TOLERA: Tolerance Enhancement in RA

NCT04120831 | Unknown Phase 2 DMC

• 1 other identifier: IM101-817
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Rheumatoid Arthritis

Outcome Measures

Primary Outcomes (1)

• Primary endpoint

  Proportion of anti CCP2 antibody seroconversions in anti-CCP2-positive

  week 52

Secondary Outcomes (1)

• secondary endpoints

  week 52

Study Arms (2)

Rituximab + Abatacept + MTX

EXPERIMENTAL

all participants receive Rituximab. Study subjects will be randomized into one of two treatment arms (Abatacept+MTX vs MTX) following a 1:1 randomization at Visit 3, at the day of the 2nd Rituximab Infusion.

Drug: Abatacept Injection

Rituximab + MTX (standard of care)

ACTIVE COMPARATOR

all participants receive Rituximab. Study subjects will be randomized into one of two treatment arms (Abatacept+MTX vs MTX) following a 1:1 randomization at Visit 3, at the day of the 2nd Rituximab Infusion.

Drug: Abatacept Injection

Interventions

Abatacept Injection DRUG

Drug

Also known as: Rituximab

Rituximab + Abatacept + MTX; Rituximab + MTX (standard of care)

Eligibility Criteria

• Age: 18 Years+
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Understand and voluntarily sign an informed consent form
• Male or female, age ≥ 18 years at time of consent
• Able to adhere to the study visits and protocol
• Satisfy the ACR-EULAR criteria of Rheumatoid Arthritis at diagnosis
• SDAI≥11 at Screening
• ACPA positive (anti CCP2 antibody compulsory at screening) (+/- rheumatoid factor)(≥ 40 RE/ml for CCP2 )
• 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, Sulfasalazine, Hydroxychloroquine and Leflunomide or bDMARDs specifically TNF-alpha inhibitors or IL-6 receptor blockers.
• 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).
• Only simultaneous therapy with Methotrexate
• Maximum Glucocorticoid dose at Baseline: 20mg Prednisolone equivalent daily
• JC-Virus antibody IgG and IgM in Serum negative at screening

You may not qualify if:

• Planned or ongoing pregnancy status or breast-feeding
• Ongoing or previously treatment with Abatacept or Rituximab
• Hypersensitivity to the active substance, mouse proteins (Rituximab), chinese hamster ovary cells (Abatacept) or other components
• 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)
• 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.
• 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
• 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.
• Contraindication for Rituximab or Abatacept treatment according to their SmPCs

Sponsors & Collaborators

• University of Erlangen-Nürnberg Medical School: lead

Study Sites (1)

Universitiy Hospital Erlangen

Erlangen, Bavaria, 91052, Germany

RECRUITING

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

Abatacept; Rituximab

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Immunoconjugates; Antibodies; Immunoglobulins; Serum Globulins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Globulins; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Immunoproteins

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This randomized, phase 2, single centre exploratory proof of concept study uses a sequential Rituximab/Abatacept treatment in ACPA positive rheumatoid arthritis. The study is composed of a non-blinded two arm design with a randomization of 1:1. A total amount of 20 ACPA positive RA patients are planned for enrolment. Duration of this study is planned for 52 weeks. Subjects willing to participate in the study have to sign a written informed consent prior to any study specific procedure, after being informed about the possible risks and possible benefits.

Study Record Dates

• First Submitted: October 4, 2019
• First Posted: October 9, 2019
• Study Start: October 7, 2019
• Primary Completion: September 1, 2020
• Study Completion: December 1, 2022
• Last Updated: October 9, 2019

Record last verified: 2019-10

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)