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

Primary Purpose

Neuromyelitis Optica Spectrum Disorder

Status

Completed

Phase

Phase 2

Locations

China

Study Type

Interventional

Intervention

Bortezomib

About this trial

This is an interventional treatment trial for Neuromyelitis Optica Spectrum Disorder focused on measuring neuromyelitis optica spectrum disorders, Bortezomib, Velcade, Proteasome inhibitor

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept 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

Sites / Locations

Tianjin Medical University General Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Bortezomib (Velcade)

Arm Description

A proteasome inhibitor

Outcomes

Primary Outcome Measures

Annual relapse rate (ARR) of NMOSD Attacks

Compare annual relapse rate before and one year after initial Bortezomib administration

Secondary Outcome Measures

Number of Participants with Adverse Events

All adverse events and side effects related to this drug will be recorded

Change in Expanded Disability Status Scale (EDDS) Score

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

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

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

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)

Compared RNFL before and one year after initial Bortezomib administration

Cognition

Compare cognition questionnaire scale before and one year after initial Bortezomib administration

Immunological assessments

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

Full Information

NCT ID

NCT02893111

First Posted

August 27, 2016

Last Updated

October 15, 2018

Sponsor

Tianjin Medical University General Hospital

1. Study Identification

Unique Protocol Identification Number

NCT02893111

Brief Title

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

Official Title

Single-center, Open Label Trial of Bortezomib as add-on Treatment in Relapsing Neuromyelitis Optica Spectrum Disorder

Study Type

Interventional

2. Study Status

Record Verification Date

October 2018

Overall Recruitment Status

Completed

Study Start Date

December 2015 (undefined)

Primary Completion Date

December 25, 2016 (Actual)

Study Completion Date

January 31, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Tianjin Medical University General Hospital

4. Oversight

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Neuromyelitis Optica Spectrum Disorder

Keywords

neuromyelitis optica spectrum disorders, Bortezomib, Velcade, Proteasome inhibitor

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

5 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Bortezomib (Velcade)

Arm Type

Experimental

Arm Description

A proteasome inhibitor

Intervention Type

Drug

Intervention Name(s)

Bortezomib

Other Intervention Name(s)

Velcade

Intervention Description

Bortezomib will be subcutaneously applicated in 4 treatment cycles with 4 injections of 1 mg Bortezomib /m2 body surface per cycle

Primary Outcome Measure Information:

Title

Annual relapse rate (ARR) of NMOSD Attacks

Description

Compare annual relapse rate before and one year after initial Bortezomib administration

Time Frame

Baseline, after 12 months of initial treatment

Secondary Outcome Measure Information:

Title

Number of Participants with Adverse Events

Description

All adverse events and side effects related to this drug will be recorded

Time Frame

Baseline, 12 months

Title

Change in Expanded Disability Status Scale (EDDS) Score

Description

The EDSS is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death) in half-point increments.

Time Frame

Baseline, 12 months

Title

Timed 25-foot Walk

Description

The Timed 25-Foot Walk test is a quantitative measure of lower extremity function

Time Frame

Baseline, 12 months

Title

Number of Subjects With Change in Visual Acuity in at Least One Eye by at Least One Point

Description

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).

Time Frame

Baseline, 12 months

Title

MRI brain and spine

Description

Time Frame

Baseline, 12 months

Title

Retinal nerve fiber layer (RNFL)

Description

Compared RNFL before and one year after initial Bortezomib administration

Time Frame

Baseline, 12 months

Title

Cognition

Description

Compare cognition questionnaire scale before and one year after initial Bortezomib administration

Time Frame

Baseline, 12 months

Title

Immunological assessments

Description

Time Frame

Baseline, 12 months

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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

Facility Information:

Facility Name

Tianjin Medical University General Hospital

City

Tianjin

State/Province

Tianjin

ZIP/Postal Code

300052

Country

China

12. IPD Sharing Statement

Plan to Share IPD

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

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