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

Sponsor

Leiden University Medical Center (Other)

Overall Status

Completed

CT.gov ID

NCT03492658

Collaborator

(none)

Enrollment

Location

Arms

46.7

Actual Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis Rheumatic Diseases	Drug: Abatacept Drug: Methotrexate	Phase 4

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 Design

Study Type:

Interventional

Actual Enrollment :

46 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Open-label, randomized, single center, two-arm, investigator-initiated, interventional clinical studyOpen-label, randomized, single center, two-arm, investigator-initiated, interventional clinical study

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

May 17, 2018

Actual Primary Completion Date :

Oct 26, 2021

Actual Study Completion Date :

Apr 6, 2022

Arms and Interventions

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.

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

Active Comparator: Methotrexate (MTX) monotherapy

Treatment with methotrexate monotherapy (10 - 25 mg once weekly) for 12 months.

Drug: Methotrexate

Outcome Measures

Primary Outcome Measures

Percentage of ACPA-expressing B cells that express the marker Ki-67 [24 weeks]
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.

Secondary Outcome Measures

Change in disease activity [24 weeks]
The change from baseline in disease activity (expressed as DAS 44).

Other Outcome Measures

Percentage of patients achieving remission [12, 24, 36 and 48 weeks]
To evaluate the percentage of patients achieving SDAI remission.
Monitor treatment-related immunological serum/plasma markers [Each study visit: baseline + 12, 24, 36 and 48 weeks]
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.
Change of expression level the marker Ki-67 [12, 36 and 48 weeks]
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.
Change in serum/plasma parameters related to disease activity [12, 24, 36 and 48 weeks]
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).
Change of expression level of the markers CD80, CD86 and HLA-DR [12, 24, 36 and 48 weeks]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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