Analysis of T and B Cell Repertoire Changes in Response to Orencia® (Abatacept) in Rheumatoid Arthritis

Rheumatoid Arthritis Clinical Trial

Official title:

Analysis of T and B Cell Repertoire Changes and CTLA4 Genetics and Gene Expression to Understand the Mechanisms of Treatment Response to Orencia ® (Abatacept) in Rheumatoid Arthritis

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05782335
• Other study ID #: 2021-0142
• Status: Recruiting
• Start date: November 1, 2022
• Est. completion date: April 30, 2025

Study information

• Verified date: March 2024
• Source: Hospital for Special Surgery, New York
• Contact: Margaret Butler, BS
• Phone: 917-260-4906
• Email: ButlerM[@]hss.edu
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The condition that will be studied is Rheumatoid Arthritis (RA), and in particular, RA patients with moderate to highly active disease who were prescribed Abatacept (Orencia®) (ABA) by their physician during their setting of care at Hospital for Special Surgery (HSS). This investigator-initiated, prospective, comparative, 3-arm observational study will examine changes in lymphocytes in RA patients starting abatacept compared to RA patients starting TNF inhibitors and to healthy controls. This will help investigators to learn more about the processes that cause joints to swell and hurt. This may also offer clues that might predict which patients will have a good or poor response to these treatments.

Description:

This is a mechanistic study examining changes in repertoires of both T cell receptors (TCR) and B cell receptors (BCR) in patients with RA initiating ABA treatment and who are followed for 6 months relative to changes in repertoires of both TCRs and BCRs in two similarly followed comparator groups: . Patterns of T and B cell repertoires in the group of patients with RA initiating treatment with ABA will be compared to (i) RA patients on stable therapy with methotrexate (MTX) or leflunomide (LEF) with or without TNF inhibitors and (ii) "controls" matched for age (+/- 7 years) and sex (approximately 75% female +/- 5%). Our primary hypothesis is that ABA treatment will affect the immune repertoires both in TCR and BCR and the distribution of immune cell subsets (particularly B cell subsets) over time to a greater extent than non-ABA treated RA patients and "controls".

The goal is to determine how abatacept changes the repertoires of both TCRs and BRCs compared to control groups. The investigators anticipate that the repertoires will change differently in ABA treated patients over time relative to similar RA patients treated with conventional synthetic DMARDS (MTX and / or Leflunomide), with or without the use of a TNF inhibitor (TNFi). Changes in repertoires will also be compared to "controls" with no inflammatory disease.with proportionately similar proportions of anti-CCP3 positivity, (but not anti-IL-6 therapy, Jak Kinase Inhibitors (JAKi's) or Rituximab)

A total of 72 people will participate in this study at HSS in three separate arms:

• Arm 1: Patients beginning abatacept as a treatment for their RA

• Arm 2: Patients beginning a TNF inhibitor as a treatment for their RA

• Arm 3: Healthy volunteers (free from autoimmune or connective tissue disease)

Once enrolled, these participants will be assessed at their baseline visit and seen 3 months and 6 months after baseline. These visits will involve a blood draw and questionnaires related to functioning and feeling with RA (where applicable) and may take up to an hour. Participants will be compensated per visit.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 72
• Est. completion date: April 30, 2025
• Est. primary completion date: October 31, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria: M or F >=18 y.o. with diagnosed RA. Disease related inclusion criteria:

1. Patients being treated with MTX with or without csDMARDS at stable doses for at least 4 weeks, who are either: (a) about to start ABA, OR, (b) who are likely to remain on stable DMARDs and who might also be using a TNFi but in whom all therapies will have been stable for 4 or more weeks.

2.) meet diagnostic criteria for RA, based on 2010 ACR Criteria or 1987 RA criteria, OR, are one point short of meeting the criteria but are being treated for RA, OR, have previously identified RA typical erosions.

3) have never received ABA or rituximab, and, if previously used a JAKi, will have stopped this for over a month, OR, if previously used an IL-6 inhibitor, will have stopped for at least 3 months.

4) RA subject must not be taking prednisone at doses over 10 mg daily, and will not have received injectable Depomedrol or equivalent within 4 weeks of baseline or prior to the 3 or 6 month study assessment. Healthy control patients cannot be taking prednisone. Any subject can use oral or nasal inhalers that include glucocorticoids 5) have evidence of recent or currently active disease depending on treatment arm. Subjects starting ABA (Arm 1) are expected to have at least moderate disease activity, OR if CDAI is between 2.81 and 10, there should be two or more swollen and tender joints. For subjects being included in Arm 2, the stable treatment arm, CDAI <13 and one swollen joint observed by a rheumatologist in the prior 6 months. Subjects recruited to the healthy control arm (Arm 3) will be free of any autoimmune disease or systemic form of an inflammatory arthritis.

6) WOCBP must be using acceptable forms of contraception to avoid pregnancy throughout the study, i.e. oral contraceptives, other hormonal contraceptives.

Specific Exclusion Criteria:

1. Have severe complications of RA that might require imminent escalation of therapy, e.g. pericarditis, active vasculitis of a major organ system.

2. Have an autoimmune disease or systemic inflammatory rheumatic disease (e.g., lupus erythematosus) that could confound T and B cell subset results

3. Have a concurrent serious medical disease (e.g., terminal malignancy)

4. Have a BMI indicating poor health (<18 or > 40)

5. Have received the following Prohibited Treatments and/or Therapies

1. treatment with rituximab

2. exposed to ABA or CTLA-4Ig

3. exposed to any investigational drug within 28 days.

4. received any live vaccines within 2 weeks prior to study start. Subjects cannot receive a live vaccine at any time during the study.

6. WOCBP with a positive pregnancy test on enrollment or prior to study start, OR who are unwilling or unable to use an acceptable method to avoid pregnancy despite continuing MTX.

7. part of a vulnerable population

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Locations

Country	Name	City	State
United States	Hospital for Special Surgery	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Hospital for Special Surgery, New York

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	T cell and B cell repertoire changes and CDAI	Association between T cell and B cell repertoire changes and clinically meaningful improvements in CDAI.	April 2024-March 2025
Other	T cell and B cell repertoire changes and SDAI.	Association between T cell and B cell repertoire changes and clinically meaningful improvements in SDAI.	April 2024-March 2025
Other	T cell and B cell repertoire changes and DAS23-ESR.	Association between T cell and B cell repertoire changes and clinically meaningful improvements in DAS23-ESR.	April 2024-March 2025
Other	T cell and B cell repertoire changes and DAS-28-CRP.	Association between T cell and B cell repertoire changes and clinically meaningful improvements in DAS28-CRP.	April 2024-March 2025
Other	RA-FQ in ABA treated vs. non-ABA treated patients	Patient reported outcome (PRO) measure (RA-FQ) in ABA treated patients over 6 months compared to non-ABA treated RA patients.	Aprill 2024-March2025
Other	MD-HAQ in ABA treated vs. non-ABA treated patients	Patient reported outcome (PRO) measure (MDHAQ) in ABA treated patients over 6 months compared to non-ABA treated RA patients.	Aprill 2024-March2025
Primary	Change in clonotype diversity of T cell and B cell repertoires	Investigators will compare the change in clonotype diversity of T cell and B cell repertoires in patients over 6 months by analyzing clonotype diversity of T cell and B cell repertoires at BL (pre-treatment), 3 months, and 6 months post treatment for each individual in each of the three groups (RA starting ABA; RA on stable MTX +/- TNFi.	April 2024-March 2025
Secondary	CTLA4 gene expression in peripheral blood at 3 times points	Investigators will assess changes in CTLA4 gene expression in peripheral blood at BL, and at 3 and 6 months post-treatment.	April 2024-March 2025
Secondary	Changes in the proportions of T and B cell subtypes	Changes in the proportions of T and B cell subtypes well as NK cells associated with ABA treatment. Flow cytometry analysis will be used to quantify the frequency of T and B cell subtypes and NK cells at each timepoint in each subject in each Arm.	April 2024-March 2025
Secondary	Expression levels in peripheral blood of genes key to the immune response.	Changes in expression levels in peripheral blood of 150 genes key to the immune response.	April 2024-March 2025