Safety and Tolerability, Pharmacokinetics (PK), Pharmacodynamics (PD) and Efficacy of Repeat Doses of GSK2982772 in Subjects With Moderate to Severe Rheumatoid Arthritis (RA)

This study is the first study with GSK2982772, a receptor-interacting protein-1 (RIP1) kinase inhibitor, in subjects with moderate to severe RA who are currently being treated with disease modifying anti-rheumatic drugs (DMARDs). The primary objective of the study is to investigate the safety and tolerability of repeat oral doses of GSK2982772 in subjects with moderate to severe RA. In addition to the PK, a number of experimental and clinical endpoints will be employed to obtain information on the PD, and preliminary efficacy in subjects with active RA. 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 RA. After a screening period of up to 30 days, approximately 24 subjects will be randomized to receive either GSK2982772 or placebo for 84 days (12 weeks), followed by a follow-up period (28 days). 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 moderate to severe RA, 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 rheumatoid arthritis according to the revised 2010 ACR-EULAR classification criteria.
* Disease duration of \>=12 weeks (time from onset of patient-reported symptoms of either pain or stiffness or swelling in hands, feet or wrists) at screening.
* Swollen joint count of \>=4 (28-joint count) and tender joint count \>=4 (28-joint count) at screening.
* Subject has a DAS28 CRP disease activity score of \>= 3.2 and CRP \>= 5.0 mg/liter (L) (\>=4.76 nanomole (nmol)/L) at screening.
* Subject must have received at least 12 weeks of non-biologic DMARD monotherapy or MTX/DMARD combination therapy prior to screening and must be on stable dose throughout the study.
* Subject is naive to any biological therapies for RA 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) from first dose.
* For subjects who have consented to synovial joint biopsy:

  • Subject has an involved knee, wrist, or ankle suitable for biopsy, as assessed by a rheumatologist at screening.
* A body mass index (BMI) within range of 18.5 - 35 kilogram/meter\^2 (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 specified in the protocol.

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

* Non-reproductive potential as defined as pre-menopausal females with either documented tubal ligation or Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion or Hysterectomy or Documented Bilateral Oophorectomy. For Postmenopausal females 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 enrollment..
* 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 30 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 these methods of contraception.
  * Capable of giving signed informed consent as described in the protocol which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.

Exclusion Criteria:

* Subject with a positive anti-double stranded deoxyribonucleic acid (DNA \[anti-dsDNA\]) and confirmed diagnosis of systemic lupus erythematosus (SLE).
* Subject with current history of Suicidal Ideation Behavior (SIB) as measured using the Columbia Suicide Severity Rating Scale (C-SSRS) or a 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 (e.g. pneumocystis jirovecii, cytomegalovirus \[CMV\] pneumonitis, 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 locally-read follow up chest x-ray, shows no evidence of current or previous pulmonary tuberculosis, the subject may be eligible for the study at the discretion of the Investigator and GSK Medical Monitor.
* Electrocardiogram QT interval corrected for heart rate (QTc) \> 450 milliseconds (msec) or QTc \> 480 msec for subjects with bundle branch block at screening.

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 manual over read. The specific formula that will be used to determine eligibility and discontinuation for an individual subject should be determined and documented prior to initiation of the study. In other words, several different formulae cannot be used to calculate the QTc for an individual subject and then the lowest QTc value used to include or discontinue the subject from the trial. For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a composite of available values of QTc will be used.

* Alanine aminotransferase (ALT) \>2x upper limit of normal (ULN) and bilirubin \>1.5xULN (isolated bilirubin \>1.5xULN 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 (mL)/minute (min)/1.73 m\^2 at screening.
* Hereditary or acquired immunodeficiency disorder, including immunoglobulin deficiency.
* A major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant.
* Any planned surgical procedures including surgical joint procedures (e.g., intra-articular, tendon sheath, or bursal corticosteroid injections) 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.
* Has undergone surgery including synovectomy or arthroplasty on the joint chosen for biopsy and/or magnetic resonance imaging (MRI).
* The subject has a history of any other joint disease other than RA at the knee, wrist or ankle joint chosen for biopsy and/or MRI (e.g., gout, pseudogout, osteoarthritis).
* Has undergone intra-articular corticosteroid injection, arthrocentesis or synovial biopsy on any joint within 6 weeks of screening.
* A known allergy to lidocaine or other local anesthetics (only applies to subjects who consent for synovial biopsy procedures).
* Contraindication to MRI scanning (as assessed by local MRI safety questionnaire) which includes but are not limited to:

  * Intracranial aneurysm clips (except SugitaTM) or other metallic objects,
  * History of intra-orbital metal fragments that have not been removed by a medical professional.
  * Pacemakers or other implanted cardiac rhythm management devices and non-MR compatible heart valves,
  * Inner ear implants,
  * History of claustrophobia which may impact participation.
* The subject has received treatment with the prohibited therapies listed in the protocol, 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 half-lives (or 2 days) plus 30 days after receiving GSK2982772.
* Contraindication to gadolinium contrast agent in accordance with local guidelines.
* 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 at the same time as participating in this clinical trial.
* Hemoglobin \<9 grams/deciliter (g/dL);hematocrit \<30 percent, white blood cell count =\<3,000/millimeter\^3 (mm\^3) (=\<3.0 x 10\^9/L); platelet count =\<100,000/ microliter (μL) (=\<100 x 10\^9/L); absolute neutrophil count =\<1.5 x 10\^9/L at screening. For subjects recruited in Germany: hemoglobin \<11 g/dL at screening.
* 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.