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Efficacy and Safety of Bortezomib as add-on Treatment in Relapsing Neuromyelitis Optica Spectrum Disorder

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Fu-Dong Shi, Tianjin Medical University General Hospital
ClinicalTrials.gov Identifier:
NCT02893111
First received: August 27, 2016
Last updated: September 2, 2016
Last verified: September 2016
August 27, 2016
September 2, 2016
December 2015
October 2017   (Final data collection date for primary outcome measure)
Annual relapse rate (ARR) of NMOSD Attacks [ Time Frame: Baseline, after 12 months of initial treatment ]
Compare annual relapse rate before and one year after initial Bortezomib administration
Same as current
No Changes Posted
  • Number of Participants with Adverse Events [ Time Frame: Baseline, 12 months ]
    All adverse events and side effects related to this drug will be recorded
  • Change in Expanded Disability Status Scale (EDDS) Score [ Time Frame: Baseline, 12 months ]
    The EDSS is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death) in half-point increments.
  • Timed 25-foot Walk [ Time Frame: Baseline, 12 months ]
    The Timed 25-Foot Walk test is a quantitative measure of lower extremity function
  • Number of Subjects With Change in Visual Acuity in at Least One Eye by at Least One Point [ Time Frame: Baseline, 12 months ]
    Visual acuity was measured using the the visual acuity subscale of the opticospinal impairment score (OSIS) for Exacerbations. This subscale ranges from 0 (normal) to 8 (no light perception).
  • MRI brain and spine [ Time Frame: Baseline, 12 months ]
    MRIs will be analyzed for counting the numbers of new lesions by T2 hyper-intensity in the brain, spinal cord and optic nerve (minimal number is 0), and the volume of T1 post-contrast enhancement (minimal volume is 0 cm3).
  • Retinal nerve fiber layer (RNFL) [ Time Frame: Baseline, 12 months ]
    Compared RNFL before and one year after initial Bortezomib administration
  • Cognition [ Time Frame: Baseline, 12 months ]
    Compare cognition questionnaire scale before and one year after initial Bortezomib administration
  • Immunological assessments [ Time Frame: Baseline, 12 months ]
    Compare Ig subclasses (serum IgG1,IgG2, IgG3 and IgG4 concentrations by mg/dL), anti-aquaporin4-ab (measured by FIPA nmol/L and FACS assay titre), cytokine kinetics (measured by ELISA assay titre), relevant plasma cells depletion (number of circulating cells measured by count/μL ) before and one year after initial Bortezomib administration
Same as current
Not Provided
Not Provided
 
Efficacy and Safety of Bortezomib as add-on Treatment in Relapsing Neuromyelitis Optica Spectrum Disorder
Single-center, Open Label Trial of Bortezomib as add-on Treatment in Relapsing Neuromyelitis Optica Spectrum Disorder

Neuromyelitis Optica Spectrum Disorders (NMOSD) is characterized by the pathogenic anti-AQP4 antibody, which can be produced by specific plasma cells. The patients who are not responsive to rituximab treatment may be due to the presence of short-lived and long-lived plasma cells. Previous studies confirmed that the proteasome inhibitor bortezomib (Velcade®, approved for therapy of multiple myeloma) eliminated both plasmablasts and plasma cells by activation of the terminal unfolded protein response. Treatment with bortezomib may help deplete plasma cells producing auto-antibodies. Therefore, the rationale for using bortezomib in NMOSD is in that bortezomib may help eliminate autoreactive plasma cells and reduce anti-AQP4 antibodies titers. It is noted that bortezomib may protect astrocytes from NFκB-dependent inflammatory damage in early events in NMOSD pathogenesis.

The purpose of this study is to determine if the drug bortezomib contributes to reduce the average relapsing rates (ARRs) and alleviate neurological disability in NMOSD patients.

It has been shown in some scientific studies that the the antibody marker specific for neuromyelitis optica spectrum disorders (NMOSD), known as AQP4-IgG, causes inflammation in brain tissues by activating NF-κB pathway. Bortezomib has already been shown to be effective in systemic lupus erythematosus (SLE).

The overall objective is to assess the efficacy and safety of bortezomib as add-on therapy to oral steroids,azathioprine or others for treatment of relapsing NMOSD, which have not reduced average relapsing rate (ARR) effectively.

The primary (most important) objectives of this study are to determine:

Whether bortezomib reduces relapse frequency in patients with relapsing NMO. The number of attacks during the one year treatment period will be compared to the number of attacks that occurred prior to initiation of bortezomib treatment.

The secondary objectives are to determine:

The safety profile of bortezomib in patients with NMO. Whether bortezomib maintains or improves walking, visual function and quality of life as measured by a variety of established disability scales. We will also assess the severity of an individual attack and the degree of recovery.

Depending on our preliminary investigations we may evaluate patient cerebrospinal fluid in the laboratory to see how effective eculizumab is at getting into the cerebrospinal fluid from the blood stream, and to see if the drug reverses the biological effects of the NMO-IgG antibody.

Interventional
Phase 2
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Neuromyelitis Optica Spectrum Disorder
Drug: Bortezomib
Bortezomib will be subcutaneously applicated in 4 treatment cycles with 4 injections of 1 mg Bortezomib /m2 body surface per cycle
Other Name: Velcade
Experimental: Bortezomib (Velcade)
A proteasome inhibitor
Intervention: Drug: Bortezomib
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
5
December 2017
October 2017   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • Age ≥18 years
  • Diagnosis of NMOSD, as defined by 2015 criteria OR NMOSD seropositive spectrum disorder (Recurrent ON or longitudinally extensive transverse myelitis (LETM)). All patients must be NMO-IgG seropositive.
  • Clinical evidence of at least 2 relapses in last 6 months or 3 relapses in the last 12 months (with at least 1 relapse occurring in the preceding 6 months)
  • The B cell count must be normal (5-20% of total lymphocytes) in subjects before administration of bortezomib
  • Provision of written informed consent to participate in the study
  • Corrected visual acuity 20/100 or better in at least one eye; otherwise, last attack was myelitis and only attacks of myelitis are outcomes
  • Ambulatory (with or without walker); otherwise, last attack was optic neuritis and only attacks of optic neuritis are outcomes

Exclusion Criteria:

  • Current evidence or known history of clinically significant infection (HSV, VZV, CMV, EBV, HIV, Hepatitis viruses, Syphilis, etc)
  • Pregnant, breastfeeding, or child-bearing potential during the course of the study
  • Patients will not participate in any other clinical therapeutic study or will not have participated in any other experimental treatment study within 30 days of screening
  • Patients with a history of splenectomy, because of a potential increased risk of developing meningococcal infection
  • Participation in another interventional trial within the last 3 months
  • Pre-existent sensory or motor polyneuropathy ≥ degree 2 (NCI CTC AE criteria), within 14 days before screening
  • Heart or kidney insufficiency
  • Tumor disease currently or within last 5 years
  • Clinically relevant liver, kidney or bone marrow function disorder
Sexes Eligible for Study: Female
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
China
 
 
NCT02893111
IRB2016-YX-021
Yes
Not Provided
Plan to Share IPD: No
Fu-Dong Shi, Tianjin Medical University General Hospital
Tianjin Medical University General Hospital
Not Provided
Not Provided
Tianjin Medical University General Hospital
September 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP