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Trial record 7 of 137 for:    "Connective Tissue Disease" | "Abatacept"

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

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ClinicalTrials.gov Identifier: NCT03492658
Recruitment Status : Not yet recruiting
First Posted : April 10, 2018
Last Update Posted : April 19, 2018
Sponsor:
Information provided by (Responsible Party):
Hans Ulrich Scherer, Leiden University Medical Center

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 46 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Open-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).
Estimated Study Start Date : May 2018
Estimated Primary Completion Date : March 2021
Estimated Study Completion Date : September 2021

Resource links provided by the National Library of Medicine


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 Name: 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.




Primary Outcome Measures :
  1. Percentage of ACPA-expressing B cells that express the marker Ki-67 [ Time Frame: 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 :
  1. Change in disease activity [ Time Frame: 24 weeks ]
    The change from baseline in disease activity (expressed as DAS 44).


Other Outcome Measures:
  1. Percentage of patients achieving remission [ Time Frame: 12, 24, 36 and 48 weeks ]
    To evaluate the percentage of patients achieving SDAI remission.

  2. Monitor treatment-related immunological serum/plasma markers [ Time Frame: 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.

  3. Change of expression level the marker Ki-67 [ Time Frame: 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.

  4. Change in serum/plasma parameters related to disease activity [ Time Frame: 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).

  5. Change of expression level of the markers CD80, CD86 and HLA-DR [ Time Frame: 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.

  6. Full mRNA transcriptome [ Time Frame: 24 and 48 weeks ]
    Determine the full mRNA transcriptome of citrullinated antigen-specific B cells versus tetanus toxoid-specific B cells in a subset of patients of the study population (10 patients in each treatment arm) by single cell full mRNA sequencing.

  7. B cell receptor repertoire [ Time Frame: Baseline + 12, 24, 36 and 48 weeks ]
    Determine the B cell receptor repertoire of the total circulating B cell pool, of citrullinated antigen-specific B cells and of tetanus toxoid-specific B cells in a subset of patients of the study population (10 patients in each treatment arm) using next generation sequencing.

  8. N-glycosylation sites in variable region genes [ Time Frame: Prior to and during abatacept therapy + after the withdrawal of abatacept treatment ]
    Determine the frequency and localisation of N-glycosylation sites in variable region genes expressed by ACPA-expressing B cells and control cells through sequence analysis of B cell receptor repertoire sequencing.

  9. Functional properties of circulating, citrullinated antigenspecific B cells [ Time Frame: 12, 24, 36 and 48 weeks ]
    Determine functional properties (e.g. cytokine secretion (IL-6, IL-8, GM-CSF, TNF-alpha) upon B cell receptor triggering) of circulating, citrullinated antigen-specific B cells.

  10. Phenotype, transcriptional profile, B cell receptor usage and functional parameters of circulating ACPA B cells [ Time Frame: 36 and 48 weeks ]
    Determine the changes (from week 24) in phenotype, transcriptional profile, B cell receptor usage and functional parameters of circulating B cells expressing anti-citrullinated protein antibodies (ACPA) after withdrawal of abatacept therapy.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03492658


Contacts
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Contact: Nienke Blomberg +31 (0) 715298733 n.j.blomberg@lumc.nl
Contact: Hans Ulrich Scherer +31 (0) 715298733 h.u.scherer@lumc.nl

Sponsors and Collaborators
Leiden University Medical Center
Investigators
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Principal Investigator: Hans Ulrich Scherer Leiden University Medical Center

Publications:
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Responsible Party: Hans Ulrich Scherer, Principal Investigator, Leiden University Medical Center
ClinicalTrials.gov Identifier: NCT03492658     History of Changes
Other Study ID Numbers: NL62584.058.17
First Posted: April 10, 2018    Key Record Dates
Last Update Posted: April 19, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

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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

Keywords provided by Hans Ulrich Scherer, Leiden University Medical Center:
abatacept
ACPA expressing B cells

Additional relevant MeSH terms:
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Connective Tissue Diseases
Abatacept
Arthritis
Arthritis, Rheumatoid
Rheumatic Diseases
Collagen Diseases
Joint Diseases
Musculoskeletal Diseases
Autoimmune Diseases
Immune System Diseases
Antibodies
Methotrexate
Immunologic Factors
Physiological Effects of Drugs
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors