TOLERA: Tolerance Enhancement in RA

• Status: Recruiting
• Trial end date: 2022-12-01
• Target enrollment: 0
• Participant gender: All

Summary

Although anti-citrullinated protein antibodies (ACPA) including anti-CCP2 antibodies are known to promote inflammation and joint destruction in patients suffering from ACPA-positive rheumatoid arthritis, there are currently no therapies available to efficiently eliminate autoantibody production and to re-induce immune tolerance in these patients. However, both a B cell-targeting therapy (Rituximab) and a T cell targeting therapy (Abatacept) were described to lower anti-CCP2 antibody levels and occasionally trigger disappearance of these autoantibodies (sero conversion). By sequentially combining Rituximab and Abatacept, we thus aim to enhance the tolerogenic potential of these drugs and seek to eliminate autoantibody production and significantly lower ACPA titers. This would for the first time correspond to a "deep" immunological remission and a re-induction of immune tolerance.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Erlangen-Nürnberg Medical School
• Treatments: Abatacept; Rituximab

Criteria

Main inclusion criteria:

Patients eligible for inclusion in this study have to fulfil all of the following criteria:

1. Understand and voluntarily sign an informed consent form

2. Male or female, age ≥ 18 years at time of consent

3. Able to adhere to the study visits and protocol

4. Satisfy the ACR-EULAR criteria of Rheumatoid Arthritis at diagnosis

5. SDAI≥11 at Screening

6. ACPA positive (anti CCP2 antibody compulsory at screening) (+/- rheumatoid factor)(≥ 40 RE/ml for CCP2 )

7. Completed vaccination for pneumococcus pneumoniae according to local guidelines at Baseline

8. Inadequate treatment response with highest tolerated dose after 3 months therapy and/or intolerance to cDMARDs specifically Methotrexate, Sulfasalazine, Hydroxychloroquine and Leflunomide or bDMARDs specifically TNF-alpha inhibitors or IL-6 receptor blockers.

9. Sulfasalazin, Hydroxychloroquine and Leflunomide must be stopped during screening phase and be replaced by Methotrexate. Leflunomide must be washed out until Baseline (Colestyramine 3x/day 8g/day for 11 days).

10. Only simultaneous therapy with Methotrexate

11. Maximum Glucocorticoid dose at Baseline: 20mg Prednisolone equivalent daily

12. JC-Virus antibody IgG and IgM in Serum negative at screening

Main exclusion criteria:

13. Planned or ongoing pregnancy status or breast-feeding

14. Ongoing or previously treatment with Abatacept or Rituximab

15. Hypersensitivity to the active substance, mouse proteins (Rituximab), chinese hamster ovary cells (Abatacept) or other components

16. Use of any other biologic immunomodulatory agent (monoclonal antibody) except insulin.

17. 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)

18. 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.

19. 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

20. 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)

21. Patients with weakened immune system defined as diagnosis of CVID, HIV and or total IgG levels lower than 600 mg/dl)

22. Requirement for immunization with live vaccine during the study period or within 4 weeks preceding baseline.

23. Contraindication for Rituximab or Abatacept treatment according to their SmPCs