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

• ClinicalTrials.gov Identifier: NCT02799472
• Recruitment Status: Completed
• First Posted: June 14, 2016
• Results First Posted: November 16, 2018
• Last Update Posted: January 11, 2021
• Sponsor: GlaxoSmithKline
• Collaborator: Parexel
• Information provided by (Responsible Party): GlaxoSmithKline

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 (Clinical Trial)
• 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: June 15, 2016
• Actual Primary Completion Date: October 30, 2017
• Actual Study Completion Date: October 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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+ [ Time Frame: 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) [ Time Frame: 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+ [ Time Frame: 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- [ Time Frame: 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 [ Time Frame: 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+ [ Time Frame: 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+ [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

United States, California

GSK Investigational Site

El Cajon, California, United States, 92020

United States, Florida

GSK Investigational Site

Fort Lauderdale, Florida, United States, 33309

GSK Investigational Site

Miami, Florida, United States, 33015

GSK Investigational Site

Pinellas Park, Florida, United States, 33781

United States, Illinois

GSK Investigational Site

Chicago, Illinois, United States, 60616

United States, Pennsylvania

GSK Investigational Site

Duncansville, Pennsylvania, United States, 16635

United States, Tennessee

GSK Investigational Site

Memphis, Tennessee, United States, 38119

United States, Texas

GSK Investigational Site

Houston, Texas, United States, 77024

Germany

GSK Investigational Site

Freiburg, Baden-Wuerttemberg, Germany, 79106

GSK Investigational Site

Puettlingen, Germany, 66346

Poland

GSK Investigational Site

Elblag, Poland, 82-300

GSK Investigational Site

Nowa Sol, Poland, 67-100

GSK Investigational Site

Piaseczno, Poland, 05-500

GSK Investigational Site

Warszawa, Poland, 00-660

GSK Investigational Site

Warszawa, Poland, 03-291

GSK Investigational Site

Wroclaw, Poland, 51-128

Sponsors and Collaborators

GlaxoSmithKline

Parexel

Investigators

• Study Director: GSK Clinical Trials; GlaxoSmithKline

  Study Documents (Full-Text)

Documents provided by GlaxoSmithKline:

Study Protocol  [PDF] March 1, 2016

Statistical Analysis Plan  [PDF] November 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 ( EudraCT Number )
• First Posted: June 14, 2016
• Results First Posted: November 16, 2018
• Last Update Posted: January 11, 2021
• Last Verified: December 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: IPD for this study is available via the Clinical Study Data Request site.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Time Frame: IPD is available via the Clinical Study Data Request site (copy the URL below to your browser)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
• URL: https://www.clinicalstudydatarequest.com/Posting.aspx?ID=20745

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; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases