Last updated: 02/16/2024 10:01:12
Mechanistic Study of GSK3196165 plus Methotrexate (MTX) in Subjects with Active Rheumatoid Arthritis
EudraCT ID
EU CT Number
Not applicable
Trial status
Completed
Completed
Trial overview
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
Trial description: 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).
Primary purpose:
Treatment
Trial design:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Allocation:
Randomized
Primary outcomes:
Change from Baseline in Target Engagement biomarkers- soluble Granulocyte-macrophage colony-stimulating factor (GM-CSF) complexed to GSK3196165
Timeframe: 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
Timeframe: Baseline and Weeks 1, 2, 4, 6, 8, 12, 12-Week FU (Week 22)
Change from Baseline in Predictive Biomarkers: Amyloid A
Timeframe: 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
Timeframe: 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)
Timeframe: Baseline and Weeks 1, 2, 4, 6, 8, 12, 12-Week FU (Week 22)
Change from Baseline in Cartilage Biomarkers
Timeframe: Baseline and Weeks 1, 2, 4, 6, 8, 12, 12-Week FU (Week 22)
Change from Baseline in Flow Cytometry: Helper/Suppressor cells
Timeframe: 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+
Timeframe: 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)
Timeframe: 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+
Timeframe: 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-
Timeframe: Baseline and Weeks 1, 4, 12, 12-Week FU (Week 22)
Change from Baseline in T Helper Cell Panel events
Timeframe: 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+
Timeframe: Baseline and Weeks 1, 4, 12, 12-Week FU (Week 22)
Change from Baseline in Flow Cytometry: CD16+ Monocyte Panel: CD14-CD16+CD66b+
Timeframe: 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)
Timeframe: 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)
Timeframe: Baseline and Weeks 1, 2, 4, 6, 8, 12, 12-Week FU (Week 22)
Change from Baseline in Mechanistic Biomarkers
Timeframe: 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
Timeframe: Baseline and Week 12, 12-Week FU (Week 22)
Change from Baseline in Safety Biomarkers: KL-6 Antigen
Timeframe: Baseline and Week 12, 12-Week FU (Week 22)
Secondary outcomes:
Number of participants with adverse events (AEs), serious adverse events (SAEs) and adverse events of special interest (AESI)
Timeframe: Up to 12-Week FU (Week 22)
Number of participants who tested positive for Anti-GSK3196165 Binding Antibody Detection at any time post-Baseline
Timeframe: 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
Timeframe: 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
Timeframe: 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
Timeframe: 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
Timeframe: 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
Timeframe: 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
Timeframe: Baseline and Weeks 4, 12 and 12-Week FU (Week 22)
Interventions:
Drug: GSK3196165
Drug: Placebo
Drug: MTX
Drug: Folic (or folinic) acid
Enrollment:
39
Observational study model:
Not applicable
Primary completion date:
2017-30-10
Time perspective:
Not applicable
Clinical 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
Medical condition
Arthritis, Rheumatoid
Product
GSK3196165, folic acid, methotrexate
Collaborators
Parexel
Study date(s)
June 2016 to October 2017
Type
Interventional
Phase
2
Participation criteria
Sex
Female & Male
Age
18+ years
Accepts healthy volunteers
No
- 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.
- 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.
Inclusion and exclusion 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.
- 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).
Active disease as defined by:
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.
Trial location(s)
Location
GSK Investigational Site
Chicago, Illinois, United States, 60616
Status
Study Complete
Location
GSK Investigational Site
Duncansville, Pennsylvania, United States, 16635
Status
Study Complete
Location
GSK Investigational Site
El Cajon, California, United States, 92020
Status
Study Complete
Location
GSK Investigational Site
Fort Lauderdale, Florida, United States, 33309
Status
Study Complete
Location
GSK Investigational Site
Freiburg, Baden-Wuerttemberg, Germany, 79106
Status
Study Complete
Location
GSK Investigational Site
Memphis, Tennessee, United States, 38119
Status
Study Complete
Location
GSK Investigational Site
Pinellas Park, Florida, United States, 33781
Status
Study Complete
Study documents
Study report synopsis
Available language(s): English
Protocol
Available language(s): English
Statistical analysis plan
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Results posted on ClinicalTrials.gov
Recruitment status
Completed
Actual primary completion date
2017-30-10
Actual study completion date
2017-30-10
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.
Additional information about the trial
Additional information
Not applicable
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