Effect of GSK1399686 in Patients With Mild to Moderately Active Ulcerative Colitis
Condition: Colitis, Ulcerative
MeSH terms: Colitis; Colitis, Ulcerative; Ulcer
Intervention: GSK1399686
Intervention description: 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.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 120.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: mesalazine; ulcerative colitis; pharmacokinetics/dynamics; GSK1399686

Summary:

      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.
    

Eligibility 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