B cell therapy followed by T cell therapy to achieve immune tolerance in rheumatoid arthritis with ACPA antiboidies (TOLERA): an unblinded clinical trial in one centre with random assignment to treatment groups in adult patients who failed methotrexate therapy
- Conditions
- Active rheumatoid arthritis with ACPA antibodies failing methotrexateMedDRA version: 23.1Level: PTClassification code 10039073Term: Rheumatoid arthritisSystem Organ Class: 10028395 - Musculoskeletal and connective tissue disordersTherapeutic area: Diseases [C] - Immune System Diseases [C20]
- Registration Number
- EUCTR2018-003877-91-DE
- Lead Sponsor
- niversitätsklinikum Erlangen
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 20
•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:
oEtanercept: 4 weeks or longer
oInfliximab: 8 weeks or longer
oAdalimumab: 10 weeks or longer
oGolimumab: 8 weeks or longer
oCertolizumab: 8 weeks or longer
oTocilizumab: 8 weeks or longer
oBaricitinib: 1 week or longer
oSecukinumab: 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
•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
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method 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<br><br>;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 Outcome Measures
Name Time Method Secondary end point(s): •Change in anti CCP2 antibody levels (RE/ml) <br>•Change in anti CCP2 antibodies Levels (RE/ml) in HLA-defined subgroups<br>•Change in total IgG, IgA, IgM and IgG subclasses<br>•Glycosylation profile of total IgG and ACPA<br>•Change in B cell numbers<br>•Change in numbers of CCP2-specific B-cells <br>•SDAI, DAS28 CRP/ESR, CDAI<br>•Number of patients in DAS28 CRP/ESR; CDAI, SDAI, Boolean remission at week 52<br>•ACR 20, 50, 70 response at week 52<br>•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