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

Sponsor

Tianjin Medical University General Hospital (Other)

Overall Status

Completed

CT.gov ID

NCT02893111

Collaborator

(none)

Enrollment

Location

Arm

Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Neuromyelitis Optica Spectrum Disorder	Drug: Bortezomib	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

5 participants

Allocation:

N/A

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

Study Start Date :

Dec 1, 2015

Actual Primary Completion Date :

Dec 25, 2016

Actual Study Completion Date :

Jan 31, 2017

Arms and Interventions

Arm	Intervention/Treatment
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 Names: Velcade

Arm

Intervention/Treatment

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 Names:

Velcade

Outcome Measures

Primary Outcome Measures

Annual relapse rate (ARR) of NMOSD Attacks [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 [Baseline, 12 months]
All adverse events and side effects related to this drug will be recorded
Change in Expanded Disability Status Scale (EDDS) Score [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 [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 [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 [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) [Baseline, 12 months]
Compared RNFL before and one year after initial Bortezomib administration
Cognition [Baseline, 12 months]
Compare cognition questionnaire scale before and one year after initial Bortezomib administration
Immunological assessments [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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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