Evaluation of Pharmacokinetics and Safety of GSK3196165 in Combination With Methotrexate in Japanese Subjects With Rheumatoid Arthritis

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
A Phase 1/2, Double-Blind, Placebo-Controlled Study of the Pharmacokinetics, Safety and Tolerability of GSK3196165 in Combination With Methotrexate Therapy, in Japanese Subjects With Active Moderate-Severe Rheumatoid Arthritis Despite Treatment With Methotrexate

Conditions
-----------------
Arthritis, Rheumatoid

Intervention / Treatment
-----------------
* Drug: GSK3196165 Dose 1
* Drug: GSK3196165 Dose 2
* Drug: GSK3196165 Dose 3
* Drug: Methotrexate
* Drug: Placebo
* Drug: Folic acid


Participation Criteria
=================
Eligibility Criteria
-----------------
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)

Ages Eligible for Study
-----------------
Minimum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK3196165 Dose 1<br>Participants will receive GSK3196165 Dose 1 weekly as a single subcutaneous (SC) injection by an un-blinded administrator. There will be 5 weekly injections (Days 1, 8, 15, 22 and 29), then every other week (EOW) injections at Days 43, 57 and 71 (Weeks 6, 8 and 10 respectively). Participants will also receive a stable dose of methotrexate during the Treatment Period. | Drug: GSK3196165 Dose 1<br>* GSK3196165 is supplied as liquid and will be administered as SC injection.<br>Drug: Methotrexate<br>* Methotrexate capsule/tablet 8-16 mg per week is given orally.<br>Drug: Folic acid<br>* Folic acid tablet 5 mg per week is given orally.<br>|
| Experimental: GSK3196165 Dose 2<br>Participants will receive GSK3196165 Dose 2 weekly as a single SC injection by an un-blinded administrator. There will be 5 weekly injections (Days 1, 8, 15, 22 and 29), then EOW injections at Days 43, 57 and 71 (Weeks 6, 8 and 10 respectively). Participants will also receive a stable dose of methotrexate during the Treatment Period. | Drug: GSK3196165 Dose 2<br>* GSK3196165 is supplied as liquid and will be administered as SC injection.<br>Drug: Methotrexate<br>* Methotrexate capsule/tablet 8-16 mg per week is given orally.<br>Drug: Folic acid<br>* Folic acid tablet 5 mg per week is given orally.<br>|
| Experimental: GSK3196165 Dose 3<br>Participants will receive GSK3196165 Dose 3 weekly as a single SC injection by an un-blinded administrator. There will be 5 weekly injections (Days 1, 8, 15, 22 and 29), then EOW injections at Days 43, 57 and 71 (Weeks 6, 8 and 10 respectively). Participants will also receive a stable dose of methotrexate during the Treatment Period. | Drug: GSK3196165 Dose 3<br>* GSK3196165 is supplied as liquid and will be administered as SC injection.<br>Drug: Methotrexate<br>* Methotrexate capsule/tablet 8-16 mg per week is given orally.<br>Drug: Folic acid<br>* Folic acid tablet 5 mg per week is given orally.<br>|
| Placebo Comparator: Placebo<br>Participants will receive placebo weekly as a single SC injection by an un-blinded administrator. There will be 5 weekly injections (Days 1, 8, 15, 22 and 29), then EOW injections at Days 43, 57 and 71 (Weeks 6, 8 and 10 respectively). Participants will also receive a stable dose of methotrexate during the Treatment Period. | Drug: Methotrexate<br>* Methotrexate capsule/tablet 8-16 mg per week is given orally.<br>Drug: Placebo<br>* Placebo is supplied as liquid as sterile 0.9% sodium chloride solution and will be administered as SC injection.<br>Drug: Folic acid<br>* Folic acid tablet 5 mg per week is given orally.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Concentration (Cmax) of GSK3196165 | Blood samples were collected at pre-dose on Days 1, 8, 15, 29, 57 and 71; and at any time during visit on Days 3, 74, 85, 106, 127 and 155. PK parameters were calculated by non-compartmental analysis using the concentration data after last dosing (Day 71). Only those participants whose parameters could be determined were analyzed. PK Population included all GSK3196165-treated participants from whom PK samples were collected and analyzed. | Pre-dose on Days 1, 8, 15, 29, 57 and 71; anytime during visit on Days 3, 74, 85, 106, 127 and 155 | 
| Area Under the Concentration-time Curve (AUC) From Time Zero to the Time of the Last Quantifiable Concentration (AUC [0-t]), AUC From Time Zero Extrapolated to Infinity (AUC [0-inf]), AUC Over the Dosing Interval (AUCtau) of GSK3196165 | Blood samples were collected at pre-dose on Days 1, 8, 15, 29, 57 and 71; and at any time during visit on Days 3, 74, 85, 106, 127 and 155. PK parameters were calculated by non-compartmental analysis using the concentration data after last dosing (Day 71). NA indicates data was not available as geometric mean and/or 95 percent confidence interval could not be calculated when number of participant was not sufficient. | Pre-dose on Days 1, 8, 15, 29, 57 and 71; anytime during visit on Days 3, 74, 85, 106, 127 and 155 | 
| Time to Reach Cmax (Tmax) of GSK3196165 | Blood samples were collected at pre-dose on Days 1, 8, 15, 29, 57 and 71; and at any time during visit on Days 3, 74, 85, 106, 127 and 155. PK parameters were calculated by non-compartmental analysis using the concentration data after last dosing (Day 71). | Pre-dose on Days 1, 8, 15, 29, 57 and 71; anytime during visit on Days 3, 74, 85, 106, 127 and 155 | 
| Terminal Half-life (t1/2) of GSK3196165 | Blood samples were collected at pre-dose on Days 1, 8, 15, 29, 57 and 71; and at any time during visit on Days 3, 74, 85, 106, 127 and 155. PK parameters were calculated by standard non-compartmental analysis from the concentration data after last dosing (Day 71). NA indicates data was not available as 95 percent confidence interval could not be calculated when number of participant was not sufficient. | Pre-dose on Days 1, 8, 15, 29, 57 and 71; anytime during visit on Days 3, 74, 85, 106, 127 and 155. | 
| Number of Participants With Any Adverse Event (AE), Serious AE (SAE) and Adverse Events of Special Interest (AESI) | An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention or event associated with liver injury and impaired liver function were categorized as SAE. AESI included serious infections including serious respiratory infections and tuberculosis and opportunistic infections, neutropenia (grade 3 or 4), respiratory events, pulmonary alveolar proteinosis, hypersensitivity reactions including anaphylaxis and injection site reactions. | Up to 22 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Vital sign measurements including SBP and DBP were measured after 5 minutes rest before each reading. Baseline was considered as the latest pre-dose assessment. The change from Baseline is defined as the difference between the post-dose visit value and Baseline value. | Baseline and up to 22 weeks | 
| Change From Baseline in Heart Rate (HR) | Vital sign measurements including HR was measured after 5 minutes rest before each reading. Baseline was considered as the latest pre-dose assessment. The change from Baseline is defined as the difference between the post-dose visit value and Baseline value. | Baseline and up to 22 weeks | 
| Change From Baseline in Body Temperature | Vital sign measurements including body temperature was measured after 5 minutes rest before each reading. Baseline was considered as the latest pre-dose assessment. The change from Baseline is defined as the difference between the post-dose visit value and Baseline value. | Baseline and up to 22 weeks | 
| Change From Baseline in Respiratory Rate | Vital sign measurements including respiratory rate was measured after 5 minutes rest before each reading. Baseline was considered as the latest pre-dose assessment. The change from Baseline is defined as the difference between the post-dose visit value and Baseline value. | Baseline and up to 22 weeks | 
| Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings | 12-Lead ECGs were taken using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT and corrected QT (QTc) intervals. Number of participants with any abnormal findings in ECG recordings were summarized as clinically significant and not clinically significant. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. | At Week 12 | 
| Number of Participants With Emergent Hematology Results Relative to Normal Range | Blood samples were collected to evaluate hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), erythrocytes, reticulocytes, white blood cells (WBC), total neutrophils, eosinophils, basophils, monocytes, lymphocytes, platelet count, activated partial thromboplastin time (APTT), prothrombin time (PT), fibrinogen, erythrocyte sedimentation rate (ESR). Participants were counted in the worst case category that their value changes to (low, normal or high), unless there is no change in their category. Participants whose lab value category was unchanged (e.g. High to High), or whose value became normal, are recorded in the 'To Normal or No Change' category. Participants were counted twice if they had values that changed 'To Low' and 'To High', so the percentages may not add to 100% in such instances. | Up to 22 weeks | 
| Number of Participants With Emergent Clinical Chemistry Results Relative to Normal Range | Blood samples were collected to evaluate Albumin, Alkaline Phosphatase (ALP), Alanine Amino Transferase (ALT), Aspartate Amino Transferase (AST), Total Bilirubin, Calcium, Cholesterol, Creatine Kinase, C-Reactive protein (CRP), Creatinine, Gamma Glutamyl Transferase (GGT), Glucose, High Density Lipids (HDL), Potassium, Lactate Dehydrogenase, Low Density Lipids (LDL), Sodium, Phosphorus inorganic, Triglycerides, Total Protein and Urea. Participants were counted in the worst case category that their value changes to (low, normal or high), unless there is no change in their category. Participants whose lab value category was unchanged (e.g. High to High), or whose value became normal, are recorded in the 'To Normal or No Change' category. Participants were counted twice if they had values that changed 'To Low' and 'To High', so the percentages may not add to 100% in such instances. | Up to 22 weeks | 
| Number of Participants With Urinalysis Dipstick Findings | Urine samples were collected for analysis of presence of glucose and protein in urine by dipstick method. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameter of urine protein and glucose can be read as negative, Trace, 1+, 2+ and 3+, indicating proportional concentrations in the urine sample | Up to 22 weeks | 
| Number of Participants With Anti-GSK3196165 Antibody Test Results | Serum samples were collected and tested for presence of antibodies that bind to GSK3196165. The presence of treatment emergent anti-drug antibodies (ADA) were determined using a GSK3196165 bridging style ADA assay with a bio-analytically determined cut point determined during assay validation. Samples taken after dosing with GSK3196165 that have a value at or above the cut-point were considered treatment-emergent ADA-positive. These ADA positive samples were further evaluated in a confirmatory assay, and confirmed positive samples were further characterized by assessment of titer. Baseline was considered as the latest pre-dose assessment. Number of participants with post-Baseline negative or positive anti-GSK3196165 antibody test results were presented. | Weeks 2, 4, 12 and 22 | 
| Change From Baseline in Disease Activity Score for 28 Different Joints C-reactive Protein (DAS28 [CRP]) at All Indicated Timepoints | DAS28 (CRP) is a measure of disease activity in rheumatoid arthritis obtained by examination of 28 joints for swelling and tenderness using CRP as a blood biomarker for inflammation. Its components include: Tender/Painful Joint Count 28 (TJC28), Swollen Joint Count 28 (SJC28), CRP and Patient's Global Assessment of Arthritis. DAS28 (CRP) was calculated by 0.56 (square root of TJC28)+ 0.28 (square root of SJC28)+ 0.36 (natural logarithm [CRP+1])+ (0.014*patients global assessment)+0.96. Scores ranges from 0 to infinity, where higher scores indicates high disease activity. Scores higher than 5.1 indicates high disease activity and scores lower than 2.6 indicates remission. Baseline was considered as the latest pre-dose assessment. The change from Baseline is defined as the difference between the post-dose visit value and Baseline value. Adjusted mean and standard error of adjusted mean are presented using Mixed Model for Repeated Measures. | Baseline, up to Week 22 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Efficacy, GSK3196165, Active Rheumatoid Arthritis, Methotrexate, Monoclonal Antibody, Electrocardiogram, Tolerability, Pharmacokinetics, Japanese Subjects