Abatacept to Silence anti-Citrullinated protein Antibody-expressing B cells in Rheumatoid Arthritis

• Register: EUCTR
• Last refreshed on: 5 March 2018
• Main ID: EUCTR2017-002878-38-NL
• Date of registration: 12/09/2017
• Prospective Registration: Yes
• Primary sponsor: Leiden University Medical Center
• Public title: Abatacept to Silence anti-Citrullinated protein Antibody-expressing B cells in Rheumatoid Arthritis
• Scientific title: Abatacept to Silence anti-Citrullinated protein Antibody-expressing B cells in Rheumatoid Arthritis - ASCARA
• Date of first enrolment: 07/02/2018
• Target sample size: 46
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-002878-38
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: yes; Single blind: no; Double blind: no; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: yes; Other specify the comparator: Methotrexate only; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

Netherlands

Contacts

• Name: CRU department Rheumatology
• Affiliation: Leiden University Medical Center

• Name: CRU department Rheumatology
• Affiliation: Leiden University Medical Center

Key inclusion & exclusion criteria

Inclusion criteria:
In order to be eligible to participate in this study, a subject must meet all of the following 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
- be at least 18 years of age
- 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

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 31
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 15

Exclusion criteria:
A potential subject who meets any of the following criteria will be excluded from participation in this study. 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 = 1.5 x the upper limit of normal range, AST, ALT = 3 x 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



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Patients with early, methotrexate-naïve, ACPA-positive rheumatoid arthritis
MedDRA version: 20.0 Level: LLT Classification code 10003268 Term: Arthritis rheumatoid System Organ Class: 100000018818

Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

Intervention(s)

Trade Name: Orencia 125 mg
Pharmaceutical Form: Solution for infusion in pre-filled syringe
INN or Proposed INN: ABATACEPT
CAS Number: 332348-12-6
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 125-

Primary Outcome(s)

Main Objective: The objective of the study is to investigate the effect of abatacept on phenotype, transcriptional profile, B cell receptor usage and functional parameters of circulating B cells expressing anti-citrullinated protein antibodies (ACPA) in patients with early, methotrexate-naïve, ACPA-positive rheumatoid arthritis.

Secondary Objective: Not applicable

Primary end point(s): The primary endpoint is the percentage of ACPA B cells circulating in peripheral blood of patients with early, ACPA-positive rheumatoid arthritis that express the marker Ki-67 at the 24 week time point in the two treatment arms. The primary endpoint will be assessed per patient by flow cytometry–based determination of the percentage of ACPA+ B cells that stain positive for Ki-67, followed by calculation of the mean of the patients in each treatment group. We expect that normal distribution of the groups can be achieved by log transformation, in which case the means of both treatment groups will be compared using an unpaired t-test. In case normality is violated, Mann-Whitney U-test will be used

Timepoint(s) of evaluation of this end point: 24 weeks time point

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: 24 weeks time point

Secondary end point(s): The secondary endpoint is the the change from baseline in disease activity (expressed as DAS 44) at week 24. Disease activity will be calculated and expressed as numerical variable (DAS 44). Baseline values for each patient will be set to 100% followed by the calculation of the Delta (change-from-baseline in %) at week 24. The mean of the Delta for each treatment group will be compared by a t-test in case of normal distribution or if normality can be achieved by log transformation. If normality is violated, medians of the Delta will be compared by Mann-Whitney U-test.

Secondary ID(s)

IM101-683

Source(s) of Monetary Support

BMS

IMI