Active rheumatoid arthritis with ACPA antibodies failing methotrexate MedDRA version: 23.1 Level: PT Classification code 10039073 Term: Rheumatoid arthritis System Organ Class: 10028395 - Musculoskeletal and connective tissue disorders
Conditions
Sponsors
Universitätsklinikum Erlangen
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Subject must be able to understand and communicate with the investigator and comply with the requirements of the study, must give a written and signed and dated informed consent before any study assessment is performed • Male or non-pregnant, non-lactating female subjects at least 18 years of age • Able to adhere to the study visits and protocol • Satisfy the ACR-EULAR 2010 classification criteria of Rheumatoid Arthritis at time point of diagnosis • SDAI > 11 at screening • ACPA positive (anti CCP2 antibody compulsory at screening) (+/- rheumatoid factor) • Completed vaccination for pneumococcus pneumoniae according to local guidelines at Baseline • Inadequate treatment response with highest tolerated dose after 3 months therapy and/or intolerance to cDMARDs specifically Methotrexate, Sulfasalzine, Hydroxychloroquine and Leflonumide or bDMARDs specifically TNF-alpha inhibitors or IL-6 receptor blockers. • Subjects who have previously been treated with other DMARDs will be allowed entry into study after appropriate wash-out period prior to baseline: o Etanercept: 4 weeks or longer o Infliximab: 8 weeks or longer o Adalimumab: 10 weeks or longer o Golimumab: 8 weeks or longer o Certolizumab: 8 weeks or longer o Tocilizumab: 8 weeks or longer o Baricitinib: 1 week or longer o Secukinumab: 20 weeks or longer For all other DMARDs not mentioned above the wash-out period should be five times the half-life of the DMARD concerned. • Sulfasalazin, Hydroxychloroquine and Leflunomide must be stopped during screening phase and be replaced by Methotrexate (if possible). •As csDMARD: only simultaneous therapy with Methotrexate allowed if tolerated • Maximum Glucocortidoiddose at Baseline: 20mg Prednisolone equivalent daily • JC-Virus DNA in Serum negative at screening 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 10 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 10
Exclusion criteria
Exclusion criteria: • Ongoing or previously treatment with Abatacept or Rituximab • Hypersensitivity to the active substance, mouse proteins (Rituximab), chinese hamster ovary cells (Abatacept) or other components • Contraindication for Rituximab or Abatacept treatment according to their SmPCs • Use of any other biologic immunomodulatory agent (monoclonal antibody) except insulin. • Active ongoing inflammatory diseases other than RA that might confound the evaluation of the benefit of the therapy (including SLE, PSS, MCTD, SpA, Behcet disease, vasculitis or autoimmune hepatitis) • Active systemic infections during the last two weeks prior to baseline (exception: common cold) • History of ongoing, chronic or recurrent infectious disease or evidence of tuberculosis infection as defined by a positive QuantiFERON TB-Gold test. If presence of latent tuberculosis is established then treatment according to local country guidelines must have been initiated but patient cannot take part in the study. • Chest X-ray or chest MRI with evidence of ongoing infectious or malignant process, obtained within 3 months prior to screening and evaluated by a qualified physician • Known active or past infection with hepatitis B or hepatitis C at screening or baseline as defined by Antibody positivity and/or positive DNA/RNA levels of hepatitis B/C • History of lymphoproliferative disease or any known malignancy or history of malignancy of any organ system within the past 5 years (except for basal cell carcinoma or actinic keratosis that have been treated with no evidence of recurrence in the past 3 months, carcinoma in situ of the cervix or non-invasive malignant colon polyps that have been removed) • Uncontrolled severe concomitant disease (including diabetes with plasma glucose >11.1 mmol/l rsp. 200 mg/dl, heart insufficiency >= NYHA III, COPD with severity >= GOLD 3, asthma according to GINA classification >= step 3) • Patients with weakened immune system defined as diagnosis of CVID, HIV and or total IgG levels lower than 600 mg/dl) • Requirement for immunization with live vaccine during the study period or within 4 weeks preceding baseline. • Underlying metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, cardiac, infectious or gastrointestinal conditions which in the opinion of the investigator immunocompromises the subject and/or places the subject at unacceptable risk for participation in an immunomodulatory therapy • Evidence of severe renal dysfunction defined as eGFR < 30 ml/min/1,73 m2 (calculated using the MDRD formula) at screening (Visit 1) • History of clinically significant liver disease or liver injury as indicated by abnormal liver function tests such as SGOT (AST) = 3 fold upper limit of normal (ULN), SGPT (ALT) ) = 3 fold ULN, alkaline phosphatase = 3 fold ULN, or serum bilirubin = 2 fold ULN . • Screening total WBC count <3,000/µL, or platelets <100,000/µL or neutrophils <1,500/µL or haemoglobin <8.5 g/dL (85g/L) • Subjects taking high potency opioid analgesics (e.g. methadone, hydromorphone, morphine) • Have a history of alcohol or substance abuse within the preceding 6 months that, in the opinion of the investigator, may increase the risks associated with study participation or study agent administration, or may interfere with interpretation of results • Prior history of suicide attempt at any time in the subject's life time prior to screening and baseline, or major psychiatric illness requiring hospital
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the effect of a sequential Rituximab/Abatacept treatment on auto-antibody production and thereby determine its potential to lower ACPA levels and to induce a potential seroconversion and thus an immunological remission ;Secondary Objective: Not applicable ;Primary end point(s): • Proportion of anti CCP2 antibody seroconversions in anti-CCP2-positive RA patients at week52 (defined as lowering of anti-CCP2 antibodies below 5RE/ml);Timepoint(s) of evaluation of this end point: Week 52 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Change in anti CCP2 antibody levels (RE/ml) • Change in anti CCP2 antibodies Levels (RE/ml) in HLA-defined subgroups • Change in total IgG, IgA, IgM and IgG subclasses • Glycosylation profile of total IgG and ACPA • Change in B cell numbers • Change in numbers of CCP2-specific B-cells • SDAI, DAS28 CRP/ESR, CDAI • Number of patients in DAS28 CRP/ESR; CDAI, SDAI, Boolean remission at week 52 • ACR 20, 50, 70 response at week 52 • Number of flares in each group between week 8 and week 52: Flare as defined as loss of remission or low-disease activity (measured by a composite score (SDAI/DAS28 CRP or ESR)) lasting longer than on a daily variation of complaints. ;Timepoint(s) of evaluation of this end point: Screening, Baseline, Week 8, Week 12, Week 24, Week 36, Week 48, Week 52 | — |
Countries
Germany
Contacts
Public ContactMedizinische Klinik 3
Universitätsklinikum Erlangen
Outcome results
None listed