Last updated: 11/07/2018 03:21:09
Effect of GSK1399686 in Patients with Mild to Moderately Active Ulcerative Colitis
EudraCT ID
EU CT Number
Not applicable
Trial status
Completed
Completed
Trial overview
Official title: 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
Trial description: 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.
Primary purpose:
Treatment
Trial design:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Allocation:
Randomized
Primary outcomes:
Number of participants with any adverse events (AE) or serious adverse events (SAE)
Timeframe: Up to Week 6
Number of participants with clinical chemistry data outside the reference range
Timeframe: Screening (Day -7 to -1), Day 1, Week 1, 2, 3, 4 and 6
Number of participants with hematology data outside the reference range
Timeframe: Screening (Day -7 to -1), Day 1, Week 1, 2, 3, 4 and 6
Number of participants of abnormal urinalysis dipstick results
Timeframe: Screening (Day -7 to -1), Week 2, 4 and 6
Number of participants with vital sign outside range of potential clinical importance (PCI)
Timeframe: Screening (Day -7 to -1), Week 2, 4 and 6
Number of participants with abnormal electrocardiography (ECG) findings
Timeframe: 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
Timeframe: Baseline (Day 1, pre dose) and Week 4
Mean concentration of GSK1399686 in colon biopsy obtained within 24 h after the last dose
Timeframe: Week 4
Secondary outcomes:
Mean Simple Clinical Colitis Activity Index (SCCAI) score
Timeframe: Up to Week 6
Number of participants with clinical response and clinical remission at Week 4 and Week 6
Timeframe: Week 4 and Week 6
Median time to clinical response and clinical remission
Timeframe: Up to Week 6
Mean fecal calprotectin levels over time
Timeframe: Up to Week 6
Mean fecal lactoferrin levels over time
Timeframe: 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
Timeframe: 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
Timeframe: 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
Timeframe: 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
Timeframe: 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)
Interventions:
Drug: GSK1399686
Enrollment:
120
Observational study model:
Not applicable
Primary completion date:
2013-10-01
Time perspective:
Not applicable
Clinical publications:
Not applicable
Medical condition
Colitis, Ulcerative
Product
GSK1399686
Collaborators
Not applicable
Study date(s)
September 2009 to January 2013
Type
Interventional
Phase
2
Participation criteria
Sex
Female & Male
Age
18 - 65 years
Accepts healthy volunteers
No
- 1. Male or female of non-childbearing potential between 18 and 65 years of age inclusive.
- 2. Presence of mild-to-moderately active ulcerative colitis spread beyond the rectum as evidenced by clinical signs and endoscopy.
- 1. 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.
- 2. History of renal sensitivity to 5-ASA or presence of nephritis, nephropathia or renal function impairment.
Inclusion and exclusion criteria
Inclusion criteria:
- 1. Male or female of non-childbearing potential between 18 and 65 years of age inclusive. 2. Presence of mild-to-moderately active ulcerative colitis spread beyond the rectum as evidenced by clinical signs and endoscopy. 3. UCDAI score 4-10 (inclusive) with rectal bleeding score ≥ 1, endoscopy score ≥ 1 and Physician’s rating of disease activity < 3. 4. Body weight > or = to 50 kg and BMI within the range 18.5-29.9 kg/m2 (inclusive). 5. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
Exclusion criteria:
- 1. 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. 2. History of renal sensitivity to 5-ASA or presence of nephritis, nephropathia or renal function impairment. 3. Presence or a history of asthma or presence or history of other serious allergic disorder. 4. Presence or history of chronic liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). 5. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening. 6. Presence of significant hematologic disorder, or significant bleeding or immune system disorder. 7. 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. 8. 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. 9. 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. 10. History of regular alcohol consumption within 6 months of the study or presence of recreational drug abuse or dependence. 11. Presence of infectious colitis as evidenced by stool culture positive for enteric pathogens or positive Clostridium difficile cytotoxin assay. 12. Suspicion of Crohn’s disease, indeterminate colitis, microscopic colitis, ischaemic colitis or radiation-induced colitis, based on medical history, endoscopy and/or histological findings. 13. Bowel surgery within last 12 months. 14. 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. 15. Treatment with systemic or topical corticosteroids within 4 weeks prior to Day 1 visit. 16. Treatment with TNF-α inhibitors or other biologics within 2 months prior to Day 1 visit. 17. 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. 18. Regular use of probiotic or prebiotic preparations, if initiated within 4 weeks prior to Day 1 visit. 19. 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. 20. 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. 21. 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. 22. 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. 23. 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). 24. Prior enrolment in the present trial. For Canadian sites only: 25. Patients with existing gastric or duodenal ulcers. 26. Patients with urinary tract obstruction
Trial location(s)
Location
GSK Investigational Site
Kiel, Schleswig-Holstein, Germany, 24105
Status
Study Complete
Location
GSK Investigational Site
Ludwigshafen, Rheinland-Pfalz, Germany, 67067
Status
Terminated/Withdrawn
Location
GSK Investigational Site
London, Ontario, Canada, N6A 4G5
Status
Terminated/Withdrawn
Location
GSK Investigational Site
Muenster, Nordrhein-Westfalen, Germany, 48149
Status
Study Complete
Location
GSK Investigational Site
Edmonton, Alberta, Canada, T6G 2C8
Status
Terminated/Withdrawn
Location
GSK Investigational Site
Hannover, Niedersachsen, Germany, 30625
Status
Study Complete
Location
GSK Investigational Site
Hamburg, Hamburg, Germany, 20148
Status
Terminated/Withdrawn
Location
GSK Investigational Site
Kingston, Ontario, Canada, K7L 5G2
Status
Terminated/Withdrawn
Study documents
Scientific result summary
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Results posted on ClinicalTrials.gov
Recruitment status
Completed
Actual primary completion date
2013-10-01
Actual study completion date
2013-10-01
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.
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