Clinical trial NCT01036022: Effect of GSK1399686 in Patients With Mild to Moderately Active Ulcerative Colitis
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Colitis, Ulcerative
Keywords: mesalazine
ulcerative colitis
pharmacokinetics/dynamics
GSK1399686
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2009-12-21
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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

Primary outcomes:
measure: Number of Participants With Any Adverse Events (AE) or Serious Adverse Events (SAE)
timeFrame: Up to Week 6
measure: 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
measure: 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
measure: Number of Participants of Abnormal Urinalysis Dipstick Results
timeFrame: Screening (Day -7 to -1), Week 2, 4 and 6
measure: Number of Participants With Vital Sign Outside Range of Potential Clinical Importance (PCI)
timeFrame: Screening (Day -7 to -1), Week 2, 4 and 6
measure: Number of Participants With Abnormal Electrocardiography (ECG) Findings
timeFrame: Screening (Day -7 to -1), Week 2, 4 and 6
measure: 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
measure: Mean Concentration of GSK1399686 in Colon Biopsy Obtained Within 24 h After the Last Dose
timeFrame: Week 4
Secondary outcomes:
measure: Mean Simple Clinical Colitis Activity Index (SCCAI) Score
timeFrame: Up to Week 6
measure: Number of Participants With Clinical Response and Clinical Remission at Week 4 and Week 6
timeFrame: Week 4 and Week 6
measure: Median Time to Clinical Response and Clinical Remission
timeFrame: Up to Week 6
measure: Mean Fecal Calprotectin Levels Over Time
timeFrame: Up to Week 6
measure: Mean Fecal Lactoferrin Levels Over Time
timeFrame: Up to Week 6
measure: 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)
measure: 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)
measure: 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)
measure: 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)
Other outcomes:
Locations:
city: Bonheiden
country: Belgium
facility: GSK Investigational Site
city: Brussels
country: Belgium
facility: GSK Investigational Site
city: Gent
country: Belgium
facility: GSK Investigational Site
city: Edmonton
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Kingston
country: Canada
facility: GSK Investigational Site
state: Ontario
city: London
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Vaughan
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Quebec
country: Canada
facility: GSK Investigational Site
city: Hannover
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Muenster
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Ludwigshafen
country: Germany
facility: GSK Investigational Site
state: Rheinland-Pfalz
city: Dresden
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Leipzig
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Kiel
country: Germany
facility: GSK Investigational Site
state: Schleswig-Holstein
city: Jena
country: Germany
facility: GSK Investigational Site
state: Thueringen
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Lørenskog
country: Norway
facility: GSK Investigational Site
city: Oslo
country: Norway
facility: GSK Investigational Site
city: Oslo
country: Norway
facility: GSK Investigational Site
city: Tønsberg
country: Norway
facility: GSK Investigational Site
city: Göteborg
country: Sweden
facility: GSK Investigational Site
city: Lund
country: Sweden
facility: GSK Investigational Site
city: Stockholm
country: Sweden
facility: GSK Investigational Site
city: Stockholm
country: Sweden
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: