|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Diseases [C] - Digestive System Diseases [C06]
|E.1.2 Medical condition or disease under investigation
|System Organ Class
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|- To evaluate the safety and tolerability of repeat doses of GSK2831781.
- To characterise the efficacy dose response of GSK2831781 during the Induction Phase.
|Secondary objectives of the trial
|- To evaluate the safety and tolerability of repeat doses of GSK2831781 during the Double-Blind Extended Treatment Phase.
- To investigate the effect of repeat doses of GSK2831781 on clinical efficacy including endoscopic mucosal healing during the Induction Phase.
- To investigate the effect of repeat doses of GSK2831781 on UC histologic disease activity during the Induction Phase.
- To investigate the effect of repeat doses of GSK2831781 on biomarkers of UC disease activity during the Induction Phase.
- To investigate the pharmacokinetics of GSK2831781 following subcutaneous dosing.
- To investigate the immunogenicity of repeat doses of GSK2831781.
- To evaluate the safety and tolerability of repeat doses of GSK2831781 in all trial phases.
|Trial contains a sub-study
|Principal inclusion criteria
|AGE and WEIGHT: Participant must be 18 years of age or older and >40kg at the time of signing the informed consent.
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS:
Participants who have a:
-Diagnosis of ulcerative colitis, established at least 3 months prior to screening, as documented by diagnostic sigmoidoscopy or colonoscopy, and biopsy.
-Complete Mayo Score of 6 to 12, with disease extending ≥15cm from the anal verge, with a centrally read endoscopic subscore of ≥2 at screening endoscopy, and a rectal bleeding subscore ≥1.
-A history of at least one of the following:
(1) Inadequate response to, loss of response to, or intolerance to azathioprine or mercaptopurine (including thiopurine methyltransferase (TPMT) genetic mutation precluding use), ciclosporin, tacrolimus or methotrexate.
(2) Inadequate response to, loss of response to, intolerance to, or demonstrated dependence on oral corticosteroids.
(3) Inadequate response to, loss of response to, or intolerance to at least one approved advanced therapy for UC, including anti-TNF therapies, anti-integrin therapies, anti-IL-12/23 monoclonal antibodies or JAK inhibitors.
- Surveillance colonoscopy (performed according to local standards) within 12 months of screening (or during screening, if required) for participants with:
(1) Pancolitis of >8 years duration; or
(2) Patients with left-sided colitis of >12 years duration; or
(3) For patients for whom this criterion does not apply, colorectal cancer surveillance should be undertaken according to local or national guidelines for patients with age ≥50, or with other known risk factors for colorectal cancer.
Both male and female participants are eligible to participate.
- A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
(1) Not a woman of childbearing potential (WOCBP),
(2) A WOCBP who agrees to use a highly effective contraceptive method for at least 4 weeks prior to dosing, until the Follow-Up visit.
-Capable of giving signed informed consent as described in the protocol
|Principal exclusion criteria
1)Current diagnosis of indeterminate colitis, inflammatory bowel disease-unclassified, CD, infectious colitis, or ischaemic colitis
2)Fulminant UC (as defined by 6 bloody stools daily AND 1 or more of: i) body temperature ≥100.4°F (or 38°C) or ii) heart rate >90 beats per minute),or toxic megacolon
3)Prior extensive colonic resection, subtotal or total colectomy, or proctocolectomy, or planned surgery for UC
4)Any uncontrolled medical conditions, other than active UC, that in the opinion of the investigator put the participant at unacceptable risk or interfere w/ study assessments or integrity of the data. Other medical conditions should be stable at the time of screening and be expected to remain stable for the duration of the study
5)Unstable lifestyle factors, such as alcohol use to excess or recreational drug use, to the extent that in the opinion of the investigator they would interfere w/ the ability of a participant to complete the study
6)An active infection or a history of serious infections as described in the protocol
7)Current or history of chronic liver or biliary disease w/ the exception of Gilbert’s syndrome, asymptomatic gallstones or uncomplicated fatty liver disease
8)Hereditary/acquired immunodeficiency disorder, including immunoglobulin deficiency unless the participant has a documented history of elective IgA deficiency
9)A major organ transplant or haematopoietic stem cell/marrow transplant
10)Any planned major surgical procedure during the study
11)A history of malignant neoplasm w/in the last 5 yrs, except for adequately treated non-metastatic basal or squamous cell cancers of the skin (w/in 1 yr) or carcinoma in situ of the uterine cervix (w/in 3 yrs) that has been fully treated and shows no evidence of recurrence
12)A change in dose of oral sulfasalazine or aminosalicylate w/in 2 wks prior to baseline endoscopy
13)≥20mg/day oral prednisolone, or a change in dose of corticosteroid w/in 2 wks prior to baseline endoscopy, or anticipated inability to maintain a stable dose of corticosteroids (≤20 mg oral prednisolone or equivalent) until Wk12
14)Topical(rectal) corticosteroids or topical(rectal) aminosalicylate w/in 2 wks prior to baseline endoscopy
15)Initiation/change in dose of mercaptopurine or azathioprine (including initiation/discontinuation of allopurinol) or methotrexate w/in 8 wks prior to baseline endoscopy
16)Treatment w/ ciclosporin, tacrolimus or thalidomide w/in 4 wks prior to baseline endoscopy
17)Treatment w/ an anti-TNF biologic w/in 8 wks prior to baseline endoscopy, anti-integrin or anti-IL-12/23 biologics w/in 12 wks prior to baseline endoscopy, or a JAK inhibitor w/in 4 wks prior to baseline endoscopy
18)History of inadequate response, loss of response, or intolerance to more than 3 classes of approved advanced therapies for UC (including anti-TNF therapies, anti-integrin therapies, anti-IL-12/23 monoclonal antibodies, or JAK inhibitors; but excluding exposure w/in a clinical trial setting), of which participants must not have had inadequate response to more than 2 classes
19)Received faecal microbiota transplantation w/in 4 wks prior to baseline endoscopy
20 Received live vaccination w/in 4 wks of Day 1 or plan to receive during the study until Follow-Up
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE:
21)Participated in a clinical trial and received an IP w/in the following time period prior to this study’s screening endoscopy day: Biologics: 3 mths, 5 half-lives, or twice the duration of the biological effect of the IP (whichever is longer); NCEs: 30 days, 5 half-lives or twice the duration of the biological effect (whichever is longer)
22)Absolute neutrophil count <1.5x10^9/L or a haemoglobin <80g/L or lymphocyte count <0.8x10^9/L
23)Estimated GFR by Chronic Kidney Disease Epidemiology Collaboration equation calculation <60 ml/min/1.73m^2 at screening
24)ALT >2xULN and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) at screening
25)Other clinically significant abnormalities of lab assessments, as judged by the investigator and/or GSK Medical Monitor, that could affect the safety of the participant, or the interpretation of the data from the study
26) Presence of hep-B surface antigen or Hep-B core antibody, or positive hep-C antibody result at screening
27) Positive serology for HIV at screening
28) Where participation in the study would result in donation of blood or blood products in excess of 500ml w/in 3 mths
29) QTc >450msec or QTc >480msec for participants w/ bundle branch block at screening and Day 1. The QTc is the QT interval corrected for heart rate according to either Bazett’s formula, Fridericia’s formula, or another method, machine or over read
Other Exclusion Criteria:
30) Participants w/ hypersensitivity to GSK2831781 or any excipients in the clinical formulation of GSK2831781
|E.5 End points
|Primary end point(s)
|- Numbers of participants with adverse events and serious adverse events up to Week 10.
- Numbers of participants with findings of potential clinical importance up to Week 10 for: Vital Signs; Clinical laboratory values (haematology, clinical chemistry and urinalysis); QTc.
- Change from baseline in Complete Mayo score at Week 10.
|Secondary end point(s)
|- Numbers of participants with adverse events and serious adverse events in the Double-Blind Extended Treatment Phase.
- Numbers of participants with findings of potential clinical importance during the Double-Blind Extended Treatment Phase for: Vital signs; Clinical laboratory values (haematology, clinical chemistry and urinalysis); QTc
- Proportion of participants who achieve an Adapted Mayo endoscopic score of 0 or 1 at Week 10.
- Proportion of participants who achieve Adapted Mayo clinical remission at Week 10.
- Proportion of participants who achieve Adapted Mayo clinical response at Week 10.
- Proportion of participants who achieve symptomatic remission over time.
- Change from baseline in partial Mayo score over time.
- Change from baseline in Adapted Mayo endoscopic score and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) at Week 10.
- Change from baseline in histological severity as determined by the Robarts Histopathology Index, Nancy Histological Index and Geboes Score at Week 10.
- Change from baseline in serum C-reactive protein over time.
- Change from baseline in faecal calprotectin over time.
- GSK2831781 PK parameters: AUC(0-tau), Cmax, tmax.
- Number of participants with anti-drug antibodies at each visit.
- Adverse events, vital signs, clinical laboratory values (haematology, clinical chemistry, and urinalysis), 12-lead ECG.
- Anti-drug antibodies over time.
|Timepoint(s) of evaluation of this end point
|Week 10 (mayo score) and end of study (safety endpoints)
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Korea, Republic of
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months
|In all countries concerned by the trial days