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

Neuromyelitis Optica Spectrum Disorder Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02893111
• Other study ID #: IRB2016-YX-021
• Status: Completed
• Phase: Phase 2
• Start date: December 2015
• Est. completion date: January 31, 2017

Study information

• Verified date: April 2024
• Source: Tianjin Medical University General Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 5
• Est. completion date: January 31, 2017
• Est. primary completion date: December 25, 2016
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Neuromyelitis Optica
• Neuromyelitis Optica Spectrum Disorder

Intervention

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

Locations

Country	Name	City	State
China	Tianjin Medical University General Hospital	Tianjin	Tianjin

Sponsors (1)

Lead Sponsor	Collaborator
Tianjin Medical University General Hospital

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Annual relapse rate (ARR) of NMOSD Attacks	Compare annual relapse rate before and one year after initial Bortezomib administration	Baseline, after 12 months of initial treatment
Secondary	Number of Participants with Adverse Events	All adverse events and side effects related to this drug will be recorded	Baseline, 12 months
Secondary	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.	Baseline, 12 months
Secondary	Timed 25-foot Walk	The Timed 25-Foot Walk test is a quantitative measure of lower extremity function	Baseline, 12 months
Secondary	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).	Baseline, 12 months
Secondary	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).	Baseline, 12 months
Secondary	Retinal nerve fiber layer (RNFL)	Compared RNFL before and one year after initial Bortezomib administration	Baseline, 12 months
Secondary	Cognition	Compare cognition questionnaire scale before and one year after initial Bortezomib administration	Baseline, 12 months
Secondary	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	Baseline, 12 months