitis spread beyond the rectum as evidenced by clinical signs and endoscopy. UCDAI score 4-10 (inclusive) with rectal bleeding score ≥ 1, endoscopy score ≥ 1 and Physician's rating of disease activity < 3. Body weight > or = to 50 kg and BMI within the range 18.5-29.9 kg/m2 (inclusive). Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form Exclusion Criteria: History of sensitivity to any component of study medications, history of hypersensitivity to ACTH, or a history of drug or other allergy that, in the opinion of the Investigator, contraindicates patient's participation in the study. History of renal sensitivity to 5-ASA or presence of nephritis, nephropathia or renal function impairment. Presence or a history of asthma or presence or history of other serious allergic disorder. Presence or history of chronic liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening. Presence of significant hematologic disorder, or significant bleeding or immune system disorder. QTcB or QTcF >450 msec; or QTc >480 msec in patients with Bundle Branch Block, based on an average QTc value of triplicate ECGs, if the first ECG showed an abnormal value. Presence of a significant cardiac, pulmonary, metabolic or infectious disease or mental disorder that, in the opinion of the Investigator, represents an unacceptable safety risk for participation in this trial. History of malignant neoplastic disease within the past 5 years other than localized basal cell skin cancer, squamous cell skin cancer or cancer in situ that has been resected. History of regular alcohol consumption within 6 months of the study or presence of recreational drug abuse or dependence. Presence of infectious colitis as evidenced by stool culture positive for enteric pathogens or positive Clostridium difficile cytotoxin assay. Suspicion of Crohn's disease, indeterminate colitis, microscopic colitis, ischaemic colitis or radiation-induced colitis, based on medical history, endoscopy and/or histological findings. Bowel surgery within last 12 months. Treatment with oral aminosalicylates at dose ≥ 2.4 g/day and/or with topical aminosalicylates at any dose within 2 weeks prior to Day 1 visit. Treatment with systemic or topical corticosteroids within 4 weeks prior to Day 1 visit. Treatment with TNF-α inhibitors or other biologics within 2 months prior to Day 1 visit. Treatment with immunosuppressants (azathioprine or 6-mercaptopurine), if initiated within 3 months prior to Day 1 visit, or if changed in terms of drug or dose within 3 months prior to Day 1 visit. Regular use of probiotic or prebiotic preparations, if initiated within 4 weeks prior to Day 1 visit. Regular daily use of non-steroidal anti-inflammatory drugs (NSAIDs), except low dose aspirin (325 mg/day) for cardioprotection, within 7 days prior to Day 1 visit. Treatment with medications known to be strong inducers of CYP3A4/5 (e.g. carbamezipine, phenobarbital, phenytoin, rifabutin, rifampin, troglitazone) or regular use of St. John's Wort within 14 days prior to Day 1 visit. Treatment with medications known to be strong inhibitors of CYP3A4/5 (e.g. ketoconazole, itraconazole, fluconazole, mibefradil, clarithromycin, erythromycin, diltiazem, verapamil), or regular use of grapefruit juice within 7 days prior to Day 1 visit. Treatment with medications known to be sensitive CYP3A4 substrates with a narrow therapeutic index (e.g. alfentanil, astemizole, cisapride, cyclosporine, diergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, terfenadine) within 7 days prior to Day 1 visit. Participation in a clinical trial and treatment with an investigational product within the following time period prior to the Day 1 visit: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). Prior enrolment in the present trial. For Canadian sites only: Patients with existing gastric or duodenal ulcers. Patients with urinary tract obstruction

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 2<br>ASACOL 800mg t.i.d. | Drug: GSK1399686<br>* 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.<br>|
| Experimental: Group 1<br>GSK1399686 at 3-4 dose levels | Drug: GSK1399686<br>* 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.<br>|
| Experimental: Group 3<br>Placebo | Drug: GSK1399686<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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). | 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. | Up to Week 6 | 
| 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. | 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. | 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). | 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). | 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. | 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. | 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mesalazine, ulcerative colitis, pharmacokinetics/dynamics, GSK1399686