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

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT02799472
• Date of registration: 26/05/2016
• Prospective Registration: Yes
• Primary sponsor: GlaxoSmithKline
• Public title: Mechanistic Study of GSK3196165 Plus Methotrexate (MTX) in Subjects With Active Rheumatoid Arthritis
• Scientific 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
• Date of first enrolment: June 15, 2016
• Target sample size: 39
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT02799472
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor).
• Phase: Phase 2

Countries of recruitment

Germany, Poland, United States

Contacts

• Name: GSK Clinical Trials
• Affiliation: GlaxoSmithKline

Key inclusion & 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.

- 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.



Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Arthritis, Rheumatoid

Intervention(s)

Drug: Folic (or folinic) acid

Drug: GSK3196165

Drug: MTX

Drug: Placebo

Primary Outcome(s)

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)]

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)]

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)]

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)]

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

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

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

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

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

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)]

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)]

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

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)]

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)]

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)]

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

Secondary Outcome(s)

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)]

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)]

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)]

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)]

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)]

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)]

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)]

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)]

Secondary ID(s)

205180

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

Parexel

Results

• Results available: Yes
• Date Posted: 16/11/2018
• URL: https://clinicaltrials.gov/ct2/show/results/NCT02799472