Mechanistic Study of GSK3196165 Plus Methotrexate (MTX) in Subjects With Active Rheumatoid Arthritis

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02799472
• Collaborator: Parexel (Industry)
• Enrollment: 39
• Locations: 16
• Arms: 2
• Actual Duration (Months): 16.5
• Patients Per Site: 2.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study is designed to explore the activity of granulocyte-macrophage colony stimulating factor (GM-CSF) signaling pathway in subjects with rheumatoid arthritis (RA), the potential impact of inhibition of this axis by GSK3196165, and to evaluate whether there are any differences in the GM-CSF axis between subjects with early RA compared with those with more established disease. This study also aims to establish the potential impact of GSK3196165 on inflammatory structural joint damage in the hand/wrist using magnetic resonance imaging (MRI). This is a randomized Phase IIa, multi-center, double-blind, placebo-controlled parallel group study. Approximately 40 subjects with active RA despite treatment with disease-modifying antirheumatic drugs (DMARDs) (including conventional or biologic) will be randomized into the study, following a screening period of up to 6 weeks. The total treatment period is up to 10 weeks, with a 12-week follow-up period after the last dose (Week 22).

Condition or Disease	Intervention/Treatment	Phase
Arthritis, Rheumatoid	Drug: GSK3196165; Drug: Placebo; Drug: MTX; Drug: Folic (or folinic) acid	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 39 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase IIa, Double-Blind, Mechanistic Study of GSK3196165 in Combination With Methotrexate Therapy in Subjects With Active Rheumatoid Arthritis Despite Treatment With DMARDs
• Actual Study Start Date: Jun 15, 2016
• Actual Primary Completion Date: Oct 30, 2017
• Actual Study Completion Date: Oct 30, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GSK3196165 + MTX arm Subjects will receive GSK3196165 (initially weekly, then every other week) in combination with MTX (15-25 mg/week) and folic (or folinic) acid (>=5 mg/week).	Drug: GSK3196165; GSK3196165 is supplied as liquid and will be administered as SC injection.; Drug: MTX; Capsule, tablet or liquid administered orally or as SC injection.; Drug: Folic (or folinic) acid; Capsule, tablet or liquid and will be administered orally.
Placebo Comparator: Placebo + MTX arm Subjects will receive placebo (initially weekly, then every other week) in combination with MTX (15-25 mg/week) and folic (or folinic) acid (>=5 mg/week).	Drug: Placebo; 0.9% weight by volume (w/v) sodium chloride solution administered as SC injection.; Drug: MTX; Capsule, tablet or liquid administered orally or as SC injection.; Drug: Folic (or folinic) acid; Capsule, tablet or liquid and will be administered orally.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Target Engagement Biomarkers- Soluble Granulocyte-macrophage Colony-stimulating Factor (GM-CSF) Complexed to GSK3196165 [Baseline and Weeks 1, 2, 4, 6, 8, 12, 12-Week follow-up (FU) (Week 22)]

   Blood samples were collected for markers which may influence rheumatoid arthritis. Target engagement biomarkers included soluble GM-CSF complexed to GSK3196165. Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. Analysis was performed using repeated measures analysis adjusted for GM-CSF - Complex log(Baseline value), treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Analysis was performed on Intent-to-Treat (ITT) Population which consisted of all participants who were randomized to treatment and who received at least one dose of study treatment. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

2. Change From Baseline in Predictive Biomarkers: 14-3-3 ETA Protein, S100 Calcium Binding Protein (CBP) A8 and A9 [Baseline and Weeks 1, 2, 4, 6, 8, 12, 12-Week FU (Week 22)]

   Blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Predictive biomarkers included analysis of 14-3-3 ETA Protein, S100 CBP A8 and A9. Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. Analysis was performed using repeated measures analysis adjusted for 14-3-3 ETA Protein (mg/L) and S100 CBP A8 and A9 log(Baseline value), treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

3. Change From Baseline in Predictive Biomarkers: Amyloid A [Baseline and Week 12, 12-Week FU (Week 22)]

   Blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Predictive biomarkers included analysis of Amyloid A. Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. Analysis was performed using repeated measures analysis adjusted for Amyloid A log(Baseline value), treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Data has been presented for only those time points at which the samples were collected.

4. Change From Baseline in Predictive Biomarkers: Amyloid A, Chemokine (C-C Motif) Ligand 17, Chemokine (C-X-C Motif) Ligand 13, Interleukin 6, Macrophage-Derived Chemokine [Baseline and Weeks 1, 2, 4, 6, 8, 12, 12-Week FU (Week 22)]

   Blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Predictive biomarkers included analysis of Chemokine (C-C Motif) Ligand 17 (CL17), Chemokine (C-X-C Motif) Ligand 13 (CL13), Interleukin 6, Macrophage-Derived Chemokine (MDC). Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. Analysis was performed using repeated measures analysis adjusted for CL17, CL13, Interleukin 6, MDC log(Baseline value), treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Data has been presented for only those time points at which the samples were collected.

5. Change From Baseline in Predictive Biomarkers: Chitinase 3 Like 1, Matrix Metalloproteinase 3 (MMP-3) [Baseline and Weeks 1, 2, 4, 6, 8, 12, 12-Week FU (Week 22)]

   Blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Predictive biomarkers included analysis of Chitinase 3 Like 1 and MMP-3. Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. Analysis was performed using repeated measures analysis adjusted for Chitinase 3 Like 1 and MMP-3 log(Baseline value), treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

6. Change From Baseline in Cartilage Biomarkers [Baseline and Weeks 1, 2, 4, 6, 8, 12, 12-Week FU (Week 22)]

   Blood samples were collected and analyzed for markers that may be predictive of rheumatoid arthritis disease activity. Cartilage biomarkers included analysis of ARGS Neo-Epitope, Citrullinated MMP-Degraded Vimentin (CMDV), MMP-Degraded C Reactive Protein (CRP), MMP-Degraded Type I Collagen (MD1C), MMP-Degraded Type II Collagen (MD2C), MMP-Degraded Type III Collagen (MD3C). Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. Analysis was performed using repeated measures analysis adjusted for ARGS Neo-Epitope, Citrullinated MMP-Degraded Vimentin, MMP-Degraded CRP, MMP-Degraded Type I Collagen, MMP-Degraded Type II Collagen and MMP-Degraded Type III Collagen log(Baseline value), treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

7. Change From Baseline in Flow Cytometry: Helper/Suppressor Cells [Baseline and Weeks 1, 4, 12, 12-Week FU (Week 22)]

   Whole blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Flow cytometry assessment included assessment of Helper/Suppressor. Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. Analysis was performed using repeated measures analysis adjusted for Helper/Suppressor log(Baseline value), treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

8. Change From Baseline in Flow Cytometry: 6 Colour TB Natural Killer (NK) Panel- CD16+CD56+, CD19, CD3, CD3+CD4+ [Baseline and Weeks 1, 4, 12, 12-Week FU (Week 22)]

   Whole blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Flow cytometry assessment included assessment of cluster of differentiation (CD)16+CD56+, CD19, CD3, CD3+CD4+. Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. Repeated measures analysis adjusted for CD16+CD56+, CD19, CD3, CD3+CD4+, CD3+CD8+ and T Cell B Cell NKL log(Baseline value), treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

9. Change From Baseline in Flow Cytometry: 6 Colour TBNK Panel- CD3+CD8+ and T Cell B Cell Natural Killer Lymphocytes (NKL) [Baseline and Weeks 1, 4, 12, 12-Week FU (Week 22)]

   Whole blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Flow cytometry assessment included assessment of CD3+CD8+ and T Cell B Cell NKL. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post-dose value from the Baseline value. Analysis was performed using repeated measures analysis adjusted for CD3+CD8+ and T Cell B Cell NKL log(Baseline value), treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

10. Change From Baseline in Flow Cytometry: T Regulatory (Reg) Cell Foxp3- CD3+ CD4+, CD3+ CD8+ and CD3+ [Baseline and Weeks 1, 4, 12, 12-Week FU (Week 22)]

    Whole blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Flow cytometry assessment included assessment of CD3+ CD4+, CD3+ CD8+ and CD3+. Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. Analysis was performed using repeated measures analysis adjusted for CD3+ CD4+, CD3+ CD8+ and CD3+ Number of Cells (10^6/L) log(Baseline value), treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

11. Change From Baseline in Flow Cytometry: T Reg Cell Foxp3: CD3+CD4+CD25+CD127-, CD3+CD4+foxP3+CD25+CD127- [Baseline and Weeks 1, 4, 12, 12-Week FU (Week 22)]

    Whole blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Flow cytometry assessment included assessment of CD3+CD4+CD25+CD127- and CD3+CD4+foxP3+CD25+CD127-. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post-dose value from the Baseline value. Analysis was performed using repeated measures analysis adjusted for CD3+CD4+CD25+CD127- and CD3+CD4+foxP3+CD25+CD127-Number of Cells (10^6 cells/L) log(Baseline value), treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

12. Change From Baseline in T Helper Cell Panel Events [Baseline and Weeks 1, 4, 12, 12-Week FU (Week 22)]

    Blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. T Helper Cell Panel included analysis of CD45+3+8-4+CCR6+CXCR3+38+DR+, CD45+3+8-4+CCR6+CXCR3-38+DR+, CD45+3+8-4+CCR6-CXCR3+38+DR+, CD45+3+8-4+CCR6-CXCR3-38+DR+, CD45+CD3+CD8-CD4+, CD45+CD3+CD8-CD4+CCR6+CXCR3+, CD45+CD3+CD8-CD4+CCR6+CXCR3-, CD45+CD3+CD8-CD4+CCR6-CXCR3+ and CD45+CD3+CD8-CD4+CCR6-CXCR3-. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post-dose value from the Baseline value. Analysis was performed using repeated measures analysis adjusted for T Helper Cell Panel Events (EVENTS) Baseline value, treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

13. Change From Baseline in Flow Cytometry: CD16+ Monocyte Panel: CD14-HLA-DR+CD11cbr+CD123-, CD14br+CD16+, CD14br+CD16-, CD14lo+CD16br+ [Baseline and Weeks 1, 4, 12, 12-Week FU (Week 22)]

    Whole blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Flow cytometry assessment included assessment of CD14-HLA-DR+CD11cbr+CD123-, CD14br+CD16+, CD14br+CD16- and CD14lo+CD16br+. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post-dose value from the Baseline value. Analysis was performed using repeated measures analysis adjusted for CD14-HLA-DR+CD11cbr+CD123-, CD14br+CD16+, CD14br+CD16- and CD14lo+CD16br+ (10^3/Liter) baseline value, treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

14. Change From Baseline in Flow Cytometry: CD16+ Monocyte Panel: CD14-CD16+CD66b+ [Baseline and Weeks 1, 4, 12, 12-Week FU (Week 22)]

    Whole blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Flow cytometry assessment included assessment of CD14-CD16+CD66b+ cell. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post-dose value from the Baseline value. Analysis was performed using repeated measures analysis adjusted for CD14-CD16+CD66b+ (10^6/Liter) baseline value, treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

15. Change From Baseline in Complement Biomarkers: Complement Component 3 (C3), Complement Component 4 (C4) [Baseline and Weeks 1, 2, 4, 6, 8, 12, 12-Week FU (Week 22)]

    Blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Complement biomarkers included analysis of Complement C3 and Complement C4. Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

16. Change From Baseline in Complement Biomarkers: Complement Component 4a (C4a), Complement Component 5a (C5a), Complement Split Factor SC5b-9, Soluble Cluster of Differentiation 163 (sCD163) [Baseline and Weeks 1, 2, 4, 6, 8, 12, 12-Week FU (Week 22)]

    Blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Complement biomarkers included analysis of Complement C4a, Complement C5a, Complement Split Factor SC5b-9 and Soluble CD163. Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

17. Change From Baseline in Mechanistic Biomarkers [Baseline and Weeks 1, 2, 4, 6, 8, 12, 12-Week FU (Week 22)]

    Blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Mechanistic biomarkers included analysis of Interleukin 1 Beta, Interleukin 10, Interleukin 15, Interleukin 17 Alpha, Interleukin 17F, Interleukin 8 and Tumor Necrosis Factor. Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. NA indicates that data is not available since 100% of the data was below limit of quantification at all time points. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

18. Change From Baseline in Safety Biomarkers: 3B-Cholestenoic Acid, Surfactant Protein D [Baseline and Week 12, 12-Week FU (Week 22)]

    Blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Safety biomarkers included analysis of 3B-Cholestenoic Acid and Surfactant Protein D. Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

19. Change From Baseline in Safety Biomarkers: KL-6 Antigen [Baseline and Week 12, 12-Week FU (Week 22)]

    Blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Safety biomarker included analysis of KL-6 Antigen. Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Secondary Outcome Measures

1. Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESI) [Up to 12-Week FU (Week 22)]

   An AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect and associated with liver injury and impaired liver function. An AESI include serious infections, opportunistic infections, neutropenia, respiratory events, pulmonary alveolar proteinosis, hypersensitivity reactions, injection site reactions, persistent cough or dyspnea.

2. Number of Participants Who Tested Positive for Anti-GSK3196165 Binding Antibody Detection at Any Time Post-Baseline [Up to 12-Week FU (Week 22)]

   Immunogenicity samples for determination of anti-drug-antibody (ADA) were collected. The presence of treatment emergent ADA was 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 had a value at or above the cut-point was considered potentially treatment-emergent ADA-positive. The immunogenicity population consisted of all participants in the ITT population, who had at least one valid immunogenicity assessment.

3. Change From Baseline in Synovitis as Assessed by Outcome Measures in Rheumatology (OMERACT) Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (RAMRIS) in the Most Affected Hand/Wrist [Baseline and Weeks 4, 12, 12-Week FU (Week 22)]

   For synovitis a total of 8 joints were evaluated. Individual joint scores range from 0-3, where 0= normal, 1=mild, 2=moderate and 3=severe. The final synovitis score is the sum of the individual joint scores. Total score range from 0 (best) to 24 (worst). If an individual location is scored either 'Not Visible' or 'Surgically Modified' then the score for that location was set to missing. Missing joint scores was imputed as the mean of the non-missing joint scores. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post-dose value from the Baseline value. Repeated measures analysis adjusted for synovitis score baseline value, treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Data has been presented for Median and 95% credible interval. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

4. Change From Baseline in Osteitis as Assessed by OMERACT RAMRI Scoring System in the Most Affected Hand/Wrist [Baseline and Weeks 4, 12, 12-Week FU (Week 22)]

   For bone edema/osteitis a total of 25 locations was evaluated. Individual location scores ranged from 0-3, where, 0: no edema; 1: 1-33% of bone edematous; 2: 34-66% of bone edematous; 3: 67-100% of bone edematous. Final bone edema/osteitis score is sum of individual location scores. Total score ranged from 0 (best) to 75 (worst). Baseline was defined at Day 1. Change from Baseline was calculated by subtracting post-dose value from Baseline value. If an individual location was scored either 'Not Visible' or 'Surgically Modified' or 'Not Assessable' then the score for that location was set to be missing. Missing joint scores was imputed as mean of non-missing location scores. Repeated measures analysis adjusted for Bone Edema/Osteitis Score baseline value, treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

5. Change From Baseline in Erosion as Assessed by OMERACT RAMRI Scoring System in the Most Affected Hand/Wrist [Baseline and Weeks 4, 12, 12-Week FU (Week 22)]

   For bone erosion a total of 25 locations were evaluated. Individual location scores range from 0-10, where, 0: no erosion; 1: 1-10% of bone eroded and 10: 91-100% of bone eroded. The final bone erosion score is the sum of the individual location scores. The total score ranged from 0 (best) to 250 (worst). If an individual location was scored either 'Not Visible' or 'Surgically Modified' or 'Not Assessable' then the score for that location was set to be missing. Missing joint scores was imputed as the mean of the non-missing location scores. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post-dose value from the Baseline value. Analysis was performed using repeated measures analysis adjusted for Bone Erosion Score baseline value, treatment group, disease duration (<=2 or >2 years), visit and treatment group. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles.

6. Change From Baseline in Synovitis as Assessed by Rheumatoid Arthritis MRI Quantitative (RAMRIQ) Assessment in the Most Affected Hand/Wrist [Baseline and Weeks 4, 12 and 12-Week FU (Week 22)]

   RAMRIQ is an automated volume quantification assessment. RAMRIQ assessed same pathologies and joints (except metacarpophalangeal joint [MCP1]) as RAMRIS allowing for direct comparison of results obtained using the two methods. Bones were automatically identified in pre-contrast, coronal T1 images using active appearance modelling (AAMs). Joint capsules and soft tissues were also segmented with AAMs, providing consistent 3D regions of interest (ROI) for synovial enhancement across all time points. Synovial volume was calculated as voxels that enhance within each ROI. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post-dose value from the Baseline value. Repeated measures analysis adjusted for Synovitis baseline value, treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

7. Change From Baseline in Osteitis as Assessed by RAMRIQ Assessment in the Most Affected Hand/Wrist [Baseline and Weeks 4, 12 and 12-Week FU (Week 22)]

   RAMRIQ is an automated volume quantification assessment for edema volume. RAMRIQ assessed the same pathologies and joints (except MCP1) as RAMRIS, allowing for direct comparison of results obtained using the two methods. Bones were automatically identified in pre-contrast, coronal T1 images using AAMs. Joint capsules and soft tissues were also segmented with AAMs, providing consistent 3D ROI for synovial enhancement across all time points. Edema volume was defined as non-erosion contrast-enhancing voxels inside the bone. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post-dose value from the Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

8. Change From Baseline in Erosion as Assessed by RAMRIQ Assessment in the Most Affected Hand/Wrist [Baseline and Weeks 4, 12 and 12-Week FU (Week 22)]

   RAMRIQ is an automated volume quantification assessment for erosion volume. RAMRIQ assessed the same pathologies and joints (except MCP1) as RAMRIS, allowing for direct comparison of results obtained using the two methods. Bones were automatically identified in pre-contrast, coronal T1 images using AAMs. Joint capsules and soft tissues were also segmented with AAMs, providing consistent 3D ROI for synovial enhancement across all time points. Erosion volume was identified inside the bone surfaces using voxel-based classification. The volume of BME and erosions was normalised to total bone volume for statistical analysis. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post-dose value from the Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age >=18 years at the time of signing informed consent.

• Meets American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 RA Classification Criteria AND subject not diagnosed before age of 16 years.

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

• Active disease as defined by:

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

AND • Disease activity score for 28 different joints with C-reactive protein (CRP) value (DAS28[CRP]) >=3.2 at screening.

AND

• CRP >=3.0 milligrams (mg)/liter (L).

• Signs of inflammation such as synovitis in the MRI scan of the most-affected hand.

• Must be currently taking MTX (15-25 mg weekly) (oral/injected) for at least 12 weeks before screening, with no change in route of administration, with a stable and tolerated dose for >=4 weeks prior to Day 1. A stable dose of MTX >=7.5 mg/week is acceptable, if the MTX dose has been reduced for reasons of documented intolerance to MTX, example (e.g.) hepatic or hematologic toxicity, or per local requirement.

• Body weight >=45 kilograms (kg).

• Male or female subjects are eligible to participate so long as they meet and agree to abide by the contraceptive criteria.

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

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

• Diffusing capacity of the lung for carbon monoxide (DLCO) >=60% predicted; forced expiratory volume in 1 second (FEV1) >=70% predicted.

• No evidence of active or latent infection with Mycobacterium tuberculosis (TB).

Exclusion Criteria:

• Pregnant or lactating, or women planning to become pregnant or initiating breastfeeding.

• 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 (in the opinion of the investigator) persistent cough or clinically significant or unstable dyspnea that is unexplained.

• Significant unstable or uncontrolled acute or chronic disease which, in the opinion of the investigator, could confound the results of the study or put the subject at undue risk.

• A history of malignancy.

• Contraindication to MRI scanning.

• Current/previous Hepatitis B virus (HBV), Hepatitis C virus (HCV) or human immunodeficiency virus (HIV) 1 or 2 infection.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	El Cajon	California	United States	92020
2	GSK Investigational Site	Fort Lauderdale	Florida	United States	33309
3	GSK Investigational Site	Miami	Florida	United States	33015
4	GSK Investigational Site	Pinellas Park	Florida	United States	33781
5	GSK Investigational Site	Chicago	Illinois	United States	60616
6	GSK Investigational Site	Duncansville	Pennsylvania	United States	16635
7	GSK Investigational Site	Memphis	Tennessee	United States	38119
8	GSK Investigational Site	Houston	Texas	United States	77024
9	GSK Investigational Site	Freiburg	Baden-Wuerttemberg	Germany	79106
10	GSK Investigational Site	Puettlingen		Germany	66346
11	GSK Investigational Site	Elblag		Poland	82-300
12	GSK Investigational Site	Nowa Sol		Poland	67-100
13	GSK Investigational Site	Piaseczno		Poland	05-500
14	GSK Investigational Site	Warszawa		Poland	00-660
15	GSK Investigational Site	Warszawa		Poland	03-291
16	GSK Investigational Site	Wroclaw		Poland	51-128

Sponsors and Collaborators

• GlaxoSmithKline
• Parexel

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

• Study Protocol - Mar 1, 2016
• Statistical Analysis Plan - Nov 28, 2017

More Information

Publications

• M Genovese, M Berkowitz, P Conaghan, C Peterfy, K Davy, E Fisheleva, A Gupta, D Inman, R Janiczek, M Layton, N Mitchell, J Patel, A Roberts, D Saurigny, J Smith, R Williamson, P-P Tak. Magnetic Resonance Imaging of the Joint and Evaluation of the GM-CSF/CCL17 axis in a Phase IIa Randomised Mechanistic Study of Otilimab in Patients with Rheumatoid Arthritis. Lancet Rheumatol. 2020; DOI: 10.1016/S2665-9913(20)30224-1

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT02799472
• Other Study ID Numbers: 205180; 2015-004386-91
• First Posted: Jun 14, 2016
• Last Update Posted: Jan 11, 2021
• Last Verified: Dec 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by GlaxoSmithKline: GSK3196165; magnetic resonance imaging (MRI); disease-modifying antirheumatic drugs (DMARDs); granulocyte-macrophage colony stimulating factor (GM-CSF); Rheumatoid Arthritis; Methotrexate
• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid

Study Results

Participant Flow

Recruitment Details	A total of 39 participants with active early/established Rheumatoid arthritis were randomized across 9 centers in 3 countries from 15 June 2016 to 30 October 2017.
Pre-assignment Detail	Out of the 88 participants screened for this study, 49 participants were screen failures and 39 participants were randomized and received treatment in the study.

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo subcutaneously (SC) into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received methotrexate (MTX) 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 milligrams (mg) SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Period Title: Overall Study
STARTED	11	28
COMPLETED	7	23
NOT COMPLETED	4	5

Baseline Characteristics

Arm/Group Title	Placebo	GSK3196165 180 mg	Total
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Total of all reporting groups
Overall Participants	11	28	39
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	50.3 (11.57)	59.1 (9.47)	56.6 (10.73)
Sex: Female, Male (Count of Participants)
Female	10 90.9%	24 85.7%	34 87.2%
Male	1 9.1%	4 14.3%	5 12.8%
Race/Ethnicity, Customized (Count of Participants)
Black or African American	2 18.2%	4 14.3%	6 15.4%
White	9 81.8%	24 85.7%	33 84.6%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Target Engagement Biomarkers- Soluble Granulocyte-macrophage Colony-stimulating Factor (GM-CSF) Complexed to GSK3196165
Description	Blood samples were collected for markers which may influence rheumatoid arthritis. Target engagement biomarkers included soluble GM-CSF complexed to GSK3196165. Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. Analysis was performed using repeated measures analysis adjusted for GM-CSF - Complex log(Baseline value), treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Analysis was performed on Intent-to-Treat (ITT) Population which consisted of all participants who were randomized to treatment and who received at least one dose of study treatment. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame	Baseline and Weeks 1, 2, 4, 6, 8, 12, 12-Week follow-up (FU) (Week 22)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
GM-CSF - Complex, Week 1, n=9, 27	0.972 (35.98)	13.799 (20.65)
GM-CSF - Complex, Week 2, n=8, 26	0.960 (31.23)	31.056 (17.58)
GM-CSF - Complex, Week 4, n=8, 27	0.959 (34.51)	53.496 (18.55)
GM-CSF - Complex, Week 6, n=7, 26	0.964 (40.96)	46.620 (22.37)
GM-CSF - Complex, Week 8, n=7, 24	0.964 (41.80)	33.404 (22.47)
GM-CSF - Complex, Week 12, n=7, 24	0.970 (44.95)	22.556 (24.38)
GM-CSF - Complex, 12-Week FU, n=8, 21	0.954 (20.80)	1.176 (12.88)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	GM-CSF - Complex, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	14.201
	Confidence Interval	(2-Sided) 95%; 6.251 to 32.262
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	GM-CSF - Complex, Week 2
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	32.360
	Confidence Interval	(2-Sided) 95%; 15.828 to 66.156
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	GM-CSF - Complex, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	55.772
	Confidence Interval	(2-Sided) 95%; 25.646 to 121.287
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	GM-CSF - Complex, Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	48.336
	Confidence Interval	(2-Sided) 95%; 19.341 to 120.798
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	GM-CSF - Complex, Week 8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	34.635
	Confidence Interval	(2-Sided) 95%; 13.690 to 87.629
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	GM-CSF - Complex, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	23.249
	Confidence Interval	(2-Sided) 95%; 8.579 to 63.005
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	GM-CSF - Complex, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.401
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.233
	Confidence Interval	(2-Sided) 95%; 0.742 to 2.048
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Change From Baseline in Predictive Biomarkers: 14-3-3 ETA Protein, S100 Calcium Binding Protein (CBP) A8 and A9
Description	Blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Predictive biomarkers included analysis of 14-3-3 ETA Protein, S100 CBP A8 and A9. Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. Analysis was performed using repeated measures analysis adjusted for 14-3-3 ETA Protein (mg/L) and S100 CBP A8 and A9 log(Baseline value), treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame	Baseline and Weeks 1, 2, 4, 6, 8, 12, 12-Week FU (Week 22)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
14-3-3 ETA Protein, Week 1, n=9, 27	1.046 (3.88)	0.986 (2.16)
14-3-3 ETA Protein, Week 2, n=8, 26	0.959 (12.14)	0.986 (6.70)
14-3-3 ETA Protein, Week 4, n=9, 26	1.128 (16.59)	0.838 (9.55)
14-3-3 ETA Protein, Week 6, n=7, 26	1.093 (15.55)	0.833 (8.88)
14-3-3 ETA Protein, Week 8, n=7, 23	0.950 (15.19)	0.842 (8.48)
14-3-3 ETA Protein, Week 12, n=7, 24	1.131 (20.90)	0.897 (11.89)
14-3-3 ETA Protein, 12-Week FU, n=7, 21	1.040 (24.06)	0.893 (13.45)
S100 CBP A8 and A9, Week 1, n=9, 27	0.940 (15.20)	0.939 (8.92)
S100 CBP A8 and A9, Week 2, n=8, 26	0.871 (15.28)	0.823 (8.65)
S100 CBP A8 and A9, Week 4, n=9, 27	0.874 (19.20)	0.889 (11.26)
S100 CBP A8 and A9, Week 6, n=7, 27	0.828 (21.92)	0.812 (11.81)
S100 CBP A8 and A9, Week 8, n=7, 25	0.804 (21.04)	0.857 (11.46)
S100 CBP A8 and A9, Week 12, n=7, 24	0.694 (21.61)	0.879 (12.05)
S100 CBP A8 and A9, 12-Week FU, n=7, 21	0.582 (20.60)	1.018 (11.83)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	14-3-3 ETA Protein, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.193
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.943
	Confidence Interval	(2-Sided) 95%; 0.861 to 1.032
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	14-3-3 ETA Protein, Week 2
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.842
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.028
	Confidence Interval	(2-Sided) 95%; 0.776 to 1.362
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	14-3-3 ETA Protein, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.127
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.743
	Confidence Interval	(2-Sided) 95%; 0.505 to 1.093
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	14-3-3 ETA Protein, Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.137
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.762
	Confidence Interval	(2-Sided) 95%; 0.531 to 1.095
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	14-3-3 ETA Protein, Week 8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.488
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.886
	Confidence Interval	(2-Sided) 95%; 0.623 to 1.259
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	14-3-3 ETA Protein, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.338
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.793
	Confidence Interval	(2-Sided) 95%; 0.488 to 1.290
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	14-3-3 ETA Protein, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.582
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.859
	Confidence Interval	(2-Sided) 95%; 0.491 to 1.502
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	S100 CBP A8 and A9, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.996
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.999
	Confidence Interval	(2-Sided) 95%; 0.699 to 1.427
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	S100 CBP A8 and A9, Week 2
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.745
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.944
	Confidence Interval	(2-Sided) 95%; 0.662 to 1.346
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	S100 CBP A8 and A9, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.939
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.017
	Confidence Interval	(2-Sided) 95%; 0.649 to 1.593
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	S100 CBP A8 and A9, Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.937
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.981
	Confidence Interval	(2-Sided) 95%; 0.595 to 1.617
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	S100 CBP A8 and A9, Week 8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.787
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.067
	Confidence Interval	(2-Sided) 95%; 0.659 to 1.727
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	S100 CBP A8 and A9, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.342
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.267
	Confidence Interval	(2-Sided) 95%; 0.769 to 2.086
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	S100 CBP A8 and A9, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.026
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.748
	Confidence Interval	(2-Sided) 95%; 1.076 to 2.838
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Change From Baseline in Predictive Biomarkers: Amyloid A
Description	Blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Predictive biomarkers included analysis of Amyloid A. Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. Analysis was performed using repeated measures analysis adjusted for Amyloid A log(Baseline value), treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Data has been presented for only those time points at which the samples were collected.
Time Frame	Baseline and Week 12, 12-Week FU (Week 22)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
Amyloid A, Week 12, n=7, 24	0.845 (49.31)	0.653 (25.45)
Amyloid A, 12-Week FU, n=7, 21	0.529 (35.12)	0.623 (19.68)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Amyloid A, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.632
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.774
	Confidence Interval	(2-Sided) 95%; 0.261 to 2.290
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Amyloid A, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.685
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.176
	Confidence Interval	(2-Sided) 95%; 0.519 to 2.663
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Change From Baseline in Predictive Biomarkers: Amyloid A, Chemokine (C-C Motif) Ligand 17, Chemokine (C-X-C Motif) Ligand 13, Interleukin 6, Macrophage-Derived Chemokine
Description	Blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Predictive biomarkers included analysis of Chemokine (C-C Motif) Ligand 17 (CL17), Chemokine (C-X-C Motif) Ligand 13 (CL13), Interleukin 6, Macrophage-Derived Chemokine (MDC). Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. Analysis was performed using repeated measures analysis adjusted for CL17, CL13, Interleukin 6, MDC log(Baseline value), treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Data has been presented for only those time points at which the samples were collected.
Time Frame	Baseline and Weeks 1, 2, 4, 6, 8, 12, 12-Week FU (Week 22)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
CL17, Week 1, n=9, 27	1.117 (18.81)	0.773 (10.94)
CL17, Week 2, n=8, 26	0.912 (24.37)	0.651 (13.60)
CL17, Week 4, n=9, 27	1.117 (21.91)	0.679 (12.51)
CL17, Week 6, n=7, 27	1.032 (24.38)	0.779 (12.48)
CL17, Week 8, n=7, 25	1.211 (20.63)	0.675 (11.21)
CL17, Week 12, n=7, 24	1.711 (24.96)	0.890 (13.90)
CL17, 12-Week FU, n=7, 20	1.434 (23.26)	1.357 (13.59)
CL13, Week 1, n=9, 27	1.198 (15.63)	0.915 (8.87)
CL13, Week 2, n=8, 26	1.090 (13.98)	1.095 (7.78)
CL13, Week 4, n=9, 27	0.947 (15.58)	1.170 (8.90)
CL13, Week 6, n=7, 27	0.839 (17.20)	1.038 (8.91)
CL13, Week 8, n=7, 25	0.913 (23.70)	1.021 (12.38)
CL13, Week 12, n=7,24	0.924 (31.17)	1.077 (16.31)
CL13, 12-Week FU, n=7,21	0.774 (27.82)	1.224 (15.04)
Interleukin 6, Week 1, n=9, 26	1.179 (27.92)	1.064 (16.38)
Interleukin 6, Week 2, n=8, 26	1.153 (29.33)	0.830 (16.63)
Interleukin 6, Week 4, n=9, 27	0.986 (26.22)	0.811 (15.10)
Interleukin 6, Week 6, n=7, 27	1.136 (24.95)	0.748 (13.51)
Interleukin 6, Week 8, n=7, 25	1.275 (23.65)	0.872 (13.35)
Interleukin 6, Week 12, n=7, 24	0.770 (21.89)	0.939 (12.35)
Interleukin 6, 12-Week FU, n=7, 21	0.817 (33.13)	1.308 (18.63)
MDC, Week 1, n=9, 27	0.987 (5.02)	0.914 (2.89)
MDC, Week 2, n=8, 26	0.925 (7.33)	0.911 (4.15)
MDC, Week 4, n=9, 27	0.936 (8.13)	0.895 (4.67)
MDC, Week 6, n=7, 27	0.984 (8.38)	0.994 (4.48)
MDC, Week 8, n=7, 25	1.049 (9.36)	0.899 (5.09)
MDC, Week 12, n=7, 24	1.245 (9.51)	1.058 (5.23)
MDC, 12-Week FU, n=7, 20	1.303 (12.66)	1.321 (7.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CL17, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.097
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.692
	Confidence Interval	(2-Sided) 95%; 0.445 to 1.074
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CL17, Week 2
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.229
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.713
	Confidence Interval	(2-Sided) 95%; 0.407 to 1.249
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CL17, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.055
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.608
	Confidence Interval	(2-Sided) 95%; 0.365 to 1.012
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CL17, Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.307
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.755
	Confidence Interval	(2-Sided) 95%; 0.435 to 1.309
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CL17, Week 8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.017
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.557
	Confidence Interval	(2-Sided) 95%; 0.348 to 0.894
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.026
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.520
	Confidence Interval	(2-Sided) 95%; 0.294 to 0.922
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CL17, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.839
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.947
	Confidence Interval	(2-Sided) 95%; 0.548 to 1.636
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CL13, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.142
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.764
	Confidence Interval	(2-Sided) 95%; 0.530 to 1.100
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CL13, Week 2
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.976
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.005
	Confidence Interval	(2-Sided) 95%; 0.726 to 1.390
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CL13, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.244
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.236
	Confidence Interval	(2-Sided) 95%; 0.859 to 1.778
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CL13, Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.278
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.237
	Confidence Interval	(2-Sided) 95%; 0.836 to 1.830
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CL13, Week 8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.677
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.118
	Confidence Interval	(2-Sided) 95%; 0.651 to 1.920
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CL13, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.661
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.165
	Confidence Interval	(2-Sided) 95%; 0.573 to 2.369
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CL13, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.154
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.581
	Confidence Interval	(2-Sided) 95%; 0.832 to 3.007
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Interleukin 6, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.751
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.903
	Confidence Interval	(2-Sided) 95%; 0.471 to 1.729
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Interleukin 6, Week 2
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.330
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.720
	Confidence Interval	(2-Sided) 95%; 0.367 to 1.413
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Interleukin 6, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.519
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.822
	Confidence Interval	(2-Sided) 95%; 0.447 to 1.512
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Interleukin 6, Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.147
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.659
	Confidence Interval	(2-Sided) 95%; 0.372 to 1.167
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Interleukin 6, Week 8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.166
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.684
	Confidence Interval	(2-Sided) 95%; 0.396 to 1.180
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Interleukin 6, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.432
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.221
	Confidence Interval	(2-Sided) 95%; 0.734 to 2.031
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Interleukin 6, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.216
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.602
	Confidence Interval	(2-Sided) 95%; 0.750 to 3.423
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MDC, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.195
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.926
	Confidence Interval	(2-Sided) 95%; 0.823 to 1.042
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MDC, Week 2
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.851
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.984
	Confidence Interval	(2-Sided) 95%; 0.829 to 1.168
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MDC, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.637
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.956
	Confidence Interval	(2-Sided) 95%; 0.790 to 1.158
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MDC, Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.915
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.010
	Confidence Interval	(2-Sided) 95%; 0.833 to 1.225
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 26

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MDC, Week 8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.157
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.857
	Confidence Interval	(2-Sided) 95%; 0.690 to 1.064
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 27

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MDC, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.142
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.849
	Confidence Interval	(2-Sided) 95%; 0.681 to 1.059
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 28

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MDC, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.929
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.013
	Confidence Interval	(2-Sided) 95%; 0.745 to 1.378
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Primary Outcome

Title	Change From Baseline in Predictive Biomarkers: Chitinase 3 Like 1, Matrix Metalloproteinase 3 (MMP-3)
Description	Blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Predictive biomarkers included analysis of Chitinase 3 Like 1 and MMP-3. Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. Analysis was performed using repeated measures analysis adjusted for Chitinase 3 Like 1 and MMP-3 log(Baseline value), treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame	Baseline and Weeks 1, 2, 4, 6, 8, 12, 12-Week FU (Week 22)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
Chitinase 3 Like 1, Week 1, n=9, 27	1.033 (13.97)	0.917 (8.13)
Chitinase 3 Like 1, Week 2, n=8, 26	1.013 (15.05)	0.966 (8.55)
Chitinase 3 Like 1, Week 4, n=9, 27	0.961 (17.14)	1.088 (9.96)
Chitinase 3 Like 1, Week 6, n=7, 27	0.897 (17.08)	1.031 (8.80)
Chitinase 3 Like 1, Week 8, n=7, 25	0.851 (18.24)	0.947 (9.70)
Chitinase 3 Like 1, Week 12, n=7, 24	1.066 (21.53)	1.071 (11.64)
Chitinase 3 Like 1, 12-Week FU, n=7, 21	0.735 (16.87)	1.019 (9.75)
MMP 3, Week 1, n=9, 27	1.076 (6.72)	0.984 (3.88)
MMP-3, Week 2, n=8, 26	1.067 (7.26)	1.024 (4.09)
MMP-3, Week 4, n=9, 27	1.112 (8.30)	1.016 (4.73)
MMP-3, Week 6, n=7, 27	1.005 (26.26)	0.804 (13.44)
MMP-3, Week 8, n=7, 25	0.939 (15.43)	1.088 (8.21)
MMP-3, Week 12, n=7, 24	1.000 (13.57)	0.951 (7.35)
MMP-3, 12-Week FU, n=7, 21	0.803 (16.05)	0.984 (9.00)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Chitinase 3 Like 1, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.463
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.887
	Confidence Interval	(2-Sided) 95%; 0.640 to 1.231
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Chitinase 3 Like 1, Week 2
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.782
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.953
	Confidence Interval	(2-Sided) 95%; 0.672 to 1.352
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Chitinase 3 Like 1, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.533
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.132
	Confidence Interval	(2-Sided) 95%; 0.759 to 1.690
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Chitinase 3 Like 1, Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.473
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.149
	Confidence Interval	(2-Sided) 95%; 0.779 to 1.694
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Chitinase 3 Like 1, Week 8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.608
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.112
	Confidence Interval	(2-Sided) 95%; 0.733 to 1.687
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Chitinase 3 Like 1, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.985
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.005
	Confidence Interval	(2-Sided) 95%; 0.613 to 1.645
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Chitinase 3 Like 1, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.102
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.386
	Confidence Interval	(2-Sided) 95%; 0.934 to 2.057
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MMP-3, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.259
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.915
	Confidence Interval	(2-Sided) 95%; 0.781 to 1.071
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MMP-3, Week 2
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.621
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.959
	Confidence Interval	(2-Sided) 95%; 0.809 to 1.137
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MMP-3, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.354
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.914
	Confidence Interval	(2-Sided) 95%; 0.752 to 1.110
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MMP-3, Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.448
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.800
	Confidence Interval	(2-Sided) 95%; 0.443 to 1.444
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MMP-3, Week 8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.402
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.160
	Confidence Interval	(2-Sided) 95%; 0.813 to 1.653
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MMP-3, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.745
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.951
	Confidence Interval	(2-Sided) 95%; 0.695 to 1.301
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MMP-3, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.279
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.226
	Confidence Interval	(2-Sided) 95%; 0.837 to 1.796
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Primary Outcome

Title	Change From Baseline in Cartilage Biomarkers
Description	Blood samples were collected and analyzed for markers that may be predictive of rheumatoid arthritis disease activity. Cartilage biomarkers included analysis of ARGS Neo-Epitope, Citrullinated MMP-Degraded Vimentin (CMDV), MMP-Degraded C Reactive Protein (CRP), MMP-Degraded Type I Collagen (MD1C), MMP-Degraded Type II Collagen (MD2C), MMP-Degraded Type III Collagen (MD3C). Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. Analysis was performed using repeated measures analysis adjusted for ARGS Neo-Epitope, Citrullinated MMP-Degraded Vimentin, MMP-Degraded CRP, MMP-Degraded Type I Collagen, MMP-Degraded Type II Collagen and MMP-Degraded Type III Collagen log(Baseline value), treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame	Baseline and Weeks 1, 2, 4, 6, 8, 12, 12-Week FU (Week 22)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
ARGS Neo-Epitope, Week 1, n=9, 27	0.979 (16.10)	1.075 (9.67)
ARGS Neo-Epitope, Week 2, n=8, 25	0.790 (17.38)	1.249 (9.87)
ARGS Neo-Epitope, Week 4, n=8, 26	0.904 (17.02)	1.104 (10.05)
ARGS Neo-Epitope, Week 6, n=6, 26	0.894 (14.28)	1.164 (7.82)
ARGS Neo-Epitope, Week 8, n=7, 24	0.854 (26.42)	1.238 (14.20)
ARGS Neo-Epitope, Week 12, n=7, 24	0.913 (13.97)	1.156 (7.78)
ARGS Neo-Epitope, 12-Week FU, n=8, 21	1.129 (17.44)	1.124 (9.86)
CMDV, Week 1,n=9,27	0.981 (24.12)	0.876 (13.80)
CMDV,Week 2,n=8,26	0.820 (28.46)	0.714 (15.89)
CMDV, Week 4,n=9,27	0.715 (27.30)	0.801 (15.52)
CMDV, Week 6,n=7,27	1.099 (30.47)	0.726 (15.94)
CMDV, Week 8,n=7,25	0.929 (24.72)	0.759 (13.39)
CMDV, Week12,n=7,24	1.123 (29.34)	0.917 (16.00)
CMDV, 12-Week FU,n=7,21	0.936 (28.05)	0.769 (15.81)
MMP-Degraded CRP, Week 1, n=9, 27	0.971 (6.83)	1.021 (3.99)
MMP-Degraded CRP, Week 2, n=8, 26	0.970 (5.55)	1.000 (3.07)
MMP-Degraded CRP, Week 4, n=9, 27	0.992 (6.01)	1.004 (3.49)
MMP-Degraded CRP, Week 6, n=7, 27	1.122 (6.55)	1.099 (3.50)
MMP-Degraded CRP, Week 8, n=7, 25	0.977 (7.37)	1.087 (4.05)
MMP-Degraded CRP, Week 12, n=7, 24	1.006 (7.13)	1.108 (3.95)
MMP-Degraded CRP, 12-Week FU, n=7, 21	1.075 (8.01)	1.129 (4.48)
MD1C, Week 1, n=9, 27	1.079 (9.60)	0.858 (5.63)
MD1C, Week 2, n=8, 26	1.028 (11.98)	0.907 (6.63)
MD1C, Week 4, n=9, 27	1.142 (14.57)	0.896 (8.35)
MD1C, Week 6, n=7, 27	1.392 (12.64)	0.889 (6.98)
MD1C, Week 8, n=7, 25	1.131 (13.05)	0.904 (7.23)
MD1C, Week 12, n=7, 24	1.148 (13.74)	1.023 (7.81)
MD1C, 12-Week FU, n=7, 21	1.095 (14.21)	0.952 (8.31)
MD2C, Week 1, n=9, 27	1.059 (11.83)	1.038 (6.88)
MD2C, Week 2, n=8, 26	1.046 (11.27)	1.015 (6.28)
MD2C, Week 4, n=9, 27	1.035 (10.18)	1.003 (5.86)
MD2C, Week 6, n=7, 27	1.158 (12.07)	1.064 (6.30)
MD2C, Week 8, n=7, 25	1.091 (11.42)	1.023 (6.12)
MD2C, Week 12, n=7, 24	1.174 (10.73)	1.072 (5.87)
MD2C, 12-Week FU, n=7, 21	1.338 (13.10)	1.041 (7.50)
MD3C, Week 1, n=9, 27	0.950 (6.44)	0.959 (3.74)
MD3C, Week 2, n=8, 26	0.920 (6.82)	0.954 (3.91)
MD3C, Week 4, n=9, 27	0.940 (8.06)	0.886 (4.68)
MD3C, Week 6, n=7, 27	1.013 (8.09)	0.894 (4.34)
MD3C, Week 8, n=7, 25	0.918 (9.04)	0.881 (4.84)
MD3C, Week 12, n=7, 24	0.929 (9.28)	0.910 (5.08)
MD3C, 12-Week FU, n=7, 21	0.847 (9.75)	0.910 (5.46)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	ARGS Neo-Epitope, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.621
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.098
	Confidence Interval	(2-Sided) 95%; 0.750 to 1.606
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	ARGS Neo-Epitope, Week 2
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.031
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.581
	Confidence Interval	(2-Sided) 95%; 1.046 to 2.388
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	ARGS Neo-Epitope, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.317
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.222
	Confidence Interval	(2-Sided) 95%; 0.817 to 1.827
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	ARGS Neo-Epitope, Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.113
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.302
	Confidence Interval	(2-Sided) 95%; 0.936 to 1.810
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	ARGS Neo-Epitope, Week 8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.217
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.450
	Confidence Interval	(2-Sided) 95%; 0.795 to 2.645
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	ARGS Neo-Epitope, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.147
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.266
	Confidence Interval	(2-Sided) 95%; 0.916 to 1.750
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	ARGS Neo-Epitope, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.985
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.996
	Confidence Interval	(2-Sided) 95%; 0.662 to 1.499
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CMDV, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.681
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.892
	Confidence Interval	(2-Sided) 95%; 0.511 to 1.560
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CMDV, Week 2
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.668
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.870
	Confidence Interval	(2-Sided) 95%; 0.454 to 1.669
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CMDV, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.717
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.120
	Confidence Interval	(2-Sided) 95%; 0.597 to 2.101
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CMDV, Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.227
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.661
	Confidence Interval	(2-Sided) 95%; 0.333 to 1.310
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CMDV, Week 8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.471
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.817
	Confidence Interval	(2-Sided) 95%; 0.464 to 1.437
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CMDV, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.541
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.816
	Confidence Interval	(2-Sided) 95%; 0.417 to 1.597
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CMDV, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.544
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.822
	Confidence Interval	(2-Sided) 95%; 0.422 to 1.602
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MMP-Degraded CRP, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.537
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.051
	Confidence Interval	(2-Sided) 95%; 0.895 to 1.233
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MMP-Degraded CRP, Week 2
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.635
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.031
	Confidence Interval	(2-Sided) 95%; 0.906 to 1.173
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MMP-Degraded CRP, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.866
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.012
	Confidence Interval	(2-Sided) 95%; 0.879 to 1.165
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MMP-Degraded CRP, Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.780
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.979
	Confidence Interval	(2-Sided) 95%; 0.842 to 1.139
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MMP-Degraded CRP, Week 8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.212
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.113
	Confidence Interval	(2-Sided) 95%; 0.938 to 1.320
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MMP-Degraded CRP, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.242
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.102
	Confidence Interval	(2-Sided) 95%; 0.934 to 1.300
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MMP-Degraded CRP, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.597
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.050
	Confidence Interval	(2-Sided) 95%; 0.870 to 1.267
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MD1C, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.047
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.795
	Confidence Interval	(2-Sided) 95%; 0.634 to 0.997
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MD1C, Week 2
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.367
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.883
	Confidence Interval	(2-Sided) 95%; 0.668 to 1.165
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MD1C, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.155
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.784
	Confidence Interval	(2-Sided) 95%; 0.558 to 1.102
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MD1C, Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.638
	Confidence Interval	(2-Sided) 95%; 0.477 to 0.855
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 26

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MD1C, Week 8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.140
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.799
	Confidence Interval	(2-Sided) 95%; 0.591 to 1.080
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 27

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MD1C, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.470
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.891
	Confidence Interval	(2-Sided) 95%; 0.647 to 1.228
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 28

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MD1C, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.401
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.869
	Confidence Interval	(2-Sided) 95%; 0.621 to 1.217
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 29

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MD2C, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.887
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.981
	Confidence Interval	(2-Sided) 95%; 0.742 to 1.296
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 30

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MD2C, Week 2
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.814
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.970
	Confidence Interval	(2-Sided) 95%; 0.744 to 1.263
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 31

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MD2C, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.794
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.969
	Confidence Interval	(2-Sided) 95%; 0.762 to 1.233
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 32

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MD2C, Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.539
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.919
	Confidence Interval	(2-Sided) 95%; 0.696 to 1.213
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 33

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MD2C, Week 8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.623
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.937
	Confidence Interval	(2-Sided) 95%; 0.719 to 1.221
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 34

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MD2C, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.467
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.913
	Confidence Interval	(2-Sided) 95%; 0.711 to 1.173
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 35

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MD2C, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.108
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.778
	Confidence Interval	(2-Sided) 95%; 0.570 to 1.061
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 36

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MD3C, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.897
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.010
	Confidence Interval	(2-Sided) 95%; 0.868 to 1.175
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 37

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MD3C, Week 2
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.644
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.037
	Confidence Interval	(2-Sided) 95%; 0.884 to 1.218
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 38

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MD3C, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.530
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.943
	Confidence Interval	(2-Sided) 95%; 0.780 to 1.139
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 39

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MD3C, Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.182
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.882
	Confidence Interval	(2-Sided) 95%; 0.733 to 1.063
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 40

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MD3C, Week 8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.691
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.960
	Confidence Interval	(2-Sided) 10%; 0.779 to 1.182
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 41

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MD3C, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.843
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.979
	Confidence Interval	(2-Sided) 95%; 0.790 to 1.214
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 42

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	MD3C, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.524
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.075
	Confidence Interval	(2-Sided) 95%; 0.855 to 1.351
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Primary Outcome

Title	Change From Baseline in Flow Cytometry: Helper/Suppressor Cells
Description	Whole blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Flow cytometry assessment included assessment of Helper/Suppressor. Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. Analysis was performed using repeated measures analysis adjusted for Helper/Suppressor log(Baseline value), treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame	Baseline and Weeks 1, 4, 12, 12-Week FU (Week 22)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
Helper/Suppressor, Week 1, n=8, 25	1.024 (6.98)	0.976 (4.00)
Helper/Suppressor, Week 4, n=8, 25	1.053 (7.18)	0.998 (4.11)
Helper/Suppressor, Week 12, n=6, 25	1.040 (6.83)	1.088 (3.49)
Helper/Suppressor, 12-Week FU, n=6, 21	1.051 (8.99)	1.065 (4.88)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Helper/Suppressor, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.558
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.953
	Confidence Interval	(2-Sided) 95%; 0.809 to 1.123
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Helper/Suppressor, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.515
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.947
	Confidence Interval	(2-Sided) 95%; 0.801 to 1.120
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Helper/Suppressor, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.565
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.046
	Confidence Interval	(2-Sided) 95%; 0.895 to 1.222
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Helper/Suppressor, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.897
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.013
	Confidence Interval	(2-Sided) 95%; 0.822 to 1.249
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Primary Outcome

Title	Change From Baseline in Flow Cytometry: 6 Colour TB Natural Killer (NK) Panel- CD16+CD56+, CD19, CD3, CD3+CD4+
Description	Whole blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Flow cytometry assessment included assessment of cluster of differentiation (CD)16+CD56+, CD19, CD3, CD3+CD4+. Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. Repeated measures analysis adjusted for CD16+CD56+, CD19, CD3, CD3+CD4+, CD3+CD8+ and T Cell B Cell NKL log(Baseline value), treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame	Baseline and Weeks 1, 4, 12, 12-Week FU (Week 22)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
CD16+CD56+, Week 1, n=8, 25	0.989 (11.39)	1.025 (6.30)
CD16+CD56+, Week 4, n=8, 25	1.163 (12.97)	0.951 (7.25)
CD16+CD56+, Week 12, n=6, 25	1.193 (15.49)	0.911 (7.81)
CD16+CD56+, 12-Week FU, n=6, 21	1.298 (15.10)	0.920 (7.98)
CD19, Week 1, n=8, 25	0.880 (11.05)	0.984 (6.23)
CD19, Week 4, n=8, 25	1.090 (15.31)	0.971 (8.60)
CD19, Week 12, n=6, 25	1.054 (12.26)	1.003 (6.51)
CD19, Week 22, n=6, 21	0.980 (17.75)	0.938 (9.75)
CD3, Week 1, n=8, 25	0.918 (8.73)	0.994 (4.95)
CD3, Week 4, n=8, 25	0.997 (11.79)	0.934 (6.66)
CD3, Week 12, n=6, 25	0.912 (9.01)	0.992 (4.60)
CD3, 12-Week FU, n=6, 21	0.931 (9.17)	0.989 (4.98)
CD3+CD4+, Week 1, n=8, 25	0.926 (9.56)	0.991 (5.42)
CD3+CD4+, Week 4, n=8, 25	1.028 (12.80)	0.933 (7.23)
CD3+CD4+, Week 12, n=6, 25	0.952 (9.69)	1.013 (4.94)
CD3+CD4+, 12-Week FU, n=6, 21	0.970 (9.92)	1.000 (5.37)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD16+CD56+, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.786
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.037
	Confidence Interval	(2-Sided) 95%; 0.794 to 1.354
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD16+CD56+, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.188
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.818
	Confidence Interval	(2-Sided) 95%; 0.603 to 1.109
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD16+CD56+, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.129
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.763
	Confidence Interval	(2-Sided) 95%; 0.536 to 1.087
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD16+CD56+, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.054
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.709
	Confidence Interval	(2-Sided) 95%; 0.499 to 1.006
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD19, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.383
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.119
	Confidence Interval	(2-Sided) 95%; 0.863 to 1.450
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD19, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.510
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.890
	Confidence Interval	(2-Sided) 95%; 0.623 to 1.271
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD19, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.724
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.952
	Confidence Interval	(2-Sided) 95%; 0.718 to 1.262
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD19, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.831
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.958
	Confidence Interval	(2-Sided) 95%; 0.635 to 1.443
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.437
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.082
	Confidence Interval	(2-Sided) 95%; 0.882 to 1.328
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.632
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.937
	Confidence Interval	(2-Sided) 95%; 0.711 to 1.234
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.413
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.088
	Confidence Interval	(2-Sided) 95%; 0.885 to 1.336
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.567
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.062
	Confidence Interval	(2-Sided) 95%; 0.858 to 1.316
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+CD4+, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.547
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.069
	Confidence Interval	(2-Sided) 95%; 0.855 to 1.338
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+CD4+, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.512
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.907
	Confidence Interval	(2-Sided) 95%; 0.673 to 1.223
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+CD4+, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.573
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.064
	Confidence Interval	(2-Sided) 95%; 0.853 to 1.328
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+CD4+, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.789
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.031
	Confidence Interval	(2-Sided) 95%; 0.818 to 1.300
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Primary Outcome

Title	Change From Baseline in Flow Cytometry: 6 Colour TBNK Panel- CD3+CD8+ and T Cell B Cell Natural Killer Lymphocytes (NKL)
Description	Whole blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Flow cytometry assessment included assessment of CD3+CD8+ and T Cell B Cell NKL. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post-dose value from the Baseline value. Analysis was performed using repeated measures analysis adjusted for CD3+CD8+ and T Cell B Cell NKL log(Baseline value), treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame	Baseline and Weeks 1, 4, 12, 12-Week FU (Week 22)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
CD3+CD8+, Week 1, n=8, 25	-0.041 (0.0390)	-0.005 (0.0222)
CD3+CD8+, Week 4, n=8, 25	0.000 (0.0580)	-0.023 (0.0327)
CD3+CD8+, Week 12, n=6, 25	-0.056 (0.0418)	-0.037 (0.0215)
CD3+CD8+, 12-Week FU, n=6, 21	-0.060 (0.0506)	-0.027 (0.0279)
T Cell B Cell NKL, Week 1, n=8, 25	-0.123 (0.1557)	-0.020 (0.0881)
T Cell B Cell NKL, Week 4, n=8, 25	0.108 (0.2174)	-0.050 (0.1229)
T Cell B Cell NKL, Week 12, n=6, 25	-0.093 (0.1792)	-0.006 (0.0925)
T Cell B Cell NKL, 12-Week FU, n=6, 21	-0.029 (0.2168)	-0.050 (0.1183)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+CD8+, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.428
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.036
	Confidence Interval	(2-Sided) 95%; -0.056 to 0.128
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+CD8+, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.733
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.023
	Confidence Interval	(2-Sided) 95%; -0.159 to 0.113
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+CD8+, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.677
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.020
	Confidence Interval	(2-Sided) 95%; -0.076 to 0.115
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+CD8+, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.569
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.033
	Confidence Interval	(2-Sided) 95%; -0.084 to 0.151
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	T Cell B Cell NKL, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.569
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.103
	Confidence Interval	(2-Sided) 95%; -0.263 to 0.469
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	T Cell B Cell NKL, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.534
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.157
	Confidence Interval	(2-Sided) 95%; -0.668 to 0.354
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	T Cell B Cell NKL, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.668
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.087
	Confidence Interval	(2-Sided) 95%; -0.323 to 0.498
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	T Cell B Cell NKL, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.934
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.021
	Confidence Interval	(2-Sided) 95%; -0.526 to 0.484
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Primary Outcome

Title	Change From Baseline in Flow Cytometry: T Regulatory (Reg) Cell Foxp3- CD3+ CD4+, CD3+ CD8+ and CD3+
Description	Whole blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Flow cytometry assessment included assessment of CD3+ CD4+, CD3+ CD8+ and CD3+. Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. Analysis was performed using repeated measures analysis adjusted for CD3+ CD4+, CD3+ CD8+ and CD3+ Number of Cells (10^6/L) log(Baseline value), treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame	Baseline and Weeks 1, 4, 12, 12-Week FU (Week 22)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
CD3+ CD4+, Week 1, n=7, 23	0.905 (10.21)	1.007 (5.65)
CD3+ CD4+, Week 4, n=7, 22	1.038 (11.31)	0.976 (6.38)
CD3+ CD4+, Week 12, n=5, 21	0.981 (10.55)	1.004 (5.31)
CD3+ CD4+, 12-Week FU, n=5, 17	0.926 (11.70)	1.003 (6.39)
CD3+ CD8+, Week 1, n=7, 23	0.885 (9.97)	0.983 (5.50)
CD3+ CD8+, Week 4, n=7, 22	0.981 (11.89)	0.939 (6.66)
CD3+ CD8+, Week 12, n=5, 21	0.878 (10.50)	0.945 (5.40)
CD3+ CD8+, 12-Week FU, n=5, 17	0.936 (10.99)	0.965 (6.05)
CD3+, Week 1, n=7, 23	0.901 (9.98)	0.992 (5.54)
CD3+, Week 4, n=7, 22	1.034 (12.99)	0.938 (7.33)
CD3+, Week 12, n=5, 21	0.959 (9.62)	0.993 (4.90)
CD3+, 12-Week FU, n=5, 17	0.944 (10.88)	0.991 (6.00)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+ CD4+, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.369
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.112
	Confidence Interval	(2-Sided) 95%; 0.876 to 1.412
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+ CD4+, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.641
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.941
	Confidence Interval	(2-Sided) 95%; 0.721 to 1.228
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+ CD4+, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.844
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.024
	Confidence Interval	(2-Sided) 95%; 0.804 to 1.303
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+ CD4+, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.558
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.082
	Confidence Interval	(2-Sided) 95%; 0.821 to 1.427
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+ CD8+, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.363
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.111
	Confidence Interval	(2-Sided) 95%; 0.880 to 1.402
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+ CD8+, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.751
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.957
	Confidence Interval	(2-Sided) 95%; 0.724 to 1.265
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+ CD8+, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.537
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.076
	Confidence Interval	(2-Sided) 95%; 0.846 to 1.370
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+ CD8+, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.806
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.032
	Confidence Interval	(2-Sided) 95%; 0.797 to 1.335
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.405
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.101
	Confidence Interval	(2-Sided) 95%; 0.872 to 1.391
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.519
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.907
	Confidence Interval	(2-Sided) 95%; 0.668 to 1.232
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.748
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.036
	Confidence Interval	(2-Sided) 95%; 0.831 to 1.291
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.704
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.049
	Confidence Interval	(2-Sided) 95%; 0.811 to 1.356
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Primary Outcome

Title	Change From Baseline in Flow Cytometry: T Reg Cell Foxp3: CD3+CD4+CD25+CD127-, CD3+CD4+foxP3+CD25+CD127-
Description	Whole blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Flow cytometry assessment included assessment of CD3+CD4+CD25+CD127- and CD3+CD4+foxP3+CD25+CD127-. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post-dose value from the Baseline value. Analysis was performed using repeated measures analysis adjusted for CD3+CD4+CD25+CD127- and CD3+CD4+foxP3+CD25+CD127-Number of Cells (10^6 cells/L) log(Baseline value), treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame	Baseline and Weeks 1, 4, 12, 12-Week FU (Week 22)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
CD3+CD4+CD25+CD127-, Week 1, n=7, 23	-3.6 (8.35)	2.9 (4.67)
CD3+CD4+CD25+CD127-, Week 4, n=7, 22	1.4 (8.34)	-0.4 (4.70)
CD3+CD4+CD25+CD127-, Week 12, n=5, 21	-9.4 (9.87)	-3.1 (4.94)
CD3+CD4+CD25+CD127-, 12-Week FU, n=5, 17	-12.9 (9.92)	-2.3 (5.43)
CD3+CD4+foxP3+CD25+CD127, Week 1, n=7, 23	0.8 (6.39)	2.8 (3.58)
CD3+CD4+foxP3+CD25+CD127, Week 4, n=7, 22	4.3 (7.05)	2.0 (3.98)
CD3+CD4+foxP3+CD25+CD127, Week 12, n=5, 21	2.7 (7.99)	-4.4 (3.91)
CD3+CD4+foxP3+CD25+CD127,12-Week FU, n=5,17	-8.7 (5.94)	-4.6 (3.15)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+CD4+CD25+CD127-, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.501
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	6.5
	Confidence Interval	(2-Sided) 95%; -13.1 to 26.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+CD4+CD25+CD127-, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.852
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.8
	Confidence Interval	(2-Sided) 95%; -21.6 to 18.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+CD4+CD25+CD127-, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.572
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	6.3
	Confidence Interval	(2-Sided) 95%; -16.4 to 29.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+CD4+CD25+CD127-, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.363
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	10.5
	Confidence Interval	(2-Sided) 95%; -13.0 to 34.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+CD4+foxP3+CD25+CD127-, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.788
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.0
	Confidence Interval	(2-Sided) 95%; -13.0 to 17.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+CD4+foxP3+CD25+CD127-, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.786
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.2
	Confidence Interval	(2-Sided) 95%; -18.8 to 14.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+CD4+foxP3+CD25+CD127-, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.433
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-7.1
	Confidence Interval	(2-Sided) 95%; -25.4 to 11.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD3+CD4+foxP3+CD25+CD127-, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.550
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	4.1
	Confidence Interval	(2-Sided) 95%; -9.8 to 18.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Primary Outcome

Title	Change From Baseline in T Helper Cell Panel Events
Description	Blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. T Helper Cell Panel included analysis of CD45+3+8-4+CCR6+CXCR3+38+DR+, CD45+3+8-4+CCR6+CXCR3-38+DR+, CD45+3+8-4+CCR6-CXCR3+38+DR+, CD45+3+8-4+CCR6-CXCR3-38+DR+, CD45+CD3+CD8-CD4+, CD45+CD3+CD8-CD4+CCR6+CXCR3+, CD45+CD3+CD8-CD4+CCR6+CXCR3-, CD45+CD3+CD8-CD4+CCR6-CXCR3+ and CD45+CD3+CD8-CD4+CCR6-CXCR3-. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post-dose value from the Baseline value. Analysis was performed using repeated measures analysis adjusted for T Helper Cell Panel Events (EVENTS) Baseline value, treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame	Baseline and Weeks 1, 4, 12, 12-Week FU (Week 22)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
CD45+3+8-4+CCR6+CXCR3+38+DR+, Week 1, n=7, 23	-48.6 (13.50)	-34.0 (7.35)
CD45+3+8-4+CCR6+CXCR3+38+DR+, Week 4, n=7, 21	-14.5 (18.36)	-6.1 (10.63)
CD45+3+8-4+CCR6+CXCR3+38+DR+, Week 12, n=5, 22	42.3 (37.80)	-6.9 (17.69)
CD45+3+8-4+CCR6+CXCR3+38+DR+,12-Week FU,n=5,18	11.5 (16.47)	-18.7 (8.66)
CD45+3+8-4+CCR6+CXCR3-38+DR+, Week 1, n=7, 23	-17.0 (6.80)	-10.5 (3.62)
CD45+3+8-4+CCR6+CXCR3-38+DR+, Week 4, n=7, 21	14.2 (15.65)	12.2 (9.10)
CD45+3+8-4+CCR6+CXCR3-38+DR+, Week 12, n=5, 22	3.4 (16.09)	-3.0 (7.55)
CD45+3+8-4+CCR6+CXCR3-38+DR+, 12-Week FU, n=5, 18	8.9 (12.29)	3.3 (6.36)
CD45+3+8-4+CCR6-CXCR3+38+DR+, Week 1, n=7, 23	-73.2 (82.46)	-129.2 (46.04)
CD45+3+8-4+CCR6-CXCR3+38+DR+, Week 4, n=7, 21	-159.6 (60.51)	-108.0 (35.05)
CD45+3+8-4+CCR6-CXCR3+38+DR+, Week 12, n=5, 22	219.2 (299.65)	77.7 (146.73)
CD45+3+8-4+CCR6-CXCR3+38+DR+, 12-Week FU, n=5, 18	33.9 (66.09)	-104.0 (34.73)
CD45+3+8-4+CCR6-CXCR3-38+DR+, Week 1, n=7, 23	-70.9 (25.90)	-70.5 (14.03)
CD45+3+8-4+CCR6-CXCR3-38+DR+, Week 4, n=7, 21	-38.9 (30.69)	-56.3 (17.93)
CD45+3+8-4+CCR6-CXCR3-38+DR+, Week 12, n=5, 22	-16.4 (198.13)	43.0 (92.38)
CD45+3+8-4+CCR6-CXCR3-38+DR+, 12-Week FU, n=5, 18	-12.7 (33.50)	-59.9 (17.32)
CD45+CD3+CD8-CD4+, Week 1, n=7, 23	-3845.3 (2648.60)	-163.0 (1444.61)
CD45+CD3+CD8-CD4+, Week 4, n=7, 21	1622.8 (2973.60)	1075.1 (1723.09)
vCD45+CD3+CD8-CD4+, Week 12, n=5, 22	2112.9 (4211.63)	1006.9 (2026.47)
CD45+CD3+CD8-CD4+, 12-Week FU, n=5, 18	1799.0 (2589.05)	-1832.0 (1366.65)
CD45+CD3+CD8-CD4+CCR6+CXCR3+, Week 1, n=7, 23	-514.6 (647.85)	-1030.2 (345.07)
CD45+CD3+CD8-CD4+CCR6+CXCR3+, Week 4, n=7, 21	-116.6 (757.58)	-316.5 (438.76)
CD45+CD3+CD8-CD4+CCR6+CXCR3+, Week 12, n=5, 22	-252.9 (827.53)	-506.4 (389.97)
CD45+CD3+CD8-CD4+CCR6+CXCR3+, 12-Week FU, n=5, 18	-688.1 (792.26)	-463.0 (412.22)
CD45+CD3+CD8-CD4+CCR6+CXCR3-, Week 1, n=7, 23	-817.1 (393.10)	-654.5 (212.18)
CD45+CD3+CD8-CD4+CCR6+CXCR3-, Week 4, n=7, 21	197.7 (475.88)	14.2 (277.06)
CD45+CD3+CD8-CD4+CCR6+CXCR3-, Week 12, n=5, 22	48.8 (541.14)	-219.7 (253.92)
CD45+CD3+CD8-CD4+CCR6+CXCR3-, 12-Week FU, n=5, 18	-311.6 (553.32)	-509.2 (291.09)
CD45+CD3+CD8-CD4+CCR6-CXCR3+, Week 1, n=7, 23	371.8 (1026.17)	1521.8 (547.18)
CD45+CD3+CD8-CD4+CCR6-CXCR3+, Week 4, n=7, 21	-24.5 (1678.23)	-292.5 (967.00)
CD45+CD3+CD8-CD4+CCR6-CXCR3+, Week 12, n=5, 22	2790.5 (2510.67)	1443.1 (1209.66)
CD45+CD3+CD8-CD4+CCR6-CXCR3+, 12-Week FU, n=5, 18	2295.9 (1787.02)	607.0 (927.11)
CD45+CD3+CD8-CD4+CCR6-CXCR3-, Week 1, n=7, 23	-3231.4 (2162.58)	45.4 (1187.37)
CD45+CD3+CD8-CD4+CCR6-CXCR3-, Week 4, n=7, 21	2084.9 (2873.95)	1637.6 (1665.46)
CD45+CD3+CD8-CD4+CCR6-CXCR3-, Week 12, n=5, 22	-1273.9 (2413.90)	161.4 (1209.82)
CD45+CD3+CD8-CD4+CCR6-CXCR3-, 12-Week FU, n=5, 18	-106.6 (1690.64)	-1316.7 (892.55)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+3+8-4+CCR6+CXCR3+38+DR+, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.350
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	14.6
	Confidence Interval	(2-Sided) 95%; -16.9 to 46.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+3+8-4+CCR6+CXCR3+38+DR+, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.697
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	8.4
	Confidence Interval	(2-Sided) 95%; -35.3 to 52.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+3+8-4+CCR6+CXCR3+38+DR+, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.249
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-49.2
	Confidence Interval	(2-Sided) 95%; -135.2 to 36.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+3+8-4+CCR6+CXCR3+38+DR+, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.119
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-30.1
	Confidence Interval	(2-Sided) 95%; -68.6 to 8.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+3+8-4+CCR6+CXCR3-38+DR+, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.403
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	6.5
	Confidence Interval	(2-Sided) 95%; -9.3 to 22.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+3+8-4+CCR6+CXCR3-38+DR+, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.910
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.1
	Confidence Interval	(2-Sided) 95%; -39.4 to 35.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+3+8-4+CCR6+CXCR3-38+DR+, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.718
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-6.5
	Confidence Interval	(2-Sided) 95%; -43.1 to 30.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+3+8-4+CCR6+CXCR3-38+DR+, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.687
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-5.7
	Confidence Interval	(2-Sided) 95%; -34.4 to 23.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+3+8-4+CCR6-CXCR3+38+DR+, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.559
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-56.0
	Confidence Interval	(2-Sided) 95%; -249.8 to 137.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+3+8-4+CCR6-CXCR3+38+DR+, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.470
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	51.6
	Confidence Interval	(2-Sided) 95%; -93.9 to 197.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+3+8-4+CCR6-CXCR3+38+DR+, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.675
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-141.5
	Confidence Interval	(2-Sided) 95%; -829.2 to 546.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+3+8-4+CCR6-CXCR3+38+DR+, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.080
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-137.9
	Confidence Interval	(2-Sided) 95%; -294.0 to 18.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+3+8-4+CCR6-CXCR3-38+DR+, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.989
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 95%; -60.5 to 61.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+3+8-4+CCR6-CXCR3-38+DR+, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.634
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-17.4
	Confidence Interval	(2-Sided) 95%; -94.3 to 59.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+3+8-4+CCR6-CXCR3-38+DR+, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.789
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	59.4
	Confidence Interval	(2-Sided) 95%; -395.2 to 513.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+3+8-4+CCR6-CXCR3-38+DR+, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.249
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-47.2
	Confidence Interval	(2-Sided) 95%; -135.5 to 41.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+CD3+CD8-CD4+, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.234
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	3682.3
	Confidence Interval	(2-Sided) 95%; -2511.9 to 9876.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+CD3+CD8-CD4+, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.875
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-547.6
	Confidence Interval	(2-Sided) 95%; -7612.6 to 6517.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+CD3+CD8-CD4+, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.815
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1106.0
	Confidence Interval	(2-Sided) 95%; -10706.0 to 8494.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+CD3+CD8-CD4+, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.230
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-3631.0
	Confidence Interval	(2-Sided) 95%; -9738.9 to 2476.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+CD3+CD8-CD4+CCR6+CXCR3+, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.489
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-515.6
	Confidence Interval	(2-Sided) 95%; -2021.4 to 990.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+CD3+CD8-CD4+CCR6+CXCR3+, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.822
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-199.8
	Confidence Interval	(2-Sided) 95%; -2001.7 to 1602.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+CD3+CD8-CD4+CCR6+CXCR3+, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.784
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-253.5
	Confidence Interval	(2-Sided) 95%; -2136.7 to 1629.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+CD3+CD8-CD4+CCR6+CXCR3+, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.804
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	225.1
	Confidence Interval	(2-Sided) 95%; -1633.1 to 2083.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+CD3+CD8-CD4+CCR6+CXCR3-, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.719
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	162.7
	Confidence Interval	(2-Sided) 95%; -754.5 to 1079.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 26

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+CD3+CD8-CD4+CCR6+CXCR3-, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.742
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-183.5
	Confidence Interval	(2-Sided) 95%; -1317.4 to 950.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 27

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+CD3+CD8-CD4+CCR6+CXCR3-, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.658
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-268.5
	Confidence Interval	(2-Sided) 95%; -1507.5 to 970.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 28

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+CD3+CD8-CD4+CCR6+CXCR3-, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.755
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-197.6
	Confidence Interval	(2-Sided) 95%; -1499.3 to 1104.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 29

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+CD3+CD8-CD4+CCR6-CXCR3+, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.333
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1150.0
	Confidence Interval	(2-Sided) 95%; -1250.0 to 3550.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 30

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+CD3+CD8-CD4+CCR6-CXCR3+, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.891
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-268.0
	Confidence Interval	(2-Sided) 95%; -4269.2 to 3733.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 31

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+CD3+CD8-CD4+CCR6-CXCR3+, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.633
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1347.4
	Confidence Interval	(2-Sided) 95%; -7073.1 to 4378.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 32

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+CD3+CD8-CD4+CCR6-CXCR3+, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.410
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1688.9
	Confidence Interval	(2-Sided) 95%; -5864.1 to 2486.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 33

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+CD3+CD8-CD4+CCR6-CXCR3-, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.196
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	3276.8
	Confidence Interval	(2-Sided) 95%; -1786.0 to 8339.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 34

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+CD3+CD8-CD4+CCR6-CXCR3-, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.894
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-447.3
	Confidence Interval	(2-Sided) 95%; -7285.5 to 6390.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 35

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+CD3+CD8-CD4+CCR6-CXCR3-, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.600
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1435.3
	Confidence Interval	(2-Sided) 95%; -4101.4 to 6972.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 36

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD45+CD3+CD8-CD4+CCR6-CXCR3-, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.534
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1210.2
	Confidence Interval	(2-Sided) 95%; -5213.1 to 2792.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Primary Outcome

Title	Change From Baseline in Flow Cytometry: CD16+ Monocyte Panel: CD14-HLA-DR+CD11cbr+CD123-, CD14br+CD16+, CD14br+CD16-, CD14lo+CD16br+
Description	Whole blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Flow cytometry assessment included assessment of CD14-HLA-DR+CD11cbr+CD123-, CD14br+CD16+, CD14br+CD16- and CD14lo+CD16br+. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post-dose value from the Baseline value. Analysis was performed using repeated measures analysis adjusted for CD14-HLA-DR+CD11cbr+CD123-, CD14br+CD16+, CD14br+CD16- and CD14lo+CD16br+ (10^3/Liter) baseline value, treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame	Baseline and Weeks 1, 4, 12, 12-Week FU (Week 22)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
CD14-HLA-DR+CD11cbr+CD123-, Week 1, n=5, 18	-2017.6 (2452.91)	738.7 (1266.25)
CD14-HLA-DR+CD11cbr+CD123-, Week 4, n=6, 22	2766.3 (3220.54)	2278.8 (1696.12)
CD14-HLA-DR+CD11cbr+CD123-, Week 12, n=5, 21	5730.4 (5085.86)	5453.0 (2399.11)
CD14-HLA-DR+CD11cbr+CD123-, 12-Week FU, n=5, 18	5785.6 (5081.59)	5474.0 (2439.59)
CD14br+CD16+, Week 1, n=5, 18	-5376.0 (4748.95)	1491.0 (2452.69)
CD14br+CD16+, Week 4, n=6, 22	-5635.3 (5971.99)	2724.3 (3117.17)
CD14br+CD16+, Week 12, n=5, 21	25351.6 (9433.73)	2668.0 (4589.28)
CD14br+CD16+, 12-Week FU, n=5, 18	8557.2 (9914.93)	4800.0 (5266.23)
CD14br+CD16-, Week 1, n=5, 18	40079.7 (40456.86)	17662.7 (21211.91)
CD14br+CD16-, Week 4, n=6, 22	-17173.8 (24181.15)	10485.9 (12635.98)
CD14br+CD16-, Week 12, n=5, 21	-2981.8 (37788.70)	13201.2 (18684.22)
CD14br+CD16-, 12-Week FU, n=5, 18	31906.6 (45766.70)	-31512.8 (24027.16)
CD14lo+CD16br+, Week 1, n=5, 18	11248.2 (6598.36)	4334.6 (3466.71)
CD14lo+CD16br+, Week 4, n=6, 22	2522.9 (3757.96)	291.3 (1959.54)
CD14lo+CD16br+, Week 12, n=5, 21	10938.4 (5088.36)	759.2 (2534.27)
CD14lo+CD16br+, 12-Week FU, n=5, 18	24737.0 (7758.65)	3992.8 (4134.52)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD14-HLA-DR+CD11cbr+CD123-, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.328
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2756.3
	Confidence Interval	(2-Sided) 95%; -2953.7 to 8466.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD14-HLA-DR+CD11cbr+CD123-, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.895
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-487.5
	Confidence Interval	(2-Sided) 95%; -8003.7 to 7028.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD14-HLA-DR+CD11cbr+CD123-, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.961
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-277.4
	Confidence Interval	(2-Sided) 95%; -12001.0 to 11446.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD14-HLA-DR+CD11cbr+CD123-, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.956
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-311.6
	Confidence Interval	(2-Sided) 95%; -11960.5 to 11337.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD14br+CD16+, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.212
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	6866.9
	Confidence Interval	(2-Sided) 95%; -4230.7 to 17964.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD14br+CD16+, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.227
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	8359.6
	Confidence Interval	(2-Sided) 95%; -5533.3 to 22252.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD14br+CD16+, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.040
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-22683.6
	Confidence Interval	(2-Sided) 95%; -44298.5 to -1068.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD14br+CD16+, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.741
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-3757.2
	Confidence Interval	(2-Sided) 95%; -27146.0 to 19631.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD14br+CD16-, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.628
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-22417.0
	Confidence Interval	(2-Sided) 95%; -116677.8 to 71843.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD14br+CD16-, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.321
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	27659.7
	Confidence Interval	(2-Sided) 95%; -28567.8 to 83887.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD14br+CD16-, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.704
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	16182.9
	Confidence Interval	(2-Sided) 95%; -70377.0 to 102742.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD14br+CD16-, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.232
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-63419.4
	Confidence Interval	(2-Sided) 95%; -170364.9 to 43526.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD14lo+CD16br+, Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.366
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-6913.6
	Confidence Interval	(2-Sided) 95%; -22588.4 to 8761.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD14lo+CD16br+, Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.603
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2231.6
	Confidence Interval	(2-Sided) 95%; -10976.8 to 6513.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD14lo+CD16br+, Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.084
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-10179.1
	Confidence Interval	(2-Sided) 95%; -21827.4 to 1469.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	CD14lo+CD16br+, 12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.026
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-20744.2
	Confidence Interval	(2-Sided) 95%; -38771.8 to -2716.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Primary Outcome

Title	Change From Baseline in Flow Cytometry: CD16+ Monocyte Panel: CD14-CD16+CD66b+
Description	Whole blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Flow cytometry assessment included assessment of CD14-CD16+CD66b+ cell. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post-dose value from the Baseline value. Analysis was performed using repeated measures analysis adjusted for CD14-CD16+CD66b+ (10^6/Liter) baseline value, treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame	Baseline and Weeks 1, 4, 12, 12-Week FU (Week 22)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
Week 1, n=5, 19	-559.0 (269.84)	-380.9 (137.31)
Week 4, n=6, 22	-581.9 (377.03)	-41.5 (196.72)
Week 12, n=5, 21	-125.9 (460.53)	-378.6 (229.47)
12-Week FU, n=5, 18	-240.9 (430.65)	-199.3 (219.73)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.564
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	178.2
	Confidence Interval	(2-Sided) 95%; -448.3 to 804.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.216
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	540.4
	Confidence Interval	(2-Sided) 95%; -335.7 to 1416.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.629
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-252.6
	Confidence Interval	(2-Sided) 95%; -1326.0 to 820.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.932
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	41.6
	Confidence Interval	(2-Sided) 95%; -962.2 to 1045.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Primary Outcome

Title	Change From Baseline in Complement Biomarkers: Complement Component 3 (C3), Complement Component 4 (C4)
Description	Blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Complement biomarkers included analysis of Complement C3 and Complement C4. Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame	Baseline and Weeks 1, 2, 4, 6, 8, 12, 12-Week FU (Week 22)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
Complement C3, Week 1, n=9, 25	0.967 (7.43)	0.982 (11.76)
Complement C3, Week 2, n=8, 26	0.957 (11.72)	0.963 (14.15)
Complement C3, Week 4, n=9, 27	1.045 (18.42)	0.959 (12.62)
Complement C3, Week 6, n=7, 27	1.060 (12.00)	0.991 (11.71)
Complement C3, Week 8, n=7, 25	1.021 (12.54)	1.009 (10.85)
Complement C3, Week 12, n=7, 24	0.988 (9.37)	1.003 (11.34)
Complement C3, 12-Week FU, n=7, 22	1.005 (19.15)	0.995 (10.65)
Complement C4, Week 1, n=9, 25	1.005 (11.40)	0.969 (13.13)
Complement C4, Week 2, n=8, 26	0.949 (9.64)	0.984 (16.45)
Complement C4, Week 4, n=9, 27	0.999 (12.06)	0.945 (14.63)
Complement C4, Week 6, n=7, 27	0.990 (10.31)	0.985 (17.32)
Complement C4, Week 8, n=7, 25	0.979 (7.66)	1.006 (13.53)
Complement C4, Week 12, n=7, 24	0.942 (15.57)	0.994 (12.75)
Complement C4, 12-Week FU, n=7, 22	0.982 (12.88)	0.986 (14.72)

16. Primary Outcome

Title	Change From Baseline in Complement Biomarkers: Complement Component 4a (C4a), Complement Component 5a (C5a), Complement Split Factor SC5b-9, Soluble Cluster of Differentiation 163 (sCD163)
Description	Blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Complement biomarkers included analysis of Complement C4a, Complement C5a, Complement Split Factor SC5b-9 and Soluble CD163. Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame	Baseline and Weeks 1, 2, 4, 6, 8, 12, 12-Week FU (Week 22)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
Complement C4a, Week 1, n=9, 27	1.159 (115.81)	0.990 (67.63)
Complement C4a, Week 2, n=8, 26	0.881 (55.58)	1.156 (75.77)
Complement C4a, Week 4, n=9, 27	0.840 (40.85)	1.100 (46.87)
Complement C4a, Week 6, n=7, 27	0.914 (66.71)	0.860 (53.87)
Complement C4a, Week 8, n=7, 25	1.017 (44.16)	0.998 (60.41)
Complement C4a, Week 12, n=7, 24	0.927 (58.05)	0.901 (93.48)
Complement C4a, 12-Week FU, n=7, 21	1.104 (40.27)	1.221 (56.53)
Complement C5a, Week 1, n=9, 27	0.927 (19.42)	0.991 (29.67)
Complement C5a, Week 2, n=8, 26	1.154 (36.82)	1.015 (55.60)
Complement C5a, Week 4, n=9, 27	0.943 (16.76)	1.010 (35.63)
Complement C5a, Week 6, n=7, 27	1.139 (61.77)	1.044 (33.94)
Complement C5a, Week 8, n=7, 25	0.980 (13.71)	0.957 (26.95)
Complement C5a, Week 12, n=7, 24	1.012 (8.41)	0.995 (29.49)
Complement C5a, 12-Week FU, n=7, 22	1.152 (42.75)	1.130 (32.16)
Complement Split Factor SC5b-9, Week 1, n=9, 27	0.971 (37.46)	1.020 (43.70)
Complement Split Factor SC5b-9, Week 2, n=8, 26	1.078 (28.80)	1.040 (60.64)
Complement Split Factor SC5b-9, Week 4, n=9, 27	0.930 (43.01)	1.126 (41.04)
Complement Split Factor SC5b-9, Week 6, n=7, 27	0.989 (23.18)	1.084 (53.90)
Complement Split Factor SC5b-9, Week 8, n=7, 25	0.889 (35.48)	1.055 (67.53)
Complement Split Factor SC5b-9, Week 12, n=7, 24	0.883 (30.26)	0.843 (72.14)
Complement Split Factor SC5b-9,12-Week FU, n=7, 22	1.039 (69.05)	1.041 (38.60)
sCD163, Week 1, n=9, 27	0.993 (24.28)	0.963 (16.38)
sCD163, Week 2, n=8, 26	1.101 (17.80)	0.954 (17.14)
sCD163, Week 4, n=9, 27	0.986 (15.89)	0.947 (27.10)
sCD163, Week 6, n=7, 27	0.938 (20.83)	0.959 (30.14)
sCD163, Week 8, n=7, 25	0.938 (30.03)	0.950 (28.73)
sCD163, Week 12, n=7, 24	0.937 (24.86)	0.915 (35.29)
sCD163, 12-Week FU, n=7, 21	1.200 (32.94)	0.994 (28.84)

17. Primary Outcome

Title	Change From Baseline in Mechanistic Biomarkers
Description	Blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Mechanistic biomarkers included analysis of Interleukin 1 Beta, Interleukin 10, Interleukin 15, Interleukin 17 Alpha, Interleukin 17F, Interleukin 8 and Tumor Necrosis Factor. Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. NA indicates that data is not available since 100% of the data was below limit of quantification at all time points. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame	Baseline and Weeks 1, 2, 4, 6, 8, 12, 12-Week FU (Week 22)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
Interleukin 1 Beta, Week 1, n=9, 26	1.000 (NA)	1.000 (NA)
Interleukin 1 Beta, Week 2, n=8, 26	1.000 (NA)	1.000 (NA)
Interleukin 1 Beta, Week 4, n=9, 27	1.000 (NA)	1.000 (NA)
Interleukin 1 Beta, Week 6, n=7, 27	1.000 (NA)	1.000 (NA)
Interleukin 1 Beta, Week 8, n=7, 25	1.000 (NA)	1.000 (NA)
Interleukin 1 Beta, Week 12, n=7, 24	1.000 (NA)	1.000 (NA)
Interleukin 1 Beta, 12-Week FU, n=7, 21	1.000 (NA)	1.000 (NA)
Interleukin 10, Week 1, n=9, 26	0.962 (11.55)	0.994 (28.47)
Interleukin 10, Week 2, n=8, 26	1.206 (45.35)	1.048 (37.27)
Interleukin 10, Week 4, n=9, 27	0.875 (41.69)	0.985 (32.52)
Interleukin 10, Week 6, n=7, 27	0.842 (47.84)	0.960 (17.66)
Interleukin 10, Week 8, n=7, 25	1.197 (50.41)	0.969 (30.23)
Interleukin 10, Week 12, n=7, 24	0.842 (47.84)	0.989 (21.36)
Interleukin 10, 12-Week FU, n=7, 21	0.842 (47.84)	1.230 (62.91)
Interleukin 15, Week 1, n=9, 27	1.001 (12.70)	0.950 (59.23)
Interleukin 15, Week 2, n=8, 26	0.882 (41.99)	0.849 (102.76)
Interleukin 15, Week 4, n=9, 27	1.206 (47.87)	0.831 (84.07)
Interleukin 15, Week 6, n=7, 27	1.297 (48.81)	0.904 (90.53)
Interleukin 15, Week 8, n=7, 25	0.871 (37.95)	0.865 (90.30)
Interleukin 15, Week 12, n=7, 24	0.871 (37.95)	0.771 (82.21)
Interleukin 15, 12-Week FU, n=7, 21	0.871 (37.95)	0.636 (111.86)
Interleukin 17 Alpha, Week 1, n=9, 25	0.806 (53.03)	1.054 (93.04)
Interleukin 17 Alpha, Week 2, n=8, 25	0.935 (75.58)	0.942 (72.24)
Interleukin 17 Alpha, Week 4, n=9, 26	0.995 (91.45)	0.911 (102.66)
Interleukin 17 Alpha, Week 6, n=7, 26	1.015 (76.60)	0.867 (90.15)
Interleukin 17 Alpha, Week 8, n=7, 23	0.905 (77.24)	1.005 (135.76)
Interleukin 17 Alpha, Week 12, n=7, 23	1.007 (87.84)	0.857 (101.45)
Interleukin 17 Alpha, 12-Week FU, n=7, 20	0.969 (155.67)	0.999 (150.12)
Interleukin 17F, Week 1, n=9, 25	1.153 (36.21)	0.797 (78.96)
Interleukin 17F, Week 2, n=8, 26	1.062 (74.38)	0.911 (72.36)
Interleukin 17F, Week 4, n=9, 26	0.966 (21.09)	0.948 (89.47)
Interleukin 17F, Week 6, n=7, 25	0.787 (32.55)	1.013 (107.49)
Interleukin 17F, Week 8, n=7, 25	0.947 (19.20)	0.815 (91.93)
Interleukin 17F, Week 12, n=7, 23	1.002 (74.09)	0.884 (100.03)
Interleukin 17F, 12-Week FU, n=7, 21	1.130 (101.51)	0.741 (90.62)
Interleukin 8, Week 1, n=9, 26	1.104 (40.98)	1.081 (74.78)
Interleukin 8, Week 2, n=8, 26	1.505 (43.78)	0.861 (78.64)
Interleukin 8, Week 4, n=9, 27	1.102 (38.30)	0.773 (82.48)
Interleukin 8, Week 6, n=7, 27	1.229 (61.82)	0.720 (72.70)
Interleukin 8, Week 8, n=7, 25	1.547 (53.88)	0.761 (80.51)
Interleukin 8, Week 12, n=7, 24	1.240 (49.03)	0.850 (80.98)
Interleukin 8, 12-Week FU, n=7, 21	1.191 (42.58)	0.841 (96.92)
Tumor Necrosis Factor, Week 1, n=9, 26	0.976 (15.20)	0.994 (18.45)
Tumor Necrosis Factor, Week 2, n=8, 26	0.951 (19.84)	0.977 (16.81)
Tumor Necrosis Factor, Week 4, n=9, 27	0.933 (17.70)	0.871 (48.19)
Tumor Necrosis Factor, Week 6, n=7, 27	1.087 (36.81)	0.929 (21.48)
Tumor Necrosis Factor, Week 8, n=7, 25	1.110 (25.33)	0.930 (20.85)
Tumor Necrosis Factor, Week 12, n=7, 24	1.021 (38.53)	0.969 (29.74)
Tumor Necrosis Factor,12-Week FU, n=7, 21	1.619 (180.16)	1.057 (34.72)

18. Primary Outcome

Title	Change From Baseline in Safety Biomarkers: 3B-Cholestenoic Acid, Surfactant Protein D
Description	Blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Safety biomarkers included analysis of 3B-Cholestenoic Acid and Surfactant Protein D. Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame	Baseline and Week 12, 12-Week FU (Week 22)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
3B-Cholestenoic Acid, Week 12, n=7, 24	1.012 (16.52)	1.094 (19.45)
3B-Cholestenoic Acid, Week 22, n=7, 22	1.020 (20.25)	1.009 (22.67)
Surfactant Protein D, Week 12, n=7, 24	1.003 (23.10)	1.134 (27.96)
Surfactant Protein D, 12-Week FU, n=7, 21	1.140 (45.71)	0.985 (31.32)

19. Primary Outcome

Title	Change From Baseline in Safety Biomarkers: KL-6 Antigen
Description	Blood samples were collected and analyzed for markers which may be predictive of rheumatoid arthritis disease activity. Safety biomarker included analysis of KL-6 Antigen. Baseline was defined at Day 1. Change from Baseline was calculated as ratio of Baseline value to post-dose value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame	Baseline and Week 12, 12-Week FU (Week 22)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
Week 12, n=6, 24	1.416 (220.58)	1.099 (66.17)
12-Week FU, n=6, 21	0.937 (62.43)	1.024 (93.56)

20. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESI)
Description	An AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect and associated with liver injury and impaired liver function. An AESI include serious infections, opportunistic infections, neutropenia, respiratory events, pulmonary alveolar proteinosis, hypersensitivity reactions, injection site reactions, persistent cough or dyspnea.
Time Frame	Up to 12-Week FU (Week 22)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
Any AEs	4 36.4%	11 39.3%
Any SAEs	0 0%	0 0%
AESI	0 0%	1 3.6%

21. Secondary Outcome

Title	Number of Participants Who Tested Positive for Anti-GSK3196165 Binding Antibody Detection at Any Time Post-Baseline
Description	Immunogenicity samples for determination of anti-drug-antibody (ADA) were collected. The presence of treatment emergent ADA was 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 had a value at or above the cut-point was considered potentially treatment-emergent ADA-positive. The immunogenicity population consisted of all participants in the ITT population, who had at least one valid immunogenicity assessment.
Time Frame	Up to 12-Week FU (Week 22)

Outcome Measure Data

Analysis Population Description

Immunogenicity Population

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
Count of Participants [Participants]	0 0%	0 0%

22. Secondary Outcome

Title	Change From Baseline in Synovitis as Assessed by Outcome Measures in Rheumatology (OMERACT) Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (RAMRIS) in the Most Affected Hand/Wrist
Description	For synovitis a total of 8 joints were evaluated. Individual joint scores range from 0-3, where 0= normal, 1=mild, 2=moderate and 3=severe. The final synovitis score is the sum of the individual joint scores. Total score range from 0 (best) to 24 (worst). If an individual location is scored either 'Not Visible' or 'Surgically Modified' then the score for that location was set to missing. Missing joint scores was imputed as the mean of the non-missing joint scores. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post-dose value from the Baseline value. Repeated measures analysis adjusted for synovitis score baseline value, treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Data has been presented for Median and 95% credible interval. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame	Baseline and Weeks 4, 12, 12-Week FU (Week 22)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
Week 4, n=6, 12	0.05	-0.07
Week 12, n=5, 21	0.84	-1.33
12-Week FU, n=7, 19	1.13	-1.13

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Week 4, For Posterior Probability Difference <0
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.547
	Comments
	Method	Repeated Measures Bayesian Model
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95%; -2.32 to 2.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Week 12, For Posterior Probability Difference <0
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.948
	Comments
	Method	Repeated Measures Bayesian Model
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	-2.18
	Confidence Interval	(2-Sided) 95%; -4.77 to 0.51
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	12-Week FU, For Posterior Probability Difference <0
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.949
	Comments
	Method	Repeated Measures Bayesian Model
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	-2.28
	Confidence Interval	(2-Sided) 95%; -5.02 to 0.45
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Week 4, For Posterior Probability Difference >0
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.453
	Comments
	Method	Repeated Measures Bayesian Model
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95%; -2.32 to 2.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Week 12, For Posterior Probability Difference >0
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.052
	Comments
	Method	Repeated Measures Bayesian Model
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	-2.18
	Confidence Interval	(2-Sided) 95%; -4.77 to 0.51
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	12-Week FU, For Posterior Probability Difference >0
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.051
	Comments
	Method	Repeated Measures Bayesian Model
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	-2.28
	Confidence Interval	(2-Sided) 95%; -5.02 to 0.45
	Parameter Dispersion	Type: Value:
	Estimation Comments

23. Secondary Outcome

Title	Change From Baseline in Osteitis as Assessed by OMERACT RAMRI Scoring System in the Most Affected Hand/Wrist
Description	For bone edema/osteitis a total of 25 locations was evaluated. Individual location scores ranged from 0-3, where, 0: no edema; 1: 1-33% of bone edematous; 2: 34-66% of bone edematous; 3: 67-100% of bone edematous. Final bone edema/osteitis score is sum of individual location scores. Total score ranged from 0 (best) to 75 (worst). Baseline was defined at Day 1. Change from Baseline was calculated by subtracting post-dose value from Baseline value. If an individual location was scored either 'Not Visible' or 'Surgically Modified' or 'Not Assessable' then the score for that location was set to be missing. Missing joint scores was imputed as mean of non-missing location scores. Repeated measures analysis adjusted for Bone Edema/Osteitis Score baseline value, treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame	Baseline and Weeks 4, 12, 12-Week FU (Week 22)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
Week 4, n=6, 12	-0.1 (0.11)	-0.1 (0.06)
Week 12, n=5, 21	0.0 (1.04)	-0.8 (0.56)
12-Week FU, n=7,19	0.5 (1.33)	-0.9 (0.74)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.940
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.2 to 0.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.521
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.8
	Confidence Interval	(2-Sided) 95%; -3.2 to 1.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.396
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.3
	Confidence Interval	(2-Sided) 95%; -4.4 to 1.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

24. Secondary Outcome

Title	Change From Baseline in Erosion as Assessed by OMERACT RAMRI Scoring System in the Most Affected Hand/Wrist
Description	For bone erosion a total of 25 locations were evaluated. Individual location scores range from 0-10, where, 0: no erosion; 1: 1-10% of bone eroded and 10: 91-100% of bone eroded. The final bone erosion score is the sum of the individual location scores. The total score ranged from 0 (best) to 250 (worst). If an individual location was scored either 'Not Visible' or 'Surgically Modified' or 'Not Assessable' then the score for that location was set to be missing. Missing joint scores was imputed as the mean of the non-missing location scores. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post-dose value from the Baseline value. Analysis was performed using repeated measures analysis adjusted for Bone Erosion Score baseline value, treatment group, disease duration (<=2 or >2 years), visit and treatment group. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles.
Time Frame	Baseline and Weeks 4, 12, 12-Week FU (Week 22)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
Week 4, n=6, 12	0.2 (0.49)	0.3 (0.30)
Week 12, n=5, 21	0.8 (0.50)	0.4 (0.26)
12-Week FU, n=7, 19	1.5 (0.47)	0.5 (0.27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.945
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -1.1 to 1.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.475
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -1.5 to 0.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.086
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.9
	Confidence Interval	(2-Sided) 95%; -2.0 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

25. Secondary Outcome

Title	Change From Baseline in Synovitis as Assessed by Rheumatoid Arthritis MRI Quantitative (RAMRIQ) Assessment in the Most Affected Hand/Wrist
Description	RAMRIQ is an automated volume quantification assessment. RAMRIQ assessed same pathologies and joints (except metacarpophalangeal joint [MCP1]) as RAMRIS allowing for direct comparison of results obtained using the two methods. Bones were automatically identified in pre-contrast, coronal T1 images using active appearance modelling (AAMs). Joint capsules and soft tissues were also segmented with AAMs, providing consistent 3D regions of interest (ROI) for synovial enhancement across all time points. Synovial volume was calculated as voxels that enhance within each ROI. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post-dose value from the Baseline value. Repeated measures analysis adjusted for Synovitis baseline value, treatment group, disease duration (<=2 or >2 years), visit and treatment group by visit interaction. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame	Baseline and Weeks 4, 12 and 12-Week FU (Week 22)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
Week 4, n=6, 12	34.1 (1052.52)	245.5 (776.24)
Week 12, n=5, 21	-912.3 (1405.77)	-1417.0 (671.54)
12-Week FU, n=7, 19	364.0 (1372.20)	-1172.1 (844.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.874
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	211.4
	Confidence Interval	(2-Sided) 95%; -2589.2 to 3012.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.749
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-504.8
	Confidence Interval	(2-Sided) 95%; -3730.4 to 2720.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.352
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1536.0
	Confidence Interval	(2-Sided) 95%; -4884.2 to 1812.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

26. Secondary Outcome

Title	Change From Baseline in Osteitis as Assessed by RAMRIQ Assessment in the Most Affected Hand/Wrist
Description	RAMRIQ is an automated volume quantification assessment for edema volume. RAMRIQ assessed the same pathologies and joints (except MCP1) as RAMRIS, allowing for direct comparison of results obtained using the two methods. Bones were automatically identified in pre-contrast, coronal T1 images using AAMs. Joint capsules and soft tissues were also segmented with AAMs, providing consistent 3D ROI for synovial enhancement across all time points. Edema volume was defined as non-erosion contrast-enhancing voxels inside the bone. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post-dose value from the Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame	Baseline and Weeks 4, 12 and 12-Week FU (Week 22)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
Week 4, n=6, 12	-0.0045 (0.0102)	0.0084 (0.0057)
Week 12, n=5, 21	-0.0045 (0.0035)	-0.0009 (0.0019)
12-Week FU, n=7, 19	-0.0038 (0.0016)	-0.0027 (0.0009)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.291
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.0128
	Confidence Interval	(2-Sided) 95%; -0.0123 to 0.0380
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.375
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.0036
	Confidence Interval	(2-Sided) 95%; -0.0046 to 0.0118
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.588
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.0010
	Confidence Interval	(2-Sided) 95%; -0.0028 to 0.0049
	Parameter Dispersion	Type: Value:
	Estimation Comments

27. Secondary Outcome

Title	Change From Baseline in Erosion as Assessed by RAMRIQ Assessment in the Most Affected Hand/Wrist
Description	RAMRIQ is an automated volume quantification assessment for erosion volume. RAMRIQ assessed the same pathologies and joints (except MCP1) as RAMRIS, allowing for direct comparison of results obtained using the two methods. Bones were automatically identified in pre-contrast, coronal T1 images using AAMs. Joint capsules and soft tissues were also segmented with AAMs, providing consistent 3D ROI for synovial enhancement across all time points. Erosion volume was identified inside the bone surfaces using voxel-based classification. The volume of BME and erosions was normalised to total bone volume for statistical analysis. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post-dose value from the Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame	Baseline and Weeks 4, 12 and 12-Week FU (Week 22)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.	Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
Measure Participants	11	28
Week 4, n=6, 12	0.0007 (0.0012)	0.0006 (0.0008)
Week 12, n=5, 21	0.0003 (0.0011)	-0.0000 (0.0006)
12-Week FU, n=7, 19	-0.0002 (0.0023)	0.0003 (0.0013)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.915
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.0002
	Confidence Interval	(2-Sided) 95%; -0.0033 to 0.0029
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.771
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.0004
	Confidence Interval	(2-Sided) 95%; -0.0028 to 0.0021
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK3196165 180 mg
	Comments	12-Week FU
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.850
	Comments
	Method	Repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.0005
	Confidence Interval	(2-Sided) 95%; -0.0048 to 0.0058
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	AEs and SAEs were collected from start of study treatment up to 12-Week FU (Week 22).
Adverse Event Reporting Description	ITT Population was used for the analysis of safety data.
Arm/Group Title	Placebo		GSK3196165 180 mg
Arm/Group Description	Eligible participants received matching placebo SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to placebo, participants also received MTX 7.5-25 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.		Eligible participants received GSK3196165 180 mg SC into thigh or abdomen once weekly for 5 weeks, and then every other week until Week 10. In addition to GSK3196165, participants also received MTX 7.5-5 mg/week and folic (or folinic) acid >=5 mg/week during the combination treatment period.
All Cause Mortality
	Placebo		GSK3196165 180 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/28 (0%)
Serious Adverse Events
	Placebo		GSK3196165 180 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/28 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		GSK3196165 180 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/11 (36.4%)		11/28 (39.3%)
Blood and lymphatic system disorders
Neutropenia	0/11 (0%)		1/28 (3.6%)
Cardiac disorders
Coronary artery disease	1/11 (9.1%)		0/28 (0%)
Tachycardia	0/11 (0%)		1/28 (3.6%)
Gastrointestinal disorders
Nausea	0/11 (0%)		1/28 (3.6%)
General disorders
Fatigue	1/11 (9.1%)		0/28 (0%)
Infections and infestations
Upper respiratory tract infection	1/11 (9.1%)		1/28 (3.6%)
Laryngitis	0/11 (0%)		1/28 (3.6%)
Nasopharyngitis	0/11 (0%)		1/28 (3.6%)
Investigations
Weight increased	0/11 (0%)		1/28 (3.6%)
Musculoskeletal and connective tissue disorders
Pain in extremity	2/11 (18.2%)		0/28 (0%)
Rheumatoid arthritis	2/11 (18.2%)		0/28 (0%)
Musculoskeletal pain	0/11 (0%)		1/28 (3.6%)
Nervous system disorders
Headache	0/11 (0%)		1/28 (3.6%)
Psychiatric disorders
Initial insomnia	0/11 (0%)		1/28 (3.6%)
Respiratory, thoracic and mediastinal disorders
Cough	0/11 (0%)		2/28 (7.1%)
Asthma	0/11 (0%)		1/28 (3.6%)
Skin and subcutaneous tissue disorders
Alopecia	1/11 (9.1%)		0/28 (0%)
Erythema	0/11 (0%)		1/28 (3.6%)
Rosacea	0/11 (0%)		1/28 (3.6%)
Seborrhoeic dermatitis	0/11 (0%)		1/28 (3.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.