Tocilizumab vs Azathioprine in Neuromyelitis Optica Spectrum Disorders

Study Overview
=================
Brief Summary
-----------------
In neuromyelitis optica spectrum disorder (NMOSD),interleukin-6 (IL-6) may play an important role in facilitating plasma cells to produce pathological aquaporin 4 (AQP4) autoantibody. Inhibition of IL-6 signaling pathway by Tocilizumab (ACTEMRA®), a humanized monoclonal antibody may have shown beneficial clinical effects in a few patients with NMOSD. Larger scale clincial trials may be needed to observe its efficacy and safety. Here, by choosing azathioprine, one of the most frequently used medication in case of relapses, the investigators compare the safety and efficacy of tocilizumab in preventing NMOSD attacks.

Detailed Description
-----------------
The investigators primarily aim to observe the time to first relapse from initiation of tocilizumab or azathioprine treatment. The proportion of participants who experience relapse-free in one year follow-up will be compared. The secondary outcomes are to determine: The safety profile of tocilizumab and azathioprine in participants with NMO and whether tocilizumab improves visual function, Expanded Disability Status Scale (EDSS), et al.

Official Title
-----------------
Safety and Efficacy of Tocilizumab Versus Azathioprine in Neuromyelitis Optica Spectrum Disorders: a Randomized, Controlled, Open-label, Phase 2 Trial

Conditions
-----------------
Neuromyelitis Optica Spectrum Disorders, Neuromyelitis Optica

Intervention / Treatment
-----------------
* Drug: Tocilizumab Injection
* Drug: Azathioprine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female patients ≥ 18 years old Diagnosis of NMO or NMO spectrum disorder Clinical evidence of at least 2 relapses in last 12 months or 3 relapses in the last 24 months Able and willing to give written informed consent and comply with the requirements of the study protocol. EDSS <= 7.5 (8 in special circumstances) Men and women of reproductive potential must agree to use a highly effective method of birth control from screening to 6 months after final dose of the investigational product. Exclusion Criteria: Current evidence or known history of clinically significant infection (Herpes simplex virus, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus,human immunodeficiency virus, 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 Participation in another interventional trial within the last 3 months Heart or kidney insufficiency Tumor disease currently or within last 5 years Clinically relevant liver, kidney or bone marrow function disorder Intolerance of azathioprine or previous relapses on azathioprine treatment Receipt of rituximab or any experimental B-cell depleting agent within 6 months prior screening and B-cells below the lower limit of normal.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tocilizumab<br>Tocilizumab Injection (ACTEMRA®) , a IL-6 receptor blockade | Drug: Tocilizumab Injection<br>* Tocilizumab Injection will be intravenously administered with a dose of 8 mg/kg every 4 weeks.<br>* Other names: ACTEMRA®;|
| Active Comparator: Azathioprine<br>Imuran | Drug: Azathioprine<br>* Azathioprine will be orally given at a dose of 2-3 mg/kg/d<br>* Other names: Imuran;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first relapse | An acute attack was defined as a new neurological worsening lasting for at least 24 hours and occurring more than 30 days after the previous attack. | From baseline to one year after | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients who experience relapse-free | To record whether the patients had no relapses in the follow-ups | From baseline to 60 weeks | 
| Worsening in EDSS | The Expanded Disability Status Scale (EDSS) is a rating system that is frequently used for classifying and standardizing the severity and progression. EDSS ranges from 0 to 10. | Worsening from baseline in EDSS to 60 weeks | 
| Time to Onset of Confirmed Disability Progression (CDP) for at Least 12 Weeks | Disability progression was defined as an increase in the Expanded Disability Status Scale (EDSS) score of: A) >=1.0 point from the baseline EDSS score when the baseline score was less than or equal to (<=) 5.5 B) >=0.5 point from the baseline EDSS score when the baseline score was >5.5 The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis). Disability progression was considered confirmed when the increase in the EDSS was confirmed at a regularly scheduled visit at least 12 weeks after the initial documentation of neurological worsening. Participants who had initial disability progression with no confirmatory EDSS assessment and who were on treatment at time of clinical cut-off date were censored at the date of their last EDSS assessment. | From baseline to 60 weeks | 
| Percentage of Participants With Confirmed Disability Improvement (CDI) for at Least 12 Weeks | Disability improvement was assessed only for the subgroup of participants with a baseline EDSS score of >= 2.0. It was defined as a reduction in EDSS score of: A) >=1.0 from the baseline EDSS score when the baseline score was >=2 and <=5.5 B) >= 0.5 when the baseline EDSS score > 5.5. The EDSS scale ranges from 0 (normal neurological exam) to 10 (death). | From baseline to 60 weeks | 
| Time to Onset of Confirmed Disability Progression (CDP) for at Least 24 Weeks | Disability progression was defined as an increase in the Expanded Disability Status Scale (EDSS) score of: A) >=1.0 point from the baseline EDSS score when the baseline score was less than or equal to (<=) 5.5 B) >=0.5 point from the baseline EDSS score when the baseline score was >5.5 The EDSS scale ranges from 0 (normal neurological exam) to 10 (death). Disability progression was considered confirmed when the increase in the EDSS was confirmed at a regularly scheduled visit at least 24 weeks after the initial documentation of neurological worsening. Participants who had initial disability progression with no confirmatory EDSS assessment and who were on treatment at time of clinical cut-off date were censored at the date of their last EDSS assessment. | From baseline to 60 weeks | 
| Percentage of Participants With Confirmed Disability Improvement (CDI) for at Least 24 Weeks | Disability improvement was assessed only for the subgroup of participants with a baseline EDSS score of >= 2.0. It was defined as a reduction in EDSS score of: A) >=1.0 from the baseline EDSS score when the baseline score was >=2 and <=5.5 B) >= 0.5 when the baseline EDSS score > 5.5. The EDSS scale ranges from 0 (normal neurological exam) to 10 (death). | From baseline to 60 weeks | 
| Percentage Change in Spectral-domain Optical Coherence Tomography (SD-OCT) Average Retinal Nerve Fiber Layer (RNFL) Thickness at Week 60 | Adjusted mean percentage change in thickness of the RNFL at Week 60 for the affected eye from the baseline as determined by SD-OCT. | From baseline to 60 weeks | 
| Percentage change in SD-OCT Average Retinal Ganglion Cell Layer/Inner Plexiform Retinal Layer (RGCL/IPL) at Week 60 | Adjusted mean change in thicknesses of the RGCL/IPL at Week 60 for the affected eye from the baseline as determined by segmentation of SD-OCT. | From baseline to 60 weeks | 
| Change in Low-contrast Letter Acuity (LCLA) at Week 60 | Adjusted mean change in LCLA at Week 60 from baseline as determined by 2.5% low contrast Sloan letter charts, adjusted for the baseline LCLA value. | From baseline to 60 weeks | 
| Change in High-contrast Letter Acuity (HCLA) at Week 60 | Adjusted mean change in HCLA at Week 60 from baseline as determined by 100% high contrast Sloan letter charts, adjusted for the baseline HCLA value. | From baseline to 60 weeks | 
| Number of New, and/or Enlarging T2 Hyperintense Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) | The total number of new and/or enlarging T2 lesions for all participants in the treatment group was calculated as the sum of the individual number of lesions at Weeks 12, 36, and 60 | From baseline to 60 weeks | 
| Overall safety and tolerability of tocilizumab or azathioprine | Adverse events related to tocilizumab or azathioprine are recorded. | From baseline to 60 weeks | 
| Number of Participants with Adverse Events as a Measure of Safety and Tolerability | Treatment-emergent adverse events, treatment-emergent serious adverse events (TESAEs), including laboratory measurements as well as their changes or shift from baseline over time | From baseline to 60 weeks | 
| Counts of peripheral blood B cell subsets | Compare peripheral blood plasma cells before and one year after initial intervention | From baseline to 60 weeks | 
| Determination of serum immunoglobulins | Compare immunoglobulins before and one year after initial intervention | From baseline to 60 weeks | 
| Determination of serum AQP4 antibodies | Compare serum AQP4-ab titers before and one year after initial intervention | From baseline to 60 weeks | 
| Determination of serum cytokines | Compare serum cytokines before and one year after initial intervention | From baseline to 60 weeks |