Safety, Tolerability, Efficacy and Dose-response of GSK2831781 in Ulcerative Colitis
Condition: Colitis, Ulcerative
MeSH terms: Colitis; Colitis, Ulcerative; Ulcer
Intervention: GSK2831781 - Double Blind Phase; Placebo; GSK2831781 - Open Label phase
Intervention description: GSK2831781 will be administered intravenously in the double blind induction phase and subcutaneously in the double blind ETP (both according to randomization).; Placebo (commercial saline solution) will be administered intravenously in the double blind induction phase and subcutaneously in the double blind ETP (both according to randomization).; GSK2831781 will be administered intravenously in the open label induction phase and subcutaneously in the open label ETP.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This is a parallel group, placebo controlled study where participants will be randomized to receive either GSK2831781 or placebo.
Masking: Double (Participant, Investigator)
Masking description: This will be a double-blind study. Induction doses will be matched with placebo. For Maintenance dosing, participant and investigator will be masked. Participants will be allocated to the next treatment phase according to their Responder status. Non-responders to the double-blind Induction Phase will receive treatment in Open-Label Induction phase where there will be no masking.
Enrollment: 104.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: GSK2831781; Ulcerative colitis; Anti-LAG3 cell Depleting monoclonal antibody; Dose-response

Summary:

      This is a Phase 2, multicenter, randomized, double-blind, parallel group, placebo-controlled
      study to investigate the safety, tolerability, efficacy and dose-response of GSK2831781 in
      participants with moderate to severe active ulcerative colitis. The study consists of a
      5-week screening window, 10-week Induction Phase, 30-week double-blind Extended Treatment
      Phase (ETP) with 42-week Follow-Up Phase. Non-Responders identified following the Week 10
      assessment will be allocated to open label treatment, consisting of Induction (Weeks 12 to
      22), an Open label ETP (Weeks 22 to 42) and a follow-Up to Week 54.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participants must be 18 years of age or older and > 40 kilograms (kg) at the time of
             signing the informed consent.

          -  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 4-domain Mayo Score of 6 to 12, with disease extending >= 15 centimeters (cm)
             from the anal verge, with a centrally read endoscopic sub score of >=2 at screening
             endoscopy, and a rectal bleeding sub score >=1.

          -  A history of at least one of the following: inadequate response to, loss of response
             to, or intolerance to azathioprine or mercaptopurine (including thiopurine
             methyltransferase [TPMT] and nudix hydrolase 15 [NUDT15] genetic mutations precluding
             use), ciclosporin, tacrolimus or methotrexate; inadequate response to, loss of
             response to, intolerance to, or demonstrated dependence on oral corticosteroids;
             inadequate response to, loss of response to, or intolerance to at least one approved
             advanced therapy for UC including anti- tumor necrosis factor (TNF) therapies (example
             given [e.g.] infliximab, adalimumab, golimumab, or biosimilar), anti-integrin
             therapies, anti-interleukin (IL)-12/23 monoclonal antibodies or Janus Kinase (JAK)
             inhibitors.

          -  Surveillance colonoscopy (performed according to local standards) within 12 months of
             screening (or during screening, if required) for participants with: Pancolitis of >8
             years duration; or participants with left-sided colitis of >12 years duration. For
             participants for whom this criterion does not apply, colorectal cancer surveillance
             should be undertaken according to local or national guidelines for participants 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: Not a woman of
             childbearing potential (WOCBP); 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.

        Exclusion Criteria:

          -  Participants with a current diagnosis of indeterminate colitis, inflammatory bowel
             disease-unclassified, Crohn's disease, infectious colitis, or ischemic colitis.

          -  Participants with fulminant ulcerative colitis (as defined by 6 bloody stools daily
             and 1 or more of body temperature >=100.4 degrees Fahrenheit (or 38 degree Celsius) or
             heart rate >90 beats per minute), or toxic megacolon.

          -  Prior extensive colonic resection, subtotal or total colectomy, or proctocolectomy, or
             planned surgery for ulcerative colitis.

          -  Participants with any uncontrolled medical conditions, other than active ulcerative
             colitis, that in the opinion of the investigator put the participant at unacceptable
             risk or interfere with 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.

          -  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 with the
             ability of a participant to complete the study.

          -  An active infection or a history of serious infections as follows: a) Use of
             antimicrobials (antibacterials, antivirals, antifungals or antiparasitic agents) for
             an infection within 30 days before first dose (topical treatments may be allowed at
             the Medical Monitor's discretion). b) A history of opportunistic infections within 1
             year of screening (e.g. Pneumocystis jirovecii, aspergillosis or Cytomegalovirus
             colitis). This does not include infections that may occur in immunocompetent
             individuals, such as fungal nail infections or vaginal candidiasis, unless it is of an
             unusual severity or recurrent nature. c) Recurrent or chronic infection or other
             active infection that, in the opinion of the Investigator, might cause this study to
             be detrimental to the participant. d) Symptomatic herpes zoster within 3 months prior
             to screening. e) History of tuberculosis (active or latent), irrespective of treatment
             status. f) A positive diagnostic tuberculosis test at screening (defined as a positive
             QuantiFERON test). In cases where the QuantiFERON test is indeterminate, the
             participant may have the test repeated once and if their second test is negative they
             will be eligible. In the event a second test is also indeterminate, the investigator
             has the option to undertake Purified Protein Derivative (PPD) testing. If the PPD
             reaction is less than (<) 5 millimeter (mm), then the participant is eligible. If the
             reaction is >= 5mm, or PPD testing is not undertaken, the participant is not eligible.
             g) Positive Clostridium difficile toxin test during screening. However, rescreening
             can be undertaken following successful treatment.

          -  Current or history of chronic liver or biliary disease (with the exception of
             Gilbert's syndrome, asymptomatic gallstones or uncomplicated fatty liver disease).

          -  Hereditary or acquired immunodeficiency disorder, including immunoglobulin deficiency
             (unless the participant has a documented history of selective immunoglobulin A
             deficiency).

          -  A major organ transplant (e.g. heart, lung, kidney, liver, pancreas) or hematopoietic
             stem cell/marrow transplant.

          -  Any planned major surgical procedure during the study.

          -  A history of malignant neoplasm within the last 5 years, except for adequately treated
             non-metastatic basal or squamous cell cancers of the skin (within 1 year) or carcinoma
             in situ of the uterine cervix (within 3 years) that has been fully treated and shows
             no evidence of recurrence.

          -  A change in dose of oral sulfasalazine or aminosalicylate within 2 weeks prior to
             Baseline endoscopy.

          -  Greater than 20 mg per day oral prednisolone (or equivalent), or a change in dose of
             corticosteroid within 2 weeks prior to Baseline endoscopy, or anticipated inability to
             maintain a stable dose of corticosteroids (<=20 mg oral prednisolone or equivalent)
             until Week 12.

          -  Topical (rectal) corticosteroids or topical (rectal) aminosalicylate within 2 weeks
             prior to Baseline endoscopy.

          -  Initiation or a change in dose of mercaptopurine or azathioprine (including initiation
             or discontinuation of allopurinol) or methotrexate within 8 weeks prior to Baseline
             endoscopy.

          -  Treatment with ciclosporin, tacrolimus or thalidomide within 4 weeks prior to Baseline
             endoscopy.

          -  Treatment with an anti-TNF biologic within 8 weeks prior to Baseline endoscopy,
             anti-integrin or anti-IL-12/23 biologics within 12 weeks prior to Baseline endoscopy,
             or a JAK inhibitor within 4 weeks prior to Baseline endoscopy.

          -  A history of inadequate response, loss of response, or intolerance to more than three
             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 within a clinical trial setting), of which participants must not
             have had inadequate response (primary non-response) to more than two classes.

          -  Received fecal microbiota transplantation within 4 weeks prior to Baseline endoscopy.

          -  Received live vaccination within 4 weeks of Day 1 or plan to receive during the study
             until Follow-Up.

          -  The participant has participated in a clinical trial and has received an
             investigational product within the following time period prior to the screening
             endoscopy day in the current study:

               1. Biologics: 3 months, 5 half-lives, or twice the duration of the biological effect
                  of the investigational product (whichever is longer);

               2. New Chemical Entities (NCEs): 30 days, 5 half-lives, or twice the duration of the
                  biological effect (whichever is longer).

          -  Absolute neutrophil count <1.5 times 10^9 cells per liter (L) or a hemoglobin <80
             grams per liter (g/L) or lymphocyte count <0.8 times 10^9 cells /L.

          -  Estimated glomerular filtration rate (GFR) by Chronic Kidney Disease Epidemiology
             Collaboration equation (CKD-EPI) calculation <60 milliliter (mL) per minute per 1.73
             m^2 at screening.

          -  ALT >2 times upper limit of normal (ULN) and bilirubin >1.5 times ULN (isolated
             bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct
             bilirubin <35 percent) at screening.

          -  Other clinically significant abnormalities of laboratory assessments, as judged by the
             investigator and/or GlaxoSmithKline Medical Monitor that could affect the safety of
             the participant, or the interpretation of the data from the study.

          -  Presence of hepatitis B surface antigen (HBsAg) or Hepatitis B core antibody (HBcAb),
             or positive hepatitis C antibody result at screening (Nota bene [NB]-Participants with
             Hepatitis C antibody due to prior resolved disease can be enrolled only if a
             confirmatory negative Hepatitis C ribonucleic acid [RNA] test is obtained).

          -  Positive serology for human immunodeficiency virus (HIV) at screening.

          -  Where participation in the study would result in donation of blood or blood products
             in excess of 500 mL within 3 months.

          -  QTc >450 milliseconds (msec) or QTc >480 msec for participants with bundle branch
             block at screening and Day 1. The QTc is the QT interval corrected for heart rate
             according to either Bazett's formula (QTcB), Fridericia's formula (QTcF), or another
             method, machine or over read.

          -  Participants with hypersensitivity to GSK2831781 or any excipients in the clinical
             formulation of GSK2831781.