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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01036022
First received: December 17, 2009
Last updated: August 29, 2013
Last verified: August 2013
  Purpose

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.


Condition Intervention Phase
Colitis, Ulcerative
Drug: GSK1399686
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Safety and tolerability as determined by: Adverse events (AEs); effects on blood pressure, heart rate, electrocardiography (ECG) parameters and haematology, clinical chemistry and urinalysis findings; and effects on basal morning cortisol [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
  • Concentration of GSK1399686 in colon biopsy obtained within 24 hours after the last dose [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Simple Clinical Colitis Activity Index (SCCAI) score over time [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
  • Clinical response rate (proportion of patients with SCCAI score decreased for > 2 points in comparison with baseline) at Week 4 and Week 6 [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
  • Time to clinical response (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 decreased for > 2 points in comparison with baseline). [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
  • Clinical remission rate (proportion of patients with SCCAI score < 3) at Week 4 and Week 6 [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
  • Time to clinical remission, 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 Frame: 4 weeks ] [ Designated as safety issue: No ]
  • Fecal calprotectin and fecal lactoferrin levels over time [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
  • PK parameters for GSK1399686 derived from observed plasma concentrations of GSK1399686 after repeated oral dosing [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]

Enrollment: 120
Study Start Date: September 2009
Study Completion Date: July 2012
Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group 2
ASACOL 800mg t.i.d.
Drug: GSK1399686
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.
Experimental: Group 1
GSK1399686 at 3-4 dose levels
Drug: GSK1399686
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.
Experimental: Group 3
Placebo
Drug: GSK1399686
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.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01036022

Locations
Belgium
GSK Investigational Site
Bonheiden, Belgium, 2820
GSK Investigational Site
Brussels, Belgium, 1200
GSK Investigational Site
Gent, Belgium, 9000
Canada, Alberta
GSK Investigational Site
Edmonton, Alberta, Canada, T6G 2C8
Canada, Ontario
GSK Investigational Site
Kingston, Ontario, Canada, K7L 5G2
GSK Investigational Site
London, Ontario, Canada, N6A 4G5
GSK Investigational Site
Vaughan, Ontario, Canada, L4L 4Y7
Canada
GSK Investigational Site
Quebec, Canada, G1S 4L8
Germany
GSK Investigational Site
Hannover, Niedersachsen, Germany, 30625
GSK Investigational Site
Muenster, Nordrhein-Westfalen, Germany, 48149
GSK Investigational Site
Ludwigshafen, Rheinland-Pfalz, Germany, 67067
GSK Investigational Site
Dresden, Sachsen, Germany, 01307
GSK Investigational Site
Leipzig, Sachsen, Germany, 04129
GSK Investigational Site
Kiel, Schleswig-Holstein, Germany, 24105
GSK Investigational Site
Jena, Thueringen, Germany, 07747
GSK Investigational Site
Berlin, Germany, 10117
GSK Investigational Site
Hamburg, Germany, 20246
GSK Investigational Site
Hamburg, Germany, 20148
Norway
GSK Investigational Site
Lørenskog, Norway, 1478
GSK Investigational Site
Oslo, Norway, 0514
GSK Investigational Site
Oslo, Norway, N-0456
GSK Investigational Site
Tønsberg, Norway, 3116
Sweden
GSK Investigational Site
Göteborg, Sweden, SE-416 85
GSK Investigational Site
Lund, Sweden, SE-221 85
GSK Investigational Site
Stockholm, Sweden, SE-171 76
GSK Investigational Site
Stockholm, Sweden, SE-111 86
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01036022     History of Changes
Other Study ID Numbers: 111407
Study First Received: December 17, 2009
Last Updated: August 29, 2013
Health Authority: Belgium: Federal Agency for Medicines and Health Products, FAMHP
Norway: Statens Legemiddelverk
Canada: Health Canada
Germany: Bundesinstitut für Arzneimittel und Medizinprodukte
Sweden: Medical Products Agency

Keywords provided by GlaxoSmithKline:
mesalazine
ulcerative colitis
pharmacokinetics/dynamics
GSK1399686

Additional relevant MeSH terms:
Colitis
Colitis, Ulcerative
Ulcer
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Colonic Diseases
Intestinal Diseases
Inflammatory Bowel Diseases
Pathologic Processes

ClinicalTrials.gov processed this record on April 17, 2014