GSK2982772 Study in Subjects With Ulcerative Colitis

This study is the first experience with GSK2982772, a receptor-interacting protein-1 (RIP1) kinase inhibitor, in subjects with active ulcerative colitis (UC). The primary objective will be to investigate the safety and tolerability of repeat oral doses of GSK2982772 60 mg or placebo three times daily for 42 days (Part A) followed by open label with GSK298772 60 mg three times daily for 42 days (Part B). In addition to pharmacokinetics (PK), a number of experimental and clinical endpoints will be employed to obtain information on the pharmacodynamics (PD), and preliminary efficacy in subjects with active UC. Although no formal hypothesis will be tested, these endpoints will enable a broader understanding of the mechanism of action and potential for clinical efficacy of GSK2982772 in UC. Within 30 Days of screening visit, subjects will be randomized to receive either GSK2982772 60 mg or placebo orally three times daily for 42 Days (6 weeks) in a 2:1 ratio in Part A study. Subjects who complete the Part A study will move to open label Part B study to receive GSK2982772 60 mg three times daily for an additional 42 Days (6 weeks). After the open label (Part B) treatment period, subjects will enter the Follow-up period which lasts for 28 Days (+/- 3 Days) post the last administration of study medication. The total duration of participation in the study will be approximately 20 Weeks from screening to the last study visit.


Eligibility Criteria:
Inclusion Criteria:

* Between 18 and 75 years of age inclusive, at the time of signing the informed consent.
* Subjects that do not have any medical conditions, other than active UC, that in the opinion of the Investigator put the subject at unacceptable risk or interfere with study assessments or integrity of the data. These medical conditions should be stable at the time of screening and are expected to remain stable for the duration of the study.
* Subject has had a confirmed diagnosis of active UC, as documented by complete diagnostic colonoscopy to the terminal ileum (TI) with biopsy performed \>=3 months prior to screening. If diagnostic colonoscopy was not performed to the TI, it must be documented by the principal investigator that the subject has diffuse inflammation from the rectum extending proximally to the colon in a continuous and uniform way.
* A Complete Mayo Score of \>=3 points and endoscopy sub score of 2 to 3 at screening, despite concurrent treatment with at least 1 of the following (oral corticosteroids or any oral 5-aminosalicylates (5-ASA) or purine analogues or all as defined): Oral 5-ASA at a stable dose (equivalent to \>=2.4 grams per day (g/day) of Asacol) for at least 4 weeks prior to first dose. Must remain on a stable dose until end of treatment; Purine analogues (azathioprine, mercaptopurine, thiopurines) or methotrexate for at least 12 weeks prior to first dose. Must remain on a stable dose until end of treatment; Stable low dose oral corticosteroid (up to 20 mg prednisolone or equivalent) for 2 weeks prior to sigmoidoscopy. Must remain on a stable dose until end of treatment.
* If on rectal 5-ASA or corticosteroids, must remain on a stable dose for at least 4 weeks prior to first dose. Must remain on stable dose until the end of treatment.
* Subject is naive to any biological therapies for UC OR Subject may have had previous exposure to a single anti-tumor necrosis factor (TNF) biologic agent which was discontinued for reasons other than primary non-response more than 8 weeks (or 5 half-lives whichever is longer) prior to first dose OR Subject may have had previous exposure to a single biologic agent (example, vedolizumab) in the context of a previous clinical trial. The biologic agent must have been discontinued more than 8 weeks (or 5 half-lives whichever is longer) prior to first dose. Note: Exposure to a single biologic agent is not required in addition to inclusion criteria listed above (number fourth and fifth on the list).
* A body mass index (BMI) within range of 18.5 to 35 kilogram per meter square (kg/m\^2) (inclusive) at screening.
* Male and Female subjects:

Males: Male subjects with female partners of child bearing potential must comply with the contraception requirements.

Females: A female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotrophin (hCG) test), not lactating, and at least one of the following conditions applies:

Non-reproductive potential defined as 1) Pre-menopausal females with one of the following: Documented tubal ligation; Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion; Hysterectomy; Documented Bilateral Oophorectomy. 2) Postmenopausal defined as 12 months of spontaneous amenorrhea in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.

Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from 30 days prior to the first dose of study medication and until at least 2 days after the last dose of study medication and completion of the follow-up visit. The Investigator is responsible for ensuring that subjects understand how to properly use methods of contraception.

* Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and protocol.

Exclusion Criteria:

* Subject with diagnosis of indeterminate colitis, Crohn's Disease, infectious colitis, or ischemic colitis.
* Subject with fulminant UC, or UC limited to the rectum (disease extent \<15 centimeters (cm) from the anal verge).
* Subject with previous small bowel or colonic surgery(with exception of appendectomy), histological evidence of colonic dysplasia or bowel stricture.
* Subject with colostomy, fistulae or known symptomatic stenosis of the intestine.
* Subject with toxic megacolon.
* Subject with positive Clostridium difficile toxin test or active/previous colonic cytomegalo virus (CMV) infection.
* Subject with current history of suicidal ideation behavior (SIB) as measures using the Columbia Suicide Severity Rating Scale (C-SSRS) or history of attempted suicide.
* An active infection, or a history of infections as follows:

Hospitalization for treatment of infection within 60 days before first dose (Day 1).

Currently on any suppressive therapy for a chronic infection (such as pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria).

Use of parenteral (intravenous (IV) or intramuscular) antibiotics (antibacterials, antivirals, antifungals, or antiparasitic agents) for an infection within 60 days before first dose.

A history of opportunistic infections within 1 year of screening (example: pneumocystis jirovecii, CMV pnemonitis, aspergillosis). 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.

Recurrent or chronic infection or other active infection that, in the opinion of the Investigator might cause this study to be detrimental to the patient.

History of tuberculosis (TB), irrespective of treatment status. A positive diagnostic TB test at screening defined as a positive QuantiFERON-TB Gold test or T-spot test. In cases where the QuantiFERON or T-spot test is indeterminate, the subject may have the test repeated once, but they will not be eligible for the study unless the second test is negative. In cases where the QuantiFERON or T-spot test is positive, but a follow-up chest x-ray, locally read by a radiologist, shows no evidence of current or previous pulmonary tuberculosis, the subject may be eligible for the study at the discretion of the Investigator and GlaxoSmithKline (GSK) Medical Monitor.

* QTc \>450 millisecond (msec) or QTc \>480 msec for subjects with bundle branch block 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.
* Current active or chronic history of liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones).
* Current or history of renal disease or estimated glomerular filtration rate (GFR) by Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) calculation \<60 milliliter per minute per 1.73 meter square (mL/min/1.73 m\^2) at screening.
* Hereditary or acquired immunodeficiency disorder, including immunoglobulin deficiency unless subject has a documented history of selective immunoglobulin A (IgA) deficiency.
* A major organ transplant (example: heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant.
* Any planned surgical procedure during the study.
* A history of malignant neoplasm within the last 5 years, except for adequately treated non-metastatic cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix that has been fully treated and shows no evidence of recurrence.
* The subject has received treatment with the protocol listed prohibited therapies or changes to those treatments, within the prescribed timeframe.

Other medications (including vitamins, herbal and dietary supplements) will be considered on a case-by-case basis, and will be allowed if in the opinion of the Investigator the medication will not interfere with the study procedures or compromise subject safety.

* History of alcohol or drug abuse that would interfere with the ability to comply with the study.
* History of sensitivity to any of the study treatments, or components thereof or a history of drug or other allergy that, in the opinion of the Investigator or Medical Monitor, contraindicates their participation.
* Received a live or attenuated vaccine within 30 days of randomization OR plan to receive a vaccination during the study until 5 half-lives (or 2 days) plus 30 days after receiving GSK2982772.
* The subject has participated in a clinical trial and has received an investigational product within 30 days or 5 half-lives, whichever is longer before the first dose of study medication, or plans to take part in another clinical trial (not inclusive of any UC registry study where no study medication is being administered) at the same time as participating in this clinical trial.
* Hemoglobin \<10 grams per deciliter (g/dL); hematocrit \<30 percent, white blood cell count \<=3,000 per millimeter cube (mm\^3) (\<=3.0 into 10\^9 per liter); platelet count \<=100,000 per microliter (\<=100 into 10\^9 per liter); absolute neutrophil count \<=1.5 into 10\^9 per liter.
* Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. As potential for and magnitude of immunosuppression with this compound is unknown, subjects with presence of hepatitis B core antibody (HBcAb) should be excluded.
* A positive serology for human immunodeficiency virus (HIV) 1 or 2 at screening.
* Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 3 months.
* Exposure to more than 4 investigational medicinal products within 12 months prior to the first dose.