Abatacept to Silence Anti-citrullinated Protein Antibody-expressing B Cells in Rheumatoid Arthritis (ASCARA)

Abatacept to Silence Anti-citrullinated Protein Antibody-expressing B Cells in Rheumatoid Arthritis (ASCARA).

To investigate the effect of CTLA4-Ig (abatacept) on phenotype, transcriptional profile, B cell receptor usage and functional parameters of circulating B cells expressing anticitrullinated protein antibodies (ACPA) in patients with early, methotrexate-naïve, ACPA positive rheumatoid arthritis.

Study Overview

• Status: Completed
• Conditions: Rheumatic Diseases; Rheumatoid Arthritis
• Intervention / Treatment: Drug: Abatacept; Drug: Methotrexate

Detailed Description

B cells expressing anti citrullinated protein antibodies (ACPA) in patients with rheumatoid arthritis (RA) display an activated, proliferative phenotype. Experimental data indicate that ACPA and ACPA-expressing B cells are actively involved in driving the disease process in RA. The present study is based on the hypothesis that targeted intervention with CTLA4-Ig (abatacept) as a means to interfere with T cell help for B cells in early, active, ACPA-positive rheumatoid arthritis can reverse the activated, proliferative phenotype of citrullinated antigen-specific B cells.

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Leiden, Netherlands
    • Leiden University Medical Center

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:

Each patient must:

• have a diagnosis of rheumatoid arthritis according to the revised 2010 EULAR/ACR criteria for classification of RA
• have a positive test for the presence of anti-citrullinated protein antibodies (ACPA) in serum as determined by routine clinical assay.
• have adequate hematologic function (ANC ≥ 4000 cells/μL, platelet count ≥ 150000/μL, and hemoglobin ≥ 10 g/dL (corresponding to 6.2 mmol/L)
• have serum creatinine concentrations < 1.5 mg/dl and/or a normal creatinine clearance
• if a female patient is of childbearing potential, agree to: comply with effective contraceptive measures, use adequate contraception since the last menses, use adequate contraception during the study, have a negative pregnancy test within one week of study entry
• be willing to receive a booster vaccination against tetanus toxoid three to four weeks prior to randomization
• be able and willing to give written informed consent prior to entry in the study

Exclusion Criteria:

Any patient who has:

• been previously treated with either abatacept and/or methotrexate or another csDMARD
• been previously treated with a kinase inhibitor
• been previously treated with rituximab or another B-cell depleting agent
• been previously treated with a biological DMARD
• received intra-articular or systemic glucocorticoid injections or has required treatment for acute RA flare (not being part of a regular therapeutic regimen) within four weeks prior to randomization or requires narcotic analgesics other than those accepted by the investigator for analgesia (e.g. paracetamol, codeine, tramadol)
• been tested negative for anti citrullinated protein antibodies
• contraindications for a booster vaccination against tetanus toxoid prior to randomization to the treatment arms; if a patient refuses booster vaccination but has detectable numbers of tetanus toxoid-specific B cells circulating in peripheral blood prior to the baseline visit, the patient can still be allowed to participate in the study at the judgement of the investigator.
• evidence of any other major chronic inflammatory disease (i.e. psoriasis, psoriatic arthritis, spondyloarthritis or inflammatory bowel disease)
• evidence of poorly controlled diabetes, history of clinically significant pulmonary disease including interstitial lung disease or methotrexate-induced lung disease, poorly controlled asthma or a history of severe life-threatening asthma attacks, history of active tuberculosis, history of latent tuberculosis without adequate medical treatment, liver cirrhosis or fibrosis, significant active infection or any underlying diseases that could predispose the subject to infections
• liver function abnormality (total bilirubin ≥ 1.5x the upper limit of normal range, AST, ALT ≥ 3x upper limit of normal range)
• concurrent treatment with an experimental drug or who has participated in another clinical trial with an investigational drug within 30 days prior to study entry
• pre-existing sensory or motor polyneuropathy ≥ Grade 2 according to NCI CTC
• past or current history of neoplasms, except for curatively treated non-melanoma skin cancer, adequately treated in situ carcinoma of the cervix or another cancer curatively treated and with no evidence of disease for at least 10 years
• significant cardiac disease, cardiac arrhythmia (Lown Grade ≥ III), uncontrolled hypertension or recent history of myocardial ischemia
• pregnant or nursing women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Combination therapy (MTX/abatacept); Treatment with a combination of methotrexate (10 - 25 mg once weekly) and abatacept (125 mg subcutaneously once weekly) for 6 months, followed by methotrexate monotherapy (10 - 25 mg once weekly) for another 6 months.	Drug: Abatacept; Patients will be randomized to treatment with either methotrexate monotherapy (10 - 25 mg once weekly) or a combination therapy of methotrexate (10 - 25 mg once weekly) and abatacept (125 mg subcutaneously once weekly) for 6 months, followed by methotrexate monotherapy (10 - 25 mg once weekly) in both groups for another 6 months.; Other Names: Orencia; Drug: Methotrexate; Patients will be randomized to treatment with either methotrexate monotherapy (10 - 25 mg once weekly) or a combination therapy of methotrexate (10 - 25 mg once weekly) and abatacept (125 mg subcutaneously once weekly) for 6 months, followed by methotrexate monotherapy (10 - 25 mg once weekly) in both groups for another 6 months.
Active Comparator: Methotrexate (MTX) monotherapy; Treatment with methotrexate monotherapy (10 - 25 mg once weekly) for 12 months.	Drug: Methotrexate; Patients will be randomized to treatment with either methotrexate monotherapy (10 - 25 mg once weekly) or a combination therapy of methotrexate (10 - 25 mg once weekly) and abatacept (125 mg subcutaneously once weekly) for 6 months, followed by methotrexate monotherapy (10 - 25 mg once weekly) in both groups for another 6 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of ACPA-expressing B cells that express the marker Ki-67	Flow cytometry-based determination of the percentage of ACPA-expressing B cells that stain positive for Ki-67, circulating in peripheral blood of patients with early, ACPA-positive rheumatoid arthritis.	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in disease activity	The change from baseline in disease activity (expressed as DAS 44).	24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patients achieving remission	To evaluate the percentage of patients achieving SDAI remission.	12, 24, 36 and 48 weeks
Monitor treatment-related immunological serum/plasma markers	to monitor treatment-related immunological serum/plasma markers (rheumatoid factor (IgM), anti-citrullinated protein antibodies and antibodies against other posttranslational modified proteins (AMPAs), anti-tetanus toxoid antibodies, IgG, IgA, IgM, and phenotypic cellular markers on circulating lymphocytes.	Each study visit: baseline + 12, 24, 36 and 48 weeks
Change of expression level the marker Ki-67	Evaluate the change of expression level (from baseline) of the marker Ki-67 on memory B cells expressing ACPA versus memory B cells specific for recall antigens (tetanus toxoid) in peripheral blood.	12, 36 and 48 weeks
Change in serum/plasma parameters related to disease activity	Evaluate the change from baseline in serum/plasma parameters related to disease activity (e.g. erythrocyte sedimentation rate, C-reactive protein, interleukin-6, -8, -10, TNF-alpha, vascular endothelial growth factor, granulocyte-monocyte colony stimulating factor).	12, 24, 36 and 48 weeks
Change of expression level of the markers CD80, CD86 and HLA-DR	Evaluate the change of expression level (from baseline) of the markers CD80, CD86 and HLA-DR on memory B cells expressing ACPA versus memory B cells specific for recall antigens (tetanus toxoid) in peripheral blood.	12, 24, 36 and 48 weeks

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Investigators: Principal Investigator: Hans Ulrich Scherer, Leiden University Medical Center

Publications and helpful links

General Publications

• Willemze A, Trouw LA, Toes RE, Huizinga TW. The influence of ACPA status and characteristics on the course of RA. Nat Rev Rheumatol. 2012 Jan 31;8(3):144-52. doi: 10.1038/nrrheum.2011.204.
• Keating GM. Abatacept: a review of its use in the management of rheumatoid arthritis. Drugs. 2013 Jul;73(10):1095-119. doi: 10.1007/s40265-013-0080-9.
• Kerkman PF, Fabre E, van der Voort EI, Zaldumbide A, Rombouts Y, Rispens T, Wolbink G, Hoeben RC, Spits H, Baeten DL, Huizinga TW, Toes RE, Scherer HU. Identification and characterisation of citrullinated antigen-specific B cells in peripheral blood of patients with rheumatoid arthritis. Ann Rheum Dis. 2016 Jun;75(6):1170-6. doi: 10.1136/annrheumdis-2014-207182. Epub 2015 Jun 1.

Study record dates

Study Major Dates

• Study Start (Actual): May 17, 2018
• Primary Completion (Actual): October 26, 2021
• Study Completion (Actual): April 6, 2022

Study Registration Dates

• First Submitted: April 3, 2018
• First Submitted That Met QC Criteria: April 3, 2018
• First Posted (Actual): April 10, 2018

Study Record Updates

• Last Update Posted (Actual): August 17, 2022
• Last Update Submitted That Met QC Criteria: August 16, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: abatacept; ACPA expressing B cells
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Rheumatic Diseases; Collagen Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Immune Checkpoint Inhibitors; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Methotrexate; Abatacept
• Other Study ID Numbers: NL62584.058.17

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No