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

NCT03492658 | Completed Phase 4 DMC

• 1 other identifier: NL62584.058.17
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 1

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.

Conditions

Rheumatoid Arthritis; Rheumatic Diseases

Keywords

abatacept; ACPA expressing B cells

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (1)

• Change in disease activity

  24 weeks

Other Outcomes (5)

• Percentage of patients achieving remission

  12, 24, 36 and 48 weeks

• Monitor treatment-related immunological serum/plasma markers

  Each study visit: baseline + 12, 24, 36 and 48 weeks

• Change of expression level the marker Ki-67

  12, 36 and 48 weeks

Study Arms (2)

Combination therapy (MTX/abatacept)

EXPERIMENTAL

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; Drug: Methotrexate

Methotrexate (MTX) monotherapy

ACTIVE COMPARATOR

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

Drug: Methotrexate

Interventions

Abatacept DRUG

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.

Also known as: Orencia

Combination therapy (MTX/abatacept)

Methotrexate DRUG

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.

Combination therapy (MTX/abatacept); Methotrexate (MTX) monotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Leiden University Medical Center: lead

Study Sites (1)

Leiden University Medical Center

Leiden, Netherlands

Location

Related Publications (3)

• 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.

  PMID: 22293763 BACKGROUND

• 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.

  PMID: 23794171 BACKGROUND

• 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.

  PMID: 26034045 BACKGROUND

MeSH Terms

Conditions

Arthritis, Rheumatoid; Rheumatic Diseases

Interventions

Abatacept; Methotrexate

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Immunoconjugates; Antibodies; Immunoglobulins; Serum Globulins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Globulins; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Hans Ulrich Scherer

  Leiden University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Open-label, randomized, single center, two-arm, investigator-initiated, interventional clinical study

Study Record Dates

• First Submitted: April 3, 2018
• First Posted: April 10, 2018
• Study Start: May 17, 2018
• Primary Completion: October 26, 2021
• Study Completion: April 6, 2022
• Last Updated: August 17, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will share

Locations

NL (1)