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).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
39
GSK3196165 is supplied as liquid and will be administered as SC injection.
0.9% weight by volume (w/v) sodium chloride solution administered as SC injection.
Capsule, tablet or liquid administered orally or as SC injection.
Capsule, tablet or liquid and will be administered orally.
GSK Investigational Site
El Cajon, California, United States
GSK Investigational Site
Fort Lauderdale, Florida, United States
GSK Investigational Site
Miami, Florida, United States
GSK Investigational Site
Pinellas Park, Florida, United States
GSK Investigational Site
Chicago, Illinois, United States
GSK Investigational Site
Duncansville, Pennsylvania, United States
GSK Investigational Site
Memphis, Tennessee, United States
GSK Investigational Site
Houston, Texas, United States
GSK Investigational Site
Freiburg im Breisgau, Baden-Wurttemberg, Germany
GSK Investigational Site
Püttlingen, Germany
...and 6 more locations
Change From Baseline in Target Engagement Biomarkers- Soluble Granulocyte-macrophage Colony-stimulating Factor (GM-CSF) Complexed to GSK3196165
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)
Change From Baseline in Predictive Biomarkers: 14-3-3 ETA Protein, S100 Calcium Binding Protein (CBP) A8 and A9
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)
Change From Baseline in Predictive Biomarkers: Amyloid A
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)
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
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)
Change From Baseline in Predictive Biomarkers: Chitinase 3 Like 1, Matrix Metalloproteinase 3 (MMP-3)
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)
Change From Baseline in Cartilage Biomarkers
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)
Change From Baseline in Flow Cytometry: Helper/Suppressor Cells
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)
Change From Baseline in Flow Cytometry: 6 Colour TB Natural Killer (NK) Panel- CD16+CD56+, CD19, CD3, CD3+CD4+
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)
Change From Baseline in Flow Cytometry: 6 Colour TBNK Panel- CD3+CD8+ and T Cell B Cell Natural Killer Lymphocytes (NKL)
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)
Change From Baseline in Flow Cytometry: T Regulatory (Reg) Cell Foxp3- CD3+ CD4+, CD3+ CD8+ and CD3+
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)
Change From Baseline in Flow Cytometry: T Reg Cell Foxp3: CD3+CD4+CD25+CD127-, CD3+CD4+foxP3+CD25+CD127-
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)
Change From Baseline in T Helper Cell Panel Events
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)
Change From Baseline in Flow Cytometry: CD16+ Monocyte Panel: CD14-HLA-DR+CD11cbr+CD123-, CD14br+CD16+, CD14br+CD16-, CD14lo+CD16br+
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)
Change From Baseline in Flow Cytometry: CD16+ Monocyte Panel: CD14-CD16+CD66b+
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)
Change From Baseline in Complement Biomarkers: Complement Component 3 (C3), Complement Component 4 (C4)
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)
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)
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)
Change From Baseline in Mechanistic Biomarkers
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)
Change From Baseline in Safety Biomarkers: 3B-Cholestenoic Acid, Surfactant Protein D
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)
Change From Baseline in Safety Biomarkers: KL-6 Antigen
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)
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESI)
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)
Number of Participants Who Tested Positive for Anti-GSK3196165 Binding Antibody Detection at Any Time Post-Baseline
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)
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
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).
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Time frame: Baseline and Weeks 4, 12, 12-Week FU (Week 22)
Change From Baseline in Osteitis as Assessed by OMERACT RAMRI Scoring System in the Most Affected Hand/Wrist
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)
Change From Baseline in Erosion as Assessed by OMERACT RAMRI Scoring System in the Most Affected Hand/Wrist
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)
Change From Baseline in Synovitis as Assessed by Rheumatoid Arthritis MRI Quantitative (RAMRIQ) Assessment in the Most Affected Hand/Wrist
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)
Change From Baseline in Osteitis as Assessed by RAMRIQ Assessment in the Most Affected Hand/Wrist
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)
Change From Baseline in Erosion as Assessed by RAMRIQ Assessment in the Most Affected Hand/Wrist
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)