Inhibition of Co-Stimulation in Rheumatoid Arthritis (ICoSRA)

The purpose of this study is to use abatacept as a clinical molecular probe to evaluate the effects of inhibiting costimulation on immune responses in patients with rheumatoid arthritis (RA).

Study Overview

• Status: Unknown
• Conditions: Arthritis, Rheumatoid
• Intervention / Treatment: Drug: Abatacept

Detailed Description

Rheumatoid arthritis (RA) is a chronic inflammatory immune mediated arthritis which leads to pain, swelling and destruction of joints. RA affects more than 500,000 subjects in the United Kingdom (UK) and incurs significant health and economic cost. Most patients require potent immune suppressing drugs such as methotrexate, which help reduce pain and stiffness, and protect the joints against damage. However, many patients do not respond or are unable to tolerate methotrexate. In these patients, biologic drugs such as abatacept are used to try to control the arthritis.

Abatacept is designed to target and inhibit a specific molecule involved in "costimulation" of the inflammatory signal that is thought to be important in RA. While abatacept has been shown to be effective in trials and clinical practice, the exact mechanism of action of abatacept in RA has not been fully elucidated. Understanding these actions is likely to inform both the use of abatacept in RA and lead to increased understanding of inflammation in humans with implications for further therapies. This six month prospective open label study, therefore, aims to investigate the effects of inhibiting costimulation on a variety of important inflammatory cell types and processes in humans with RA.

25 participants with RA who have bad prognostic genetic markers (Anti-citrullinated protein antibodies (ACPA) and human leukocyte antigen (HLADR4) and who were scheduled to receive subcutaneous abatacept as part of their standard clinical treatment will be recruited. Consenting participants will followed for a total of 24 weeks during which time they will have additional venous blood and urine samples taken to investigate the effects of abatacept on their immune cells and system. The primary endpoint of the study is the characterisation of the immune response following costimulatory modulation in RA patients at 12 weeks. Secondary endpoints include change in immunological response and its association with clinical outcome measures up to 24 weeks.

• Study Type: Interventional
• Enrollment (Anticipated): 25
• Phase: Phase 4

Contacts and Locations

Study Locations

• United Kingdom
  • Glasgow, United Kingdom
    • NHS Greater Glasgow and Clyde
  • Newcastle upon Tyne, United Kingdom
    • Newcastle upon Tyne Hospitals NHS Foundation Trust

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• RA as defined by the 2010 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria

• Eligible for abatacept therapy according to local/national guidelines

  • Active RA defined by DAS28 score required by local guidelines for eligibility for abatacept
  • Have previously failed (efficacy or tolerance) at least one disease-modifying antirheumatic drug (DMARD)
  • Have no contraindications to treatment with abatacept
• Be able to tolerate methotrexate at dose of 10-25mg/week, either orally or subcutaneously
• Anti-cyclic citrullinated peptide (CCP) positive
• Human leukocyte antigen D related (HLA-DR) B1*0401 or 0404) positive
• Able and willing to give written informed consent and comply with the requirements of the study protocol

Exclusion Criteria:

• History of or current autoimmune rheumatic disease other than RA
• Concomitant use of any biologic agent, including tumor necrosis factor (TNF) inhibitors
• Previous abatacept treatment
• Patients requiring >10mg prednisolone daily or intramuscular (IM) corticosteroids
• Active infection
• Known HIV or hepatitis B/C infection
• Latent tuberculosis (TB) infection
• Malignancy (other than non-melanoma skin cell cancers) within 5 years
• Women who are pregnant, women of childbearing potential who are unwilling to use appropriate contraception or breast-feeding
• Inability to give informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Abatacept; Abatacept 125mg administered via subcutaneous injection once a week for 24 weeks	Drug: Abatacept; Abatacept 125mg/ml

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunological response	Change in T cell immune response to citrullinated peptides following costimulatory modulation	Baseline and 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunological response	Change in immunological response from baseline, as measured by transcriptional profile of relevant cell subset	Baseline, 4, 12 and 24 weeks
Clinical response American College of Rheumatology (ACR) 20	Change in ACR 20 from baseline	Baseline and 24 weeks
Clinical response Disease Activity Score (DAS)28	Change in DAS 28 from baseline	Baseline and 24 weeks
T cell profile	Change in T cell subpopulation profile from baseline	Baseline, 12 and 24 weeks
T cell response	Antigen-specific T cell response to tetanus	24 weeks
DC (CD11c+) phenotype	Dendritic cell (DC) (CD11c+) phenotype as measured by major histocompatibility complex (MHC) II expression	24 weeks
Biomarkers	Preliminary identification of biomarkers of response using urinary metabol/proteomic analysis	24 weeks

Collaborators and Investigators

• Sponsor: NHS Greater Glasgow and Clyde
• Collaborators: University of Glasgow
• Investigators: Principal Investigator: Iain McInnes, Prof, University of Glasgow

Study record dates

Study Major Dates

• Study Start: January 1, 2016
• Primary Completion (Anticipated): January 1, 2019
• Study Completion (Anticipated): January 1, 2019

Study Registration Dates

• First Submitted: January 8, 2016
• First Submitted That Met QC Criteria: January 8, 2016
• First Posted (Estimate): January 11, 2016

Study Record Updates

• Last Update Posted (Estimate): January 12, 2016
• Last Update Submitted That Met QC Criteria: January 11, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Immune Checkpoint Inhibitors; Abatacept
• Other Study ID Numbers: GN13RH410; 2014-004419-35 (EudraCT Number)