A Study In Neuromyelitis Optica Spectrum Disorder (NMOSD) With Satralizumab As An Intervention

Study Overview
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Brief Summary
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Objective of the trial is to describe the efficacy and safety of satralizumab in patients with aquaporin-4 (AQP4) antibody seropositive NMOSD, either treatment naive or inadequate responders to previous treatment with rituximab (RTX) (or its biosimilar)

Detailed Description
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Neuromyelitis optica (NMO) and neuromyelitis optica spectrum disorder (NMOSD) are severe demyelinating inflammatory autoimmune neurological disorders. The estimated global pooled prevalence of NMOSD is 1.82 per 100 000 people (Etemadifar et al. 2015). The disorder is characterized by inflammatory lesions in the optic nerve, spinal cord, brainstem, and cerebrum; and clinically by optic neuritis (ON) and/or transverse myelitis causing potentially severe motor and sensory impairment, bladder dysfunction, vision loss, pain, and other debilitating symptoms (Wingerchuk et al. 2015). Recovery is variable, and inflammatory attacks often result in permanent disability. Untreated, the risks of severe disability or death are substantial (Jarius et al. 2014). NMOSD is radiologically and prognostically distinct from multiple sclerosis (MS), and has a pathophysiology unresponsive to typical MS treatment (Weinshenker 2007; Oh, and Levy et al. 2012).

Official Title
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SAkuraBonsai: Clinical, Imaging And Biomarker Open-Label Study In Neuromyelitis Optica Spectrum Disorder (NMOSD) With Satralizumab As An Intervention

Conditions
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Neuromyelitis Optica Spectrum Disorder, NMOSD

Intervention / Treatment
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* Drug: Satralizumab 120 mg


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Age 18 to 74 years, inclusive, at the time of informed consent Have a diagnosis of AQP4 antibody seropositive NMOSD according to the International Panel for NMO Diagnosis (IPND) criteria For women of childbearing potential: agreement to either remain abstinent (refrain from heterosexual intercourse) or to use reliable means of contraception (physical barrier [patient or partner] in conjunction with a spermicidal product, contraceptive pill, patch, injectables, intrauterine device or intrauterine system) during the treatment period and for at least 3 months after the last dose of study drug Cohort 1 (treatment-naïve NMOSD patients) Confirmation of NMOSD diagnosis with AQP4+ antibodies Have clinical evidence of at least 1 documented attack or relapse (including first attack) in the last year prior to screening Naive to maintenance therapy (disease-modifying therapy [DMT] or immunosuppressive therapy [IST]) Cohort 2 (NMOSD patients with inadequate response to RTX [or its biosimilar]) Confirmation of NMOSD diagnosis and AQP4+ antibodies in the disease history of the patient Have a length of disease duration from first symptom of ≤5 years History of ongoing treatment with RTX (or its biosimilar) (at least 2 infusions) for NMOSD with a maximum duration of 6 months since last administration prior to enrolment in the study Ongoing disease activity after last RTX (or its biosimilar) infusion i.e., relapse and/or any new inflammatory event, confirmed by magnetic resonance imaging (MRI) or ophthalmological assessment Exclusion criteria Exclusion criteria for both the cohorts Inability to complete an MRI Participants who are pregnant or breastfeeding, or intending to become pregnant during the study or within 3 months after the final dose of satralizumab Any surgical procedure (except for minor surgeries) within 4 weeks prior to baseline Evidence of other demyelinating disease, including MS or progressive multifocal leukoencephalopathy (PML) Evidence of serious uncontrolled concomitant diseases that may preclude patient participation Active or presence of recurrent bacterial, viral, fungal, mycobacterial infection or other infection (excluding fungal infections of nail beds or caries dentium) at baseline Infection requiring hospitalization or treatment with intravenous (IV) anti-infective agents within 4 weeks prior to baseline visit Evidence of chronic active hepatitis B Evidence of active tuberculosis (TB) History or laboratory evidence of coagulation disorders Receipt of a live or live-attenuated vaccine within 6 weeks prior to baseline Presence or history of malignancy History of drug or alcohol abuse within 1 year prior to baseline History of diverticulitis that, in the Investigator's opinion, may lead to increased risk of complications such as lower gastrointestinal perforation History of severe allergic reaction to a biologic agent Active suicidal ideation within 6 months prior to screening, or history of suicide attempt within 3 years prior to screening Treatment with any investigational agent within 6 months prior to baseline or 5 drug elimination half-lives of the investigational agent (whichever is longer) Cohort 1 (treatment-naïve NMOSD patients) Any previous treatment with IL-6 inhibitory therapy (e.g., tocilizumab), alemtuzumab, total body irradiation, stem-cell therapy, or bone marrow transplantation Any previous treatment with eculizumab, belimumab, natalizumab, glatiramer acetate, fingolimod, teriflunomide, dimethyl fumarate, siponimod, or ozanimod Any previous treatment with anti-CD4, cladribine or mitoxantrone Any previous treatment with B-cell depleting agents Any previous treatment with immunosuppressants Cohort 2 (NMOSD patients with inadequate response to RTX) Discontinued RTX (or biosimilar) treatment due to any other reason than inadequate response to treatment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: treatment-naïve NMOSD patients<br>Patients will be treated with 120 mg satralizumab subcutaneously (SC) as monotherapy at Weeks 0, 2 (±3 days), 4 (±3 days), and then every 4 weeks (±3 days) till the last administration at Week 92 followed by a clinical evaluation at Week 96. The first dose at Week 0 (baseline visit) will be administered at the study site by the designated site staff during the scheduled study visit. All assessments (clinical, laboratory and imaging) should be performed before satralizumab administration. The next dose at Week 2 will be self-administered by the patient under the supervision of a designated study staff at the study site. All the subsequent doses will be self-administered by the patient following training from a healthcare provider (for patients who are not able to administer satralizumab SC by themselves, support by a caregiver/nurse is advised). | Drug: Satralizumab 120 mg<br>* Satralizumab 120 mg will be administered as monotherapy (SC) in the abdominal or femoral region at Weeks 0, 2 (±3 days), 4 (±3 days), and then every 4 weeks (±3 days) till the last administration at Week 92 followed by a clinical evaluation at Week 96. The first dose at Weeks 0 (baseline visit) will be administered at the study site by the designated site staff during the scheduled study visit. The next dose at Week 2 will be self-administered by the patient under the supervision of a designated study staff at the study site. All the subsequent doses will be self-administered by the patient following training from a healthcare provider (for patients who are not able to administer satralizumab SC by themselves, support by a caregiver/nurse is advised).<br>|
| Experimental: Cohort 2: NMOSD patients who are inadequate responders to previous treatment with RTX<br>Patients will be treated with 120 mg satralizumab subcutaneously (SC) as monotherapy at Weeks 0, 2 (±3 days), 4 (±3 days), and then every 4 weeks (±3 days) till the last administration at Week 92 followed by a clinical evaluation at Week 96. The first dose at Week 0 (baseline visit) will be administered at the study site by the designated site staff during the scheduled study visit. All assessments (clinical, laboratory and imaging) should be performed before satralizumab administration. The next dose at Week 2 will be self-administered by the patient under the supervision of a designated study staff at the study site. All the subsequent doses will be self-administered by the patient following training from a healthcare provider (for patients who are not able to administer satralizumab SC by themselves, support by a caregiver/nurse is advised). | Drug: Satralizumab 120 mg<br>* Satralizumab 120 mg will be administered as monotherapy (SC) in the abdominal or femoral region at Weeks 0, 2 (±3 days), 4 (±3 days), and then every 4 weeks (±3 days) till the last administration at Week 92 followed by a clinical evaluation at Week 96. The first dose at Weeks 0 (baseline visit) will be administered at the study site by the designated site staff during the scheduled study visit. The next dose at Week 2 will be self-administered by the patient under the supervision of a designated study staff at the study site. All the subsequent doses will be self-administered by the patient following training from a healthcare provider (for patients who are not able to administer satralizumab SC by themselves, support by a caregiver/nurse is advised).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of relapse-free patients |  | Up to Week 96 | 
| Annualized relapse rate (ARR) |  | Up to Week 96 | 
| Time to first relapse (TFR) |  | Up to Week 96 | 
| Mean change from baseline in Expanded Disability Status Scale (EDSS) score over the course of the study | The Expanded Disability Status Scale ranges from 0 to 10 in 0.5 unit increments. Higher results represent higher levels of disability. | Baseline (Day -28 to Day -1) to Week 96 | 
| Time to onset of confirmed disability progression (CDP) sustained for at least 12 weeks and 24 weeks |  | Baseline (Day -28 to Day -1) to Week 96 | 
| Change from baseline in the Symbol Digital Modalities Test (SDMT) over the course of the study |  | Baseline (Day -28 to Day -1) to Week 96 | 
| Change in high-contrast (100%) and lowcontrast (2.5%) visual acuity using appropriate high-and low-contrast letter acuity (LCLA) charts over the course of the study |  | Baseline (Day -28 to Day -1) to Week 96 | 
| Proportion of participants hospitalized due to relapse |  | Up to Week 96 | 
| Proportion of participants using corticosteroids due to relapse |  | Up to Week 96 | 
| Proportion of participants in need of rescue therapy due to relapse |  | Up to Week 96 | 
| Proportion of participants in need of plasma exchange due to relapse |  | Up to Week 96 | 
| Proportion of participants with disability (measured by Expanded Disability Status Scale EDSS) due to relapse |  | Up to Week 96 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Count, volume and regional distribution of T2-weighted fluid-attenuated inversion-recovery (FLAIR) hyperintense lesions | Including new and enlarging lesions of the cerebrum, optic nerves, optic chiasm, area postrema, brainstem and cerebellum; Fazekas scoring | Up to Week 96 | 
| Global and regional brain volume loss including basal ganglia, cerebellum and upper cervical spinal cord. |  | At Screening, Weeks 48 and 96 | 
| New and persisting short T1 inversion recovery (STIR)/Proton Density (PD) hyperintense lesions and T1-weighted contrast enhancement |  | Up to Week 96 | 
| Quantitative T1 mapping (magnetizationprepared rapid gradient echo sequence [MP2RAGE]) |  | Up to Week 96 | 
| Quantitative diffusion/diffusion tensor imaging (DTI) |  | Up to Week 96 | 
| Change in the retinal nerve fiber layer (RNFL) thickness |  | Baseline (Day -28 to Day -1) to Week 96 | 
| Change in the ganglion cell plus inner plexiform (GCIP) layer thickness |  | Baseline (Day -28 to Day -1) to Week 96 | 
| Incidence and severity of adverse events (AEs), serious AEs (SAEs) and AEs of special interest (AESIs) |  | Up to Week 96 |