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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:
ClinicalTrials.gov Identifier:
NCT02893111
First Posted: September 8, 2016
Last Update Posted: September 8, 2016
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Fu-Dong Shi, Tianjin Medical University General Hospital
  Purpose

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.


Condition Intervention Phase
Neuromyelitis Optica Spectrum Disorder Drug: Bortezomib Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Single-center, Open Label Trial of Bortezomib as add-on Treatment in Relapsing Neuromyelitis Optica Spectrum Disorder

Resource links provided by NLM:


Further study details as provided by Fu-Dong Shi, Tianjin Medical University General Hospital:

Primary Outcome Measures:
  • 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


Secondary Outcome Measures:
  • 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


Enrollment: 5
Study Start Date: December 2015
Estimated Study Completion Date: December 2017
Estimated Primary Completion Date: October 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Bortezomib (Velcade)
A proteasome inhibitor
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

Detailed Description:

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.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02893111


Locations
China, Tianjin
Tianjin Medical University General Hospital
Tianjin, Tianjin, China, 300052
Sponsors and Collaborators
Tianjin Medical University General Hospital
  More Information

Responsible Party: Fu-Dong Shi, Director of Neurology, Tianjin Medical University General Hospital
ClinicalTrials.gov Identifier: NCT02893111     History of Changes
Other Study ID Numbers: IRB2016-YX-021
First Submitted: August 27, 2016
First Posted: September 8, 2016
Last Update Posted: September 8, 2016
Last Verified: September 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Fu-Dong Shi, Tianjin Medical University General Hospital:
neuromyelitis optica spectrum disorders
Bortezomib
Velcade
Proteasome inhibitor

Additional relevant MeSH terms:
Disease
Neuromyelitis Optica
Pathologic Processes
Myelitis, Transverse
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Optic Neuritis
Optic Nerve Diseases
Cranial Nerve Diseases
Demyelinating Diseases
Eye Diseases
Autoimmune Diseases
Immune System Diseases
Bortezomib
Proteasome Inhibitors
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action