A Study To Evaluate The Efficacy, Safety, Pharmacokinetics, And Pharmacodynamics Of Satralizumab In Patients With Anti-N-Methyl-D-Aspartic Acid Receptor (NMDAR) Or Anti-Leucine-Rich Glioma-Inactivated 1 (LGI1) Encephalitis

Study Overview
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Brief Summary
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The purpose of this study is to assess the efficacy, safety, pharmacokinetics, and pharmacodynamics of satralizumab in participants with anti-N-methyl-D-aspartic acid receptor (NMDAR) and anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis.

Official Title
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A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Basket Study To Evaluate The Efficacy, Safety, Pharmacokinetics, And Pharmacodynamics Of Satralizumab In Patients With Anti-N-Methyl-D-Aspartic Acid Receptor (NMDAR) Or Anti-Leucine-Rich Glioma-Inactivated 1 (LGI1) Encephalitis

Conditions
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NMDAR Autoimmune Encephalitis, LGI1 Autoimmune Encephalitis

Intervention / Treatment
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* Drug: Satralizumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Reasonable exclusion of tumor or malignancy before baseline visit (randomization) Onset of autoimmune encephalitis (AIE) symptoms <=9 months before randomization Meet the definition of New Onset or Incomplete Responder AIE For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use adequate contraception during the treatment period and for at least 3 months after the final dose of satralizumab or placebo For participants enrolled in the extended China enrollment phase at National Medical Products Administration (NMPA)-recognized sites: participants who are current residents of mainland China, Hong Kong, or Taiwan, and of Chinese ancestry N-methyl-D-aspartic acid receptor (NMDAR) AIE Cohort Age >=12 years Diagnosis of probable or definite NMDAR encephalitis Leucine-rich glioma-inactivated 1 (LGI1) AIE Cohort Age >=18 years Diagnosis of LGI1 encephalitis Exclusion Criteria: Any untreated teratoma or thymoma at baseline visit (randomization) History of carcinoma or malignancy, unless deemed cured by adequate treatment with no evidence of recurrence for >=5 years before screening For patients with NMDAR AIE, history of negative anti-NMDAR antibody in cerebrospinal fluid (CSF) using a cell-based assay within 9 months of symptom onset Historically known positivity to an intracellular antigen with high cancer association or GAD-65 Historically known positivity to any cell surface neuronal antibodies other than NMDAR and LGI1 Confirmed paraneoplastic encephalitis Confirmed central or peripheral nervous system demyelinating disease Alternative causes of associated symptoms History of herpes simplex virus encephalitis in the previous 24 weeks Any previous/concurrent treatment with IL-6 inhibitory therapy (e.g., tocilizumab), alemtuzumab, total body irradiation, or bone marrow transplantation Any previous treatment with anti-CD19 antibody, complement inhibitors, neonatal Fc receptor antagonists, anti-B-lymphocyte stimulator monoclonal antibody Any previous treatment with T-cell depleting therapies, cladribine, or mitoxantrone Treatment with oral cyclophosphamide within 1 year prior to baseline Treatment with any investigational drug (including bortezomib) within 24 weeks prior to screening Concurrent use of more than one IST as background therapy Contraindication to all of the following rescue treatments: rituximab, IVIG, high-dose corticosteroids, or intravenous (IV) cyclophosphamide Any surgical procedure, except laparoscopic surgery or minor surgeries within 4 weeks prior to baseline, excluding surgery for thymoma or teratoma removal Planned surgical procedure during the study Evidence of progressive multifocal leukoencephalopathy Evidence of serious uncontrolled concomitant diseases that may preclude patient participation Congenital or acquired immunodeficiency, including HIV infection Active or presence of recurrent bacterial, viral, fungal, mycobacterial infection, or other infection Infection requiring hospitalization or treatment with IV anti-infective agents within 4 weeks prior to baseline visit Positive hepatitis B (HBV) and hepatitis C (HCV) test at screening Evidence of latent or active tuberculosis (TB) History of drug or alcohol abuse within 1 year prior to baseline History of diverticulitis or concurrent severe gastrointestinal (GI) disorders that, in the investigator's opinion, may lead to increased risk of complications such as GI perforation Receipt of live or live-attenuated vaccine within 6 weeks prior to baseline visit History of blood donation (1 unit or more), plasma donation or platelet donation within 90 days prior to screening 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 Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes safe participation in and completion of the study Pregnant or breastfeeding, or intending to become pregnant during the study or within 3 months after the final dose of study drug Laboratory abnormalities at Screening

Ages Eligible for Study
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Minimum Age: 12 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: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NMDAR autoimmune encephalitis (AIE) cohort<br>Adults and adolescents with definite or probable NMDAR encephalitis | Drug: Satralizumab<br>* In Part 1, study drug will be administered after all other study related procedures have been performed at a site visit at Weeks 0, 2, 4, and Q4W thereafter. Participants will receive satralizumab according to body weight. Study drug will be administered by SC injection in the abdominal or femoral region after all other study-related procedures have been performed at a site visit. In Part 2, participants will be asked to choose from one of the following options: Option 1: continue on randomized, double-blind study drug; Option 2: start open-label satralizumab based on body weight; Option 3: stop study treatment and continue follow-up assessments<br>|
| Experimental: LGI1 AIE cohort<br>Adults with LGI1 encephalitis | Drug: Satralizumab<br>* In Part 1, study drug will be administered after all other study related procedures have been performed at a site visit at Weeks 0, 2, 4, and Q4W thereafter. Participants will receive satralizumab according to body weight. Study drug will be administered by SC injection in the abdominal or femoral region after all other study-related procedures have been performed at a site visit. In Part 2, participants will be asked to choose from one of the following options: Option 1: continue on randomized, double-blind study drug; Option 2: start open-label satralizumab based on body weight; Option 3: stop study treatment and continue follow-up assessments<br>|
| Placebo Comparator: NMDAR autoimmune encephalitis (AIE) Placebo cohort<br>Adults and adolescents with definite or probable NMDAR encephalitis | Other: Placebo<br>* Satralizumab placebo PFS is identical in composition to satralizumab PFS, but does not contain the satralizumab active ingredient and will be identical in appearance and packaging to satralizumab. A PFS (assembled with an NSD and extended finger flange) filled with 0.5 mL of solution, corresponding to 60 mg satralizumab, may be used in Part 2 once it becomes available at the study site.<br>|
| Placebo Comparator: LGI1 AIE Placebo cohort<br>Adults with LGI1 encephalitis | Other: Placebo<br>* Satralizumab placebo PFS is identical in composition to satralizumab PFS, but does not contain the satralizumab active ingredient and will be identical in appearance and packaging to satralizumab. A PFS (assembled with an NSD and extended finger flange) filled with 0.5 mL of solution, corresponding to 60 mg satralizumab, may be used in Part 2 once it becomes available at the study site.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Proportion of participants with mRS score improvement ≥ 1 from baseline and no use of rescue therapy at Week 24 | mRS = Modified Rankin Scale | Baseline up to Week 24 | 
| Part 2: Percentage of participants with adverse events |  | From Week 52 up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Time to mRS score improvement ≥ 1 from baseline without use of rescue therapy | mRS = Modified Rankin Scale | Baseline up to Week 52 | 
| Part 1: Time to rescue therapy |  | Baseline up to Week 52 | 
| Part 1: Time to seizure freedom or cessation of status epilepticus without use of rescue therapy | Seizure freedom defined as a cessation of seizures for at least 6 consecutive weeks | Baseline up to Week 24 | 
| Part 1: Change in CASE score from baseline at Week 24 | CASE = Clinical Assessment Scale in Autoimmune Encephalitis | Baseline up to Week 24 | 
| Part 1: MOCA total score at Week 24 | MOCA = Montreal Overall Cognitive Assessment; | Baseline up to Week 24 | 
| Part 1: RAVLT score at Week 24 (LGI1 AIE cohort) | RAVLT = Rey Auditory Verbal Learning Test. | Baseline up to Week 24 | 
| Part 1: mRS score at Week 24 (as measured on a 7-point scale; NMDAR AIE cohort) | mRS = Modified Rankin Scale | Baseline up to Week 24 | 
| Part 1: Percentage of participants with adverse events | Severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 | Baseline, Week 52, 2 Years |