Evaluation of Pharmacokinetics and Safety of GSK3196165 in Combination With Methotrexate in Japanese Subjects With Rheumatoid Arthritis
Evaluation of Pharmacokinetics and Safety of GSK3196165 in Combination With Methotrexate in Japanese Subjects With Rheumatoid Arthritis
This is a randomized, double-blind, parallel group, 3 dosage level, placebo-controlled, Phase
 1/2 study designed to evaluate the pharmacokinetics, safety, tolerability, and efficacy of
 the monoclonal antibody GSK3196165, in Japanese subjects with active moderate-severe
 rheumatoid arthritis (RA) despite treatment with methotrexate(MTX). The subjects will receive
 GSK3196165 in combination with methotrexate therapy for the 12 weeks of treatment period.
 Approximately 55 subjects will be screened to achieve 40 randomized subjects, so as to have
 approximately 10 subjects in each treatment group.
Inclusion Criteria:

 -  Age: >=20 years at the time of signing informed consent - Japanese rheumatoid
 arthritis (RA) subjects who meets American College of Rheumatology or European League
 Against Rheumatism (ACR/EULAR) 2010 RA Classification Criteria

 -  Functional class I, II or III defined by the 1992 ACR Classification of Functional
 Status in RA

 -  Disease duration of >=12 weeks (time from onset of subject-reported symptoms of either
 pain or stiffness or swelling in hands, feet or wrists).

 -  Swollen joint count of >=4 (66-joint count) and tender joint count of >=4 (68-joint
 count) at screening and at Day 1

 -  DAS28(CRP) >=3.2 at screening

 -  C-Reactive Protein (CRP) >=0.5 milligrams (mg)/deciliter (dL) at screening

 -  Must have previously received methotrexate (MTX) (8-16 mg weekly) orally for at least
 12 weeks before screening, with a stable and tolerated dose for >=4 weeks prior to Day
 1

 -  >=40 kilograms (kg) - Male or female subjects are eligible to participate so long as
 they meet and agree to abide by the contraceptive criteria

 -  Written informed consent prior to any of the screening procedures including
 discontinuation of prohibited medications

 -  Willing to continue or initiate treatment with oral folic acid (5 mg/week) and be
 treated during the entire study (mandatory co-medication for MTX treatment)

 -  Diffusing capacity of lung for carbon monoxide (DLCO) >=60% predicted; forced
 expiratory volume in 1 second (FEV1) >=70% predicted; forced vital capacity (FVC)
 >=80% predicted

 -  For subjects with DLCO values ≥60% to <70%, a baseline chest high-resolution
 computed tomography (HRCT) must be performed during the screening period, and it
 is recommended that the subject be reviewed by a local pulmonologist to exclude
 significant pre-existing respiratory disease.

 -  No evidence of active or latent infection with Mycobacterium tuberculosis (TB), as
 defined by all of the following:

 -  No history of active or latent TB infection irrespective of treatment status

 -  A negative T-spot test within 4 weeks of baseline (Day 1)

 -  Chest X-ray within 12 weeks of Day 1, locally read by a radiologist, with no
 evidence of current or previous pulmonary tuberculosis

 Exclusion Criteria:

 -  Pregnant or lactating women

 -  History of other inflammatory rheumatologic or autoimmune disorders, other than
 Sjögren's syndrome secondary to RA

 -  History of any respiratory disease which (in the opinion of the investigator) would
 compromise subject safety or the ability of the subject to complete the study (e.g.
 significant interstitial lung disease, such as pulmonary fibrosis, chronic obstructive
 pulmonary disease (COPD), moderate-severe asthma, bronchiectasis, previous pulmonary
 alveolar proteinosis (PAP)

 -  Clinically-significant or unstable (in the opinion of the investigator) persistent
 cough or dyspnea that is unexplained

 -  QT interval corrected for heart rate (QTc) >450 milliseconds (msec) or QTc >480 msec
 for subjects with bundle branch block. The QTc is the QT interval corrected for heart
 rate according to Fridericia's formula (QTcF)

 -  Liver function tests: alanine aminotransferase (ALT) >=1.5x upper limit of normal
 (ULN); aspartate transaminase (AST) >=1.5xULN; alkaline phosphatase and bilirubin
 >=1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and
 direct bilirubin <35%)

 -  Current active liver or biliary disease (with the exception of Gilbert's syndrome or
 asymptomatic gallstones or otherwise stable chronic liver disease per investigator
 assessment)

 -  Clinically significant unstable or uncontrolled acute or chronic disease (e.g.,
 cardiovascular including uncompensated congestive cardiac failure New York Heart
 Association [NYHA] III or IV, myocardial infarction within 12 months, unstable angina
 pectoris, uncontrolled hypertension, uncontrolled hypercholesterolemia) pulmonary,
 hematologic, gastrointestinal (including Crohn's Disease or ulcerative colitis),
 hepatic, renal, neurological, psychiatric, malignancy, endocrinological or infectious
 diseases, which, in the opinion of the investigator, could confound the results of the
 study or put the subject at undue risk

 -  A history of malignant neoplasm within the last 10 years or breast cancer within the
 last 20 years, except for non-melanoma skin cancers that have been excised and cured
 or carcinoma in situ of the uterine cervix

 -  Kidney disease: Current or history of renal disease, or estimated creatinine clearance
 <60 milliliter (mL)/minute (min)/1.73 m2 (MDRD formula) or serum creatinine >1.5xULN
 within 4 weeks of Day 1

 -  Hereditary or acquired immunodeficiency disorder, including immunoglobulin deficiency

 -  History of infected joint prosthesis at any time, with the prosthesis still in situ.
 History of leg ulcers, catheters, chronic sinusitis or recurrent chest or urinary
 tract infections

 -  Active infections, or history of recurrent infections (excluding recurrent fungal
 infections of the nail bed), or have required management of acute or chronic
 infections, as follows:

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

 -  OR Hospitalization for treatment of infection within 26 weeks of Day 1

 -  OR Use of parenteral (Intravenous (IV) or Intramuscular (IM) antimicrobials
 (antibacterials, antivirals, antifungals, or antiparasitic agents) within 26
 weeks of Day 1 or oral antimicrobials within 2 weeks of Day 1

 -  A vaccination (live or attenuated) within 30 days of Day 1 or Bacillus Calmette-Guérin
 (BCG) vaccination within 1 year of Day 1, or a live vaccination planned during the
 course of the study (including follow-up period).

 -  Any surgical procedure, including bone or joint surgery/synovectomy within 12 weeks
 prior to Day 1 or any planned surgery within the duration of the study (including
 follow-up period)

 -  Use of prohibited medications Prior to AND throughout the study:

 Any conventional DMARDs other than MTX (including sulfasalazine, bucillamine, iguratimod,
 tacrolimus) should be withdrawn at least 2 weeks prior to Day 1.

 Subjects may require longer to discontinue azathioprine or leflunomide prior to Day 1:
 Azathioprine must be discontinued >=4 weeks prior to randomization; Leflunomide must be
 discontinued >=12 weeks prior to Day 1 (or >=14 days after 11 days of standard
 cholestyramine or activated charcoal washout).

 -  For these subjects, written informed consent for the study must be obtained prior to
 beginning the screening period. However, other screening assessments, other than
 consent, must occur within 4 weeks prior to Day 1.

 -  Any biologic agents (such as Tumor necrosis factor (TNF) inhibitors [including
 adalimumab, etanercept, infliximab, certolizumab pegol, golimumab] or non-TNF
 inhibitors [including abatacept, rituximab, tocilizumab, belimumab]).

 -  Any Janus kinase (JAK) inhibitors (such as tofacitinib).

 -  Any anti-rheumatic investigational compounds.

 -  Any alkylating agents (such as cyclophosphamide).

 -  Plasmapheresis or intravenous immunoglobulin (IVIG) within 26 weeks of Day 1.

 Corticosteroids:

 -  Any Intramascular (IM), Intravenous (IV) or Intra-arterial (IA) corticosteroids within
 8 weeks of Day 1.

 -  Oral corticosteroids:

 -  Any treatment with >10 mg/day dose oral prednisolone (or equivalent) within 4
 weeks of Day 1.

 -  New oral corticosteroid or changes in corticosteroid dose within the 4 weeks
 prior to Day 1. (New topical steroids and immunosuppressive agents (e.g., eye
 drops, creams) are permitted)

 -  Non-steroidal anti-inflammatory drugs (NSAIDs):

 -  New or change in dose of NSAID within 2 weeks of Day 1

 -  Any non-anti-rheumatic investigational treatment must be discontinued for at least 4
 weeks or 5 half-lives, whichever is longer, prior to Day 1

 -  Have current drug or alcohol abuse or dependence, or a history of drug or alcohol
 abuse or dependence within a year prior to Day 1

 -  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

 -  Abnormal chest X-ray within 12 weeks of Day 1 (locally read and reported by a
 radiologist) judged by the investigator as clinically-significant

 -  Any Grade 3 or 4 hematology or clinical chemistry laboratory abnormality, within 4
 weeks of Day 1

 -  Hemoglobin ≤9 g/dL; white blood cell count ≤3.0 x 109/L; platelet count ≤100 x 109/L;
 absolute neutrophil count ≤1.5 x 109/L; lymphocyte count ≤0.5 x 109/L within 4 weeks
 of Day 1

 -  Serologic evidence of current/previous Hepatitis B virus (HBV) infection based on the
 results of testing for Hepatitis B surface antigen (HBsAg) and anti-Hepatitis B core
 (anti-HBc) antibody as follows within 4 weeks of Day 1

 -  Subjects positive for HBsAg and/or positive for anti-HBc antibody (regardless of
 anti-HBs antibody status) are excluded

 -  Subjects with positive anti-HBs antibody and HBV-DNA (>=2.1 log copies/mL) are
 excluded.

 -  Hepatitis C: Positive test for Hepatitis C virus (HCV) antibody confirmed on a
 subsequent blood sample by ribonucleic acid - polymerized chain reaction (RNA-PCR)
 assay within 4 weeks of Day 1.

 -  Subjects who are positive for Hepatitis C antibody and negative when the
 Hepatitis C RNA-PCR assay is performed on a subsequent sample will be eligible to
 participate. Subjects who are positive for Hepatitis C antibody and have a
 positive result for the HCV when the Hepatitis C RNA-PCR assay is performed on
 the subsequent sample will not be eligible to participate

 -  Positive serology for human immunodeficiency virus (HIV) 1 or 2 (within 4 weeks of Day
 1)