| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045365 |
| E.1.2 | Term | Ulcerative colitis |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To evaluate the safety and tolerability of GSK1399686 after repeated oral dosing in patients with active ulcerative colitis.
• To determine GSK1399686 concentrations in rectal mucosa after repeated oral dosing in patients with active ulcerative colitis.
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives are:
• To assess the anti-inflammatory activity of GSK1399686 in patients with active ulcerative colitis using clinical indices of disease activity and fecal markers of intestinal inflammation.
• To assess the systemic exposure after repeated oral dosing of GSK1399686 in patients with active ulcerative colitis.
Exploarory objectives are:
• To explore therapeutic efficacy of GSK1399686 in patients with active ulcerative colitis, including endoscopic and histologic response to therapy.
• To explore the relationship between GSK1399686 concentrations in plasma/rectal mucosa and pharmacodynamic parameters identified to be of interest (e.g., fecal calprotectin, fecal lactoferrin, SCCAI score, UCDAI score), if possible.
• To explore the relationship between fecal markers of intestinal inflammation and clinical presentation of disease and their potential utility for early detection of anti-inflammatory activity in patients with active ulcerative colitis.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study only if all of the following criteria apply:
1.Male or female of non-childbearing potential, 18 years of age or older at the time of signing the informed consent.
o Non-childbearing potential is defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<140 pmol/L) is confirmatory].
2. Presence of mild-to-moderately active ulcerative colitis spread beyond the rectum (inflammation extending ≥ 15 cm from anal verge) as evidenced by clinical signs and endoscopy.
3. UDCAI score 4-10 (inclusive) with rectal bleeding score ≥ 1, endoscopy score ≥ 1 and Physician’s rating of disease activity < 3.
4. Body weight ≥50 kg and BMI within the range 18.5-34.9 kg/m2 (inclusive).
5. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
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| E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
1. History of sensitivity to aminosalicylates, macrolides, coricosteroids or any component of study medications, history of hypersensitivity to ACTH, SYNACTHEN or SYNACTHEN DEPOT, 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, as evidenced by any of the following: serum creatinine >130 µmol/L, 2+ proteinuria on dipstick urinalysis, or presence of casts (red cell casts, white cell casts or epithelial cell casts) in urine sediment.
3. Presence or a history of asthma or presence or history of other serious allergic disorder that, in the opinion of the Investigator, increases the risk of allergic reaction to SYNACTHEN.
4. Presence or history of chronic liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) as evidenced by medical history or by AST and ALT ≥ 2xULN, alkaline phosphatase and bilirubin > 1.5xULN.
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 as evidenced by neutrophil count <1.5x109/L, platelet count <150x109/L, 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 defined as an average weekly intake of >14 drinks (one drink is equivalent to 12 ounces [360 mL] of beer, 5 ounces [150 mL] of wine or 1.5 ounces [45 mL] of 80 proof distilled spirits AND a history 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 >3 g/day or dose modification (except a transient shift lasting up to 3 days) within 4 weeks prior to Day 1 visit or treatment 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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Safety and tolerability as determined by:
- Adverse events (AEs);
- Treatment effects on blood pressure, heart rate, electrocardiography (ECG) parameters and haematology, clinical chemistry and urinalysis findings;
- Treatment effects on basal morning cortisol and ACTH-stimulated cortisol levels at Week 4 in comparison with baseline.
• Concentration of GSK1399686 in colon biopsy obtained within 24 hours after the last dose.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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