Therapy of Antibody-mediated Autoimmune Diseases by Bortezomib (TAVAB)

Overview

The aim of this pilot study is to investigate the application of proteasome inhibitor Bortezomib (Velcade®, approved for therapy of multiple myeloma) in patients with therapy-refractory antibody-mediated autoimmune diseases. The investigators hypothesis is that the proteasome inhibition will lead to reduced antibody titers and improved clinical outcome.

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: N/A
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: August 30, 2019

Interventions

  • Drug: Bortezomib
    • Bortezomib will be subcutaneously applicated in 2 treatment cycles with 4 injections of 1.3 mg Bortezomib /m2 body surface per cycle.

Arms, Groups and Cohorts

  • Experimental: Bortezomib (Velcade)

Clinical Trial Outcome Measures

Primary Measures

  • change in disease specific antibody titers after application of Bortezomib
    • Time Frame: 6 months after end of therapy (6 weeks) compared to baseline (before therapy)
    • Change in disease specific antibody titers (anti-ACh for myasthenia gravis, anti-dsDNA for systemic lupus erythematosus, anti-ACPA for rheumatoid arthritis) 6 months after end of Bortezomib therapy (duration 6 weeks) compared to baseline (before therapy).

Secondary Measures

  • Change in disease specific antibody titer after Bortezomib application
    • Time Frame: at regular intervals up to 30 weeks compared to baseline
    • Change in disease specific antibody titer after Bortezomib application (except at time point 6 months after end of therapy = primary outcome measure)
  • Change in quality of life (Qol score)
    • Time Frame: at regular intervals up to 30 weeks compared to baseline
  • Change in Activities of Daily Living (Adl score)
    • Time Frame: at regular intervals up to 30 weeks compared to baseline
  • change in dose of immunosuppressive co-medication
    • Time Frame: at regular intervals up to 30 weeks compared to baseline
  • Change in titers of protective antibodies (e.g. measles)
    • Time Frame: at regular intervals up to 30 weeks compared to baseline
    • Change in titers of protective antibodies against measles virus, rubella virus, varicella zoster virus, pneumococcus, cytomegalovirus
  • Change in number of antibody producing plasmablasts/cells
    • Time Frame: at regular intervals up to 30 weeks compared to baseline
    • Change in number of antibody producing plasmablasts/cells in peripheral blood
  • Change in concentration of soluble mediators (e.g. IL-6)
    • Time Frame: at regular intervals up to 30 weeks compared to baseline
    • Change in concentration of soluble mediators (e.g. IL-6) in peripheral blood
  • need for hospitalisation
    • Time Frame: at regular intervals up to 30 weeks

Participating in This Clinical Trial

(main) Inclusion Criteria:

  • age 18 – 75 years at screening – ability to give written consent, informed written consent – negative pregnancy test at screening – therapy-refractory Myasthenia Gravis (generalized) or Systemic Lupus Erythematosus or Rheumatoid Arthritis (main) Exclusion Criteria:

  • Belimumab therapy within the last 6 months – B-cell-depletion therapy within the last 9 months – heart or kidney insufficiency – known intolerability to Bortezomib – participation in another interventional trial within the last 3 months – liver cirrhosis – preexistent sensory or motor polyneuropathy ≥ degree 2 (NCI CTC AE criteria), within 14 days before screening – hints on clinically apparent herpes zoster reactivation – active systemic infection, or viral infection (CMV, EBV) within last 6 month before screening – serologically active hepatitis B and /or C, known HIV infection – tumor disease currently or within last 5 years – clinically relevant liver, kidney or bone marrow function disorder – pregnancy or lactation

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 75 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Charite University, Berlin, Germany
  • Collaborator
    • Prof. Dr. med. Falk Hiepe (Charité, Internal Medicine / Rheumathology)
  • Provider of Information About this Clinical Study
    • Principal Investigator: Andreas Meisel, Prof. Dr. – Charite University, Berlin, Germany
  • Overall Official(s)
    • Andreas Meisel, Prof. Dr., Principal Investigator, Charité – Universitätsmedizin Berlin, NeuroCure Clinical Research Center
    • Falk Hiepe, Prof. Dr., Principal Investigator, Charité – Universitätsmedizin Berlin, Internal Medicine / Rheumatology

References

Kohler S, Losen M, Alexander T, Hiepe F, Meisel A. Myasthenia gravis: subgroup classifications. Lancet Neurol. 2016 Apr;15(4):356-7. doi: 10.1016/S1474-4422(16)00033-8. No abstract available.

Kohler S, Marschenz S, Grittner U, Alexander T, Hiepe F, Meisel A. Bortezomib in antibody-mediated autoimmune diseases (TAVAB): study protocol for a unicentric, non-randomised, non-placebo controlled trial. BMJ Open. 2019 Jan 28;9(1):e024523. doi: 10.1136/bmjopen-2018-024523.

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