Clinical trial NCT02799472: Mechanistic Study of GSK3196165 Plus Methotrexate (MTX) in Subjects With Active Rheumatoid Arthritis
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Arthritis, Rheumatoid
Keywords: GSK3196165
magnetic resonance imaging (MRI)
disease-modifying antirheumatic drugs (DMARDs)
granulocyte-macrophage colony stimulating factor (GM-CSF)
Rheumatoid Arthritis
Methotrexate
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2016-06-14
Enrollment: 39
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


Eligibility 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.

Primary outcomes:
measure: 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)
measure: 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)
measure: Change From Baseline in Predictive Biomarkers: Amyloid A
timeFrame: Baseline and Week 12, 12-Week FU (Week 22)
measure: 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)
measure: 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)
measure: Change From Baseline in Cartilage Biomarkers
timeFrame: Baseline and Weeks 1, 2, 4, 6, 8, 12, 12-Week FU (Week 22)
measure: Change From Baseline in Flow Cytometry: Helper/Suppressor Cells
timeFrame: Baseline and Weeks 1, 4, 12, 12-Week FU (Week 22)
measure: 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)
measure: 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)
measure: 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)
measure: 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)
measure: Change From Baseline in T Helper Cell Panel Events
timeFrame: Baseline and Weeks 1, 4, 12, 12-Week FU (Week 22)
measure: 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)
measure: Change From Baseline in Flow Cytometry: CD16+ Monocyte Panel: CD14-CD16+CD66b+
timeFrame: Baseline and Weeks 1, 4, 12, 12-Week FU (Week 22)
measure: 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)
measure: 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)
measure: Change From Baseline in Mechanistic Biomarkers
timeFrame: Baseline and Weeks 1, 2, 4, 6, 8, 12, 12-Week FU (Week 22)
measure: Change From Baseline in Safety Biomarkers: 3B-Cholestenoic Acid, Surfactant Protein D
timeFrame: Baseline and Week 12, 12-Week FU (Week 22)
measure: Change From Baseline in Safety Biomarkers: KL-6 Antigen
timeFrame: Baseline and Week 12, 12-Week FU (Week 22)
Secondary outcomes:
measure: 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)
measure: 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)
measure: 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)
measure: 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)
measure: 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)
measure: 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)
measure: 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)
measure: 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)
Other outcomes:
Locations:
city: El Cajon
country: United States
facility: GSK Investigational Site
state: California
city: Fort Lauderdale
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Pinellas Park
country: United States
facility: GSK Investigational Site
state: Florida
city: Chicago
country: United States
facility: GSK Investigational Site
state: Illinois
city: Duncansville
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Memphis
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Freiburg
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Puettlingen
country: Germany
facility: GSK Investigational Site
city: Elblag
country: Poland
facility: GSK Investigational Site
city: Nowa Sol
country: Poland
facility: GSK Investigational Site
city: Piaseczno
country: Poland
facility: GSK Investigational Site
city: Warszawa
country: Poland
facility: GSK Investigational Site
city: Warszawa
country: Poland
facility: GSK Investigational Site
city: Wroclaw
country: Poland
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Genovese MC, Berkowitz M, Conaghan PG, Peterfy C, Davy K, Fisheleva E, Gupta A, Inman D, Janiczek R, Layton M, Mitchell N, Patel J, Roberts A, Saurigny D, Smith JE, Williamson R, Tak PP. MRI of the joint and evaluation of the granulocyte-macrophage colony-stimulating factor-CCL17 axis in patients with rheumatoid arthritis receiving otilimab: a phase 2a randomised mechanistic study. Lancet Rheumatol. 2020 Nov;2(11):e666-e676. doi: 10.1016/S2665-9913(20)30224-1. Epub 2020 Oct 7.