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TOLERA: Tolerance Enhancement in RA (TOLERA)

Primary Purpose

Rheumatoid Arthritis

Status

Unknown status

Phase

Phase 2

Locations

Germany

Study Type

Interventional

Intervention

Abatacept Injection

About this trial

This is an interventional treatment trial for Rheumatoid Arthritis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Main inclusion criteria:

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

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
Main exclusion criteria:
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

Sites / Locations

Universitiy Hospital ErlangenRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Rituximab + Abatacept + MTX

Rituximab + MTX (standard of care)

Arm Description

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.

Outcomes

Primary Outcome Measures

Primary endpoint

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

Secondary Outcome Measures

secondary endpoints

Explorative serological biomarkers: Change in anti CCP2 antibody levels (RE/ml) Change in anti CCP2 antibodies in HLA-defined subgroups Change in levels of total IgG, IgG subclasses, IgA and IgM Glycosylation profile of total IgG, and of ACPA Change in B cell numbers Change in CCP2-specific B-cell numbers Clinical outcome: Number of patients in DAS28, SDAI and ACR-EULAR Boolean remission at week 52 DAS28 , SDAI, CDAI, CRP and ESR change over 52 weeks Response: ACR20, 50, 70 response at week 52

Full Information

NCT ID

NCT04120831

First Posted

October 4, 2019

Last Updated

October 7, 2019

Sponsor

University of Erlangen-Nürnberg Medical School

1. Study Identification

Unique Protocol Identification Number

NCT04120831

Brief Title

TOLERA: Tolerance Enhancement in RA

Acronym

TOLERA

Official Title

Sequential B Cell/T Cell Therapy to Re-induce Humoral Immune TOLErance in ACPA- Positive Rheumatoid Arthritis A Prospective, Randomized Controlled Open Label Single-centre Clinical Trial in Adult Subjects With Active ACPA-positive Rheumatoid Arthritis Failing Methotrexate

Study Type

Interventional

2. Study Status

Record Verification Date

October 2019

Overall Recruitment Status

Unknown status

Study Start Date

October 7, 2019 (Actual)

Primary Completion Date

September 1, 2020 (Anticipated)

Study Completion Date

December 1, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Erlangen-Nürnberg Medical School

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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.

Detailed Description

Based on fact that both a B cell-targeting therapy with Rituximab and a T cell-targeting therapy with Abatacept affect ACPA levels and can occasionally induce seroconversion and an immunological remission as well immune tolerance in ACPA-positive RA patients, we conclude that T/B cell-mediated autoimmunity can be in principle reversed in RA patients suffering from active disease. We hypothesize that we can increase the tolerance-inducing potency of Rituximab and Abatacept by combining these two approaches and delivering a sequential B cell/T cell therapy with Rituximab and Abatacept. Such a combined approach might increase the rate of seroconversions in RA patients and thus re-induce tolerance in a significant number of patients which would pave the way for a long-lasting "deep immunological" and drug-free remission. In the proposed project, we thus plan to perform a sequential treatment with initial B cell depletion with Rituximab followed by blockade of the immunological synapse by Abatacept. Such an approach aims to deplete autoreactive B cells and plasmablasts, which constitute the major source for ACPA (3) and thus reboot part of the immune system, before blocking the immunological synapse in order to enable reconstitution of self-tolerance. Based on their recently discovered pathogenic properties and to determine a potential immunological remission in the participating RA patients, we primarily plan to evaluate the effect of a sequential Rituximab/Abatacept treatment on changes in the levels of anti CCP2 antibodies between Baseline and Week 52 and will determine the rate of seroconversions. Secondary, we plan to perform an additional quantitative and qualitative analysis of the ACPA response. Glycosylation of ACPA was shown to modulate their inflammatory activity and is thus considered to control the onset of arthritis in ACPA-positive individuals (9). We will therefore measure glycosylation (galactosylation, fucosylation and sialylation) of ACPA and total IgG. Moreover, we plan to determine changes in total IgG, IgA and IgM subclasses, numbers of total B cells and plasmablasts as well as of CCP2-specific B cells and plasmablasts in the peripheral blood of the participating patients. The clinical outcome will be measured at week 52 described by disease activity parameters and patient questionnaires. The longitudinal setup of this proof of concept mode of action study is to evaluate the efficacy of a subsequent Abatacept therapy post B cell depletion in regard to ACPA seroconversion, ACPA titers and B cell phenotype changes.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Rheumatoid Arthritis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Model Description

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.

Masking

Outcomes Assessor

Allocation

Randomized

Enrollment

20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Rituximab + Abatacept + MTX

Arm Type

Experimental

Arm Description

Arm Title

Rituximab + MTX (standard of care)

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Abatacept Injection

Other Intervention Name(s)

Rituximab

Intervention Description

Drug

Primary Outcome Measure Information:

Title

Primary endpoint

Description

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

Time Frame

week 52

Secondary Outcome Measure Information:

Title

secondary endpoints

Description

Time Frame

week 52

10. Eligibility

Sex

All

Gender Based

Yes

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Facility Information:

Facility Name

Universitiy Hospital Erlangen

City

Erlangen

State/Province

Bavaria

ZIP/Postal Code

91052

Country

Germany

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Arnd Kleyer, MD

Phone

0049 9131 85 32093

arnd.kleyer@uk-erlangen.de

First Name & Middle Initial & Last Name & Degree

Sara Bayat, MD

Phone

0049 9131 85 43016

sara.bayat@uk-erlangen.de

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

TOLERA: Tolerance Enhancement in RA

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