Ofatumumab in AQP4-IgG Seropositive NMOSD

Study Overview
=================
Brief Summary
-----------------
This is an open-label, single-arm, multicentre prospective pilot study to assess the efficacy and safety of ofatumumab in patients with AQP4-IgG seropositive neuromyelitis optica spectrum disorder (NMOSD) in China.

Detailed Description
-----------------
Neuromyelitis optica spectrum disorder (NMOSD) is a rare but severe demyelinating disorder that affects mainly adult patients. It is associated with a pathological B cell-mediated humoral immune response against the aquaporin-4 (AQP4) water channel. Monoclonal antibodies against CD20 have been shown to be effective for prevention of relapses in patients with NMOSD, and therefore been recommended as first-line therapy for this disorder. Ofatumumab (OFA), a fully humanized anti-CD20 monoclonal antibody, has been approved for multiple sclerosis treatment. However, prospective multicenter studies are needed to determine the efficacy and safety of ofatumumab in treating NMOSD.

Official Title
-----------------
Efficacy and Safety of Ofatumumab in AQP4-IgG Seropositive NMOSD: an Open-label, Single-arm, Multicentre Prospective Pilot Study

Conditions
-----------------
Neuromyelitis Optica Spectrum Disorder

Intervention / Treatment
-----------------
* Drug: Ofatumumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of NMOSD according to the 2015 International Panel Diagnostic Criteria for NMOSD with AQP4-IgG. Clinical evidence of at least 2 relapses (including first attack) in past 24 months with at least 1 relapse occurring in the preceding 12 months. Adults aged ≥18 years old. Expanded disability status scale (EDSS) score between 0 and 7.5 (inclusive). Provision of written informed consent to participate in this study. Only oral corticosteroids were permitted at screening (≤10mg equivalent per day), which should be terminated within one month. Effective contraception was used for female patients with fertility during the treatment or at least 3 months after stopping medication. Exclusion Criteria: Progressive neurological deterioration unrelated to relapses of NMOSD, or presence of neurological findings suspected with PML. Pregnant or breastfeeding patients and those with family planning during the study period. Patients participating in any other clinical therapeutic study at the screening or within 30 days of screening. Patients with splenectomy or history of no spleen, and those with planned surgery (excluding minor surgery) during the study period. Presence of uncontrolled severe concurrent diseases; long-term glucocorticoids or immunosuppressants use due to other autoimmune diseases, or presence of other chronic diseases that cannot receiving immunosuppression. Active infection at within 4 weeks before baseline. Positive for HBV or HCV. Evidence of latent or active tuberculosis (TB). Have received any live or live-attenuated vaccine within 6 weeks before baseline. History of malignancy in past 5 years, including solid tumor, malignant hematopathy and carcinoma in situ. History of severe allergic reactions to biological agents. Inability to provide written informed consent.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ofatumumab<br>The enrolled patients will receive ofatumumab (20 mg/0.4 ml) subcutaneously administered at baseline, Day 7, Day 14 and monthly thereafter. Patients will receive ofatumumab therapy for a total of 48 weeks. | Drug: Ofatumumab<br>* The enrolled patients will receive ofatumumab (20 mg/0.4 ml) subcutaneously administered at baseline, Day 7, Day 14 and monthly thereafter. Patients will receive ofatumumab therapy for a total of 48 weeks. The first 4 infusions will be administered at study center site; subsequent infusions will be given in the patient's home with a nurse online interview to administer the infusion.<br>* Other names: Arzerra;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in annual relapse rate (ARR) at last follow-up visit | Pre-treatment ARR was determined at baseline by the total number of attacks divided by disease course from onset to baseline; post-treatment ARR is determined at 12 months after treatment by the number of relapses divided by 12 months. | baseline, 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Expanded Disability Status Scale (EDSS) score | Patients are followed up and EDSS score is determined. In general, the minimum and maximum scores of EDSS are 0 and 10, respectively, with higher scores meaning a worse outcome. | baseline, 3 months, 6 months, 9 months, 12 months | 
| Change from baseline in lesion burden on MRI T2-weighted images | MRI is conducted to measure the lesion burden on T2-weighted images. | baseline, 6 months, 12 months | 
| Change from baseline in optic coherence tomography (OCT) measures | OCT is done to measure peripapillary retinal nerve fiber layer (RNFL) thickness, macular ganglion cell-inner plexiform layer (GCIPL) thickness, and macular inner nuclear layer (INL) thickness. | baseline, 6 months, 12 months | 
| Change from baseline in the frequencies of circulating B cell subsets | Circulating B cell monitoring is conducted to evaluate the effectiveness of B-cell-depletion therapy. FACS is used to measure the frequencies of CD19+ B cells, CD19+CD27+ memory B cells, and CD19+CD38+CD27+ plasmablasts. | baseline, 1 week, 2 weeks, 1 month, 3 months, 6 months, 9 months, 12 months | 
| Change from baseline in immune landscape | The dynamic changes of immune cells and cytokines are monitored, such as Th1 cells, Th2 cells, Th17 cells, NK cells, IL-1β, IL-2, IL-4, etc. | baseline, 1 week, 2 weeks, 1 month, 3 months, 6 months, 9 months, 12 months | 
| Biochemical indicators monitoring | Blood routine test, liver and kidney function, immunoglobulins, complement, and serum AQP4-IgG titer. | baseline, 1 month, 3 months, 6 months, 9 months, 12 months | 
| Assessment of functional questionnaire | SF-36, Functional Assessment of Chronic Illness Therapy (FACIT), EuroQol Health State (EQ-5D), Visual Analogue Pain Scale (VAPS), Timed 25-foot Walk Test, etc. | baseline, 1 month, 3 months, 6 months, 9 months, 12 months | 
| Adverse events | Ofatumumab-related adverse events (AEs) are evaluated and the rate of AEs is recorded. | 1 week, 2 weeks, 1 month, 3 months, 6 months, 9 months, 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Neuromyelitis Optica Spectrum Disorder, Aquaporin 4, Ofatumumab