Clinical trial NCT03492658: Abatacept to Silence Anti-citrullinated Protein Antibody-expressing B Cells in Rheumatoid Arthritis (ASCARA)
Official title: Abatacept to Silence Anti-citrullinated Protein Antibody-expressing B Cells in Rheumatoid Arthritis (ASCARA).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Rheumatoid Arthritis
Rheumatic Diseases
Keywords: abatacept
ACPA expressing B cells
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
First posted: 2018-04-10
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Open-label, randomized, single center, two-arm, investigator-initiated, interventional clinical study
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Percentage of ACPA-expressing B cells that express the marker Ki-67
timeFrame: 24 weeks
Secondary outcomes:
measure: Change in disease activity
timeFrame: 24 weeks
Other outcomes:
measure: Percentage of patients achieving remission
timeFrame: 12, 24, 36 and 48 weeks
measure: Monitor treatment-related immunological serum/plasma markers
timeFrame: Each study visit: baseline + 12, 24, 36 and 48 weeks
measure: Change of expression level the marker Ki-67
timeFrame: 12, 36 and 48 weeks
measure: Change in serum/plasma parameters related to disease activity
timeFrame: 12, 24, 36 and 48 weeks
measure: Change of expression level of the markers CD80, CD86 and HLA-DR
timeFrame: 12, 24, 36 and 48 weeks
Locations:
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
Study officials:
affiliation: Leiden University Medical Center
name: Hans Ulrich Scherer
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.