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Rheumatoid ArthritisPhase 2TOLERANCT04120831

TOLERA: Tolerance Enhancement in RA

A Phase 2 study testing Abatacept Injection in people with Rheumatoid Arthritis, run by University of Erlangen-Nürnberg Medical School at 1 site in Germany.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Rheumatoid Arthritis
What is being tested?
Abatacept Injection
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
20 participants
Where
1 siteGermany
Study dates
7 Oct 2019to 1 Dec 2022
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

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

Trial locations and contacts

1 site in 1 country.

Germany1 site, 1 recruiting

  • Universitiy Hospital Erlangen

    Erlangen, Bavaria, 91052

    Arnd Kleyer, MD, 0049 9131 85 32093, arnd.kleyer@uk-erlangen.de

    Sara Bayat, MD, 0049 9131 85 43016, sara.bayat@uk-erlangen.de

    Recruiting

Other trials in Germany

About this study

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

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.

Read the 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.

Being tested
Abatacept Injection
Medical subject headings
Arthritis, Rheumatoid

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Abatacept InjectionDrug

    Also called Rituximab

    Drug

Study groups in NCT04120831
Study groupRoleWhat they receive
Rituximab + Abatacept + MTXExperimentalall 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.
Receives: Drug: Abatacept Injection
Rituximab + MTX (standard of care)Active comparatorall 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.
Receives: Drug: Abatacept Injection

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Primary endpoint

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

    Measured: week 52

Secondary outcomes (1)

  1. 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

    Measured: week 52

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted9 Oct 2019
  2. Study start7 Oct 2019
  3. Primary completion1 Sep 2020 (estimated)
  4. Study completion1 Dec 2022 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
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
Single blind
Who is masked
Outcomes assessor
Enrolment
20 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04120831
Sponsor's protocol ID
IM101-817
Acronym
TOLERA
Status last verified
Oct 2019
First submitted
4 Oct 2019
Last updated
9 Oct 2019
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Abatacept Injection in people with Rheumatoid Arthritis, run by University of Erlangen-Nürnberg Medical School at 1 site in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 9 Oct 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Each site lists its own contact: choose the nearest one under Trial locations. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Primary endpoint (time frame: week 52). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04120831.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Oct 2019.

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