The ExTINGUISH Trial of Inebilizumab in NMDAR Encephalitis

Study Overview
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Brief Summary
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Determine the difference in the modified Rankin score at 16 weeks in participants with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis treated with first-line immunomodulatory therapies provided as standard-of-care, and either inebilizumab (investigational agent) or placebo.

Detailed Description
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N-methyl-D-aspartate receptor (NMDAR) encephalitis is one of the most common causes of autoimmune encephalitis, with prevalence exceeding herpes encephalitis in industrialized nations. Typically, the disease affects patients age 10-50 causing prominent psychiatric symptoms, altered consciousness, seizures, movement disorders and life-threatening dysautonomia. Intensive care, including cardiorespiratory support is required in 75% of cases. The diagnosis is confirmed by detection of IgG autoantibodies against central nervous system NMDAR in the cerebrospinal fluid. Despite the severity of the illness, NMDAR encephalitis is a treatable neurological disease, with retrospective case series establishing the benefit of off-label intravenous steroids and immunoglobulins. These treatments are presumed to work through effects on IgG NMDAR autoantibody levels in the CSF, although prospective data informing predictors of treatment responses are limited. Even with prompt treatment,  50% of patients remain disabled, requiring prolonged hospital admissions. Various off-label therapies have been proposed as second-line treatments in NMDAR encephalitis. The majority of second-line treatments target circulating B-cells with various degrees of blood brain penetrance and efficacy, and poor consensus on the timing, dose and route of delivery of candidate agents. High-quality evidence is needed to inform the treatment of NMDAR encephalitis. Inebilizumab is a promising therapeutic monoclonal antibody for the treatment of NMDAR encephalitis. This humanized monoclonal antibody against the B-cell surface antigen CD19 was recently shown to be safe and efficacious in the treatment of neuromyelitis optica spectrum disorder-another antibody-mediated disorder of the central nervous system. Compared to other off label B-cell depleting therapies, such as rituximab, inebilizumab not only depletes CD20+ B-cells, but also CD20- plasmablasts and plasma cells, resulting in robust and sustained suppression of B-cell expression. The ExTINGUISH Trial will randomize 116 participants with moderate-to-severe NMDAR encephalitis to receive either inebilizumab or placebo in addition to first-line therapies. Patient outcomes will be ascertained at standard intervals using the modified Rankin scale and accepted safety measures (primary outcomes at 16 weeks), together with comprehensive validated neuropsychological tests, bedside cognitive screening tools, quality of life/ functional indices, and outcome prediction measures. Clinical data will be combined with quantitative measures of NMDAR autoantibody titers and cytokines implicated in B-cell activation and antibody production within the intrathecal compartment to identify treatment responders, inform the biologic contributors to outcomes, and evaluate for biomarkers that may serve as early predictors of favorable outcomes in future clinical trials in NMDAR encephalitis. The ExTINGUISH Trial will prospectively study an optimized B-cell depletion therapy to promote better long-term outcomes in NMDAR encephalitis, to determine more meaningful cognitive endpoints, and to identify better biologic biomarkers to predict outcome.

Official Title
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A Phase-2b, Double-Blind, Randomized Controlled Trial to Evaluate the Activity and Safety of Inebilizumab in Anti-Nmda Receptor Encephalitis and Assess Markers of Disease

Conditions
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Autoimmune Encephalitis, Encephalitis

Intervention / Treatment
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* Drug: Inebilizumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion Criteria 1. Diagnosis of NMDAR encephalitis, defined by both (a) and (b): A subacute onset of change in mental status consistent with autoimmune encephalitis, A positive cell-based assay for anti-NMDA receptor IgG antibody in the CSF confirmed in study-specified laboratories. 2. Age ≥ 18 years 3. Written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act [HIPAA] in the United States of America (USA), European Union [EU] Data Privacy Directive in the EU) obtained from the participant/legal representative prior to performing any protocol-related procedures, including screening evaluations. 4. Females of childbearing potential who are sexually active with a nonsterilized male partner must agree to use a highly effective method of contraception beginning at screening or upon discharge from hospitalization/inpatient rehabilitation (for participants who were incapacitated at the time of screening), and to continue precautions for 6 months after the final dose of investigational product. 5. Nonsterilized males who are sexually active with a female partner of childbearing potential must agree to use a highly effective method of contraception at screening or upon discharge from hospitalization/inpatient rehabilitation (for participants who were incapacitated at the time of screening), and to continue precautions for 3 months after the final dose of investigational product. Male patients with female partners of childbearing potential must have that female partner use at least one form of highly effective contraception, starting at least one menstrual cycle before (the male patient's) first study drug administration and continuing until at least 3 months after their male partner's last dose of the study drug. 6. Willing to forego other immunomodulatory therapies (investigational or otherwise) for NMDAR encephalitis during the study. 7. Patient must have received at least 3 days of methylprednisolone 1000 mg IV or equivalent corticosteroid within 30 days prior to randomization (Day 1). In addition, patients must have received EITHER of the following treatments within 30 days before randomization. IVIg, at a minimum dose of 2 g/kg Plasma exchange or plasmapheresis, with a minimum of 5 treatments. NOTE: These treatments may be provided during the screening period, but must be completed prior to randomization. 8. mRS of ≥3 at the screening visit, indicating at least moderate disability. 9. Ability and willingness to attend study visits and complete the study Exclusion Criteria: Any condition that, in the opinion of the investigator, would interfere with the evaluation or administration of the investigational product, interpretation of participant safety or study results, or would make participation in the study an unacceptable risk. This specifically includes recent history (last 5 years) of herpes simplex virus encephalitis or known central nervous system demyelinating disease (e.g., multiple sclerosis). Presence of an active or chronic infection that is serious in the opinion of the investigator. Concurrent/previous enrollment in another clinical study involving an investigational treatment within 4 weeks or 5 published half-lives of the investigational treatment, whichever is the longer, prior to randomization. Lactating or pregnant females, or females who intend to become pregnant anytime from study enrollment to 6 months following last dose of investigational agent. Known history of allergy or reaction to any component of the investigational agent formulation or history of anaphylaxis following any biologic therapy. At screening (one repeat test may be conducted to confirm results prior to randomization within the same screening period), any of the following: Aspartate transaminase (AST) > 2.5 × upper limit of normal (ULN) Alanine transaminase (ALT) > 2.5 × upper limit of normal (ULN) Total bilirubin > 1.5 × ULN (unless due to Gilbert's syndrome) Platelet count < 75,000/μL (or < 75 × 109/L) Hemoglobin < 8 g/dL (or < 80 g/L) Total white blood count <2,500 cells/mm3 Total immunoglobulin < 600 mg/dL Absolute neutrophil count < 1200 cells/μL CD4 T lymphocyte count < 300 cells/µL Receipt of the following at any time prior to randomization: Alemtuzumab Total lymphoid irradiation Bone marrow transplant T-cell vaccination therapy Receipt of rituximab or any experimental B-cell depleting agent, unless the CD19 B-cell level has returned to above the lower limit of normal prior to randomization. Receipt of any of the following within 3 months prior to randomization Natalizumab (Tysabri®) Cyclosporine Methotrexate Mitoxantrone Cyclophosphamide Azathioprine Mycophenolate mofetil Severe drug allergic history or anaphylaxis to two or more food products or medicines (including known sensitivity to acetaminophen/paracetamol, diphenhydramine or equivalent antihistamine, and methylprednisolone or equivalent glucocorticoid). Known history of a primary immunodeficiency (congenital or acquired) or an underlying condition such as human immunodeficiency virus (HIV) infection or splenectomy that predisposes the participant to infection. 13. Confirmed positive test for hepatitis B serology (hepatitis B surface antigen and core antigen) and/or hepatitis C PCR positive at screening. 14. History of cancer, apart from ovarian or extra-ovarian teratoma (also known as a dermoid cyst) or germ cell tumor, or squamous cell carcinoma of the skin or basal cell carcinoma of the skin. Squamous cell and basal cell carcinomas should be treated with documented success of curative therapy > 3 months prior to randomization. 15. Any live or attenuated vaccine within 3 weeks prior to Day 1 (administration of killed vaccines is acceptable). 16. Bacillus of Calmette and Guérin (BCG) vaccine within 1 year of enrollment. 17. Recurrence of previously treated NMDAR encephalitis within the last 3 or 5 years, or suspicion of symptomatic untreated NMDAR encephalitis of greater than 3 months duration at the time of screening.

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Active Comparator: Inebilizumab<br>Approximately 58 patients will receive Inebilizumab in addition to first line immunotherapy. (Approximately 116 participants will be randomized in a 1:1 ratio to 2 treatment groups; approximately 58 participants to each treatment group). All participants will also receive a 3 day course of IVIg. | Drug: Inebilizumab<br>* RCP: Blinded treatment on Day 1, Day 15, Inebilizumab group: Inebilizumab 300 mg intravenous (IV) Placebo group: IV matching placebo Prior to enrollment, all participants will receive standard of care, including high-dose corticosteroids (minimum of 3 days of treatment, 1 g methylprednisolone daily or equivalent) AND either IVIg (total dose range between 1.2 and 2 g/kg) OR plasmapheresis (defined as 5 or 6 exchanges). Rescue therapy will be given to participants in either treatment group based on the results of the Week 6 assessments. Rescue therapy is cyclophosphamide 750 mg/m2 IV followed by additional doses every 28-30 days until the mRS score is ≤ 3 (at site Principal Investigator's discretion under standard of care).<br>* Other names: UPLIZNA;|
| Placebo Comparator: Placebo<br>Approximately 58 patients will receive placebo in addition to first line immunotherapy. (Approximately 116 participants will be randomized in a 1:1 ratio to 2 treatment groups; approximately 58 participants to each treatment group). All participants will also receive a 3 day course of IVIg. | Drug: Placebo<br>* The placebo group will receive IV matching placebo on Day 1 and Day 15,<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of modified Rankin score at 16 weeks | Change in modified Rankin score (mRS) (0 to 6; 0=normal and 6=death) at 16 weeks determined by rank analyses, integrating need for rescue therapy and time to achievement of the mRS. | 16 weeks | 
| Inebilizumab safety measures by the number of treatment-emergent adverse events and serious adverse events | Inebilizumab safety, as measured by the number of treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs) | 96 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to mRS ≤ 2, corrected for baseline value. | Time to mRS ≤ 2, corrected for baseline value. | 96 weeks | 
| Clinical Assessment Scale in Autoimmune Encephalitis (CASE) Score (continuous logistic regression), corrected from baseline value to week 24 (weeks 6 and 16). | Clinical Assessment Scale in Autoimmune Encephalitis (CASE) Score (ranges of 0 to 27 with 0 being normal and 27 being worse)(continuous logistic regression), corrected from baseline value to week 24 (weeks 6 and 16). | 16 weeks | 
| mRS at week 6 as measured by proportional odds logistic regression/shift analysis. | mRS at week 6 as measured by proportional odds logistic regression/shift analysis. | 6 weeks | 
| Proportion of participants who meet the protocol-defined criteria for needing rescue therapy at week 6. | Proportion of participants who meet the protocol-defined criteria for needing rescue therapy at week 6. | 6 weeks | 
| Cognitive outcome at week 24 as measured by mean scaled score on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) + components of Delis-Kaplan Executive Function System (D-KEFS). | Cognitive outcome at week 24 as measured by mean scaled score on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) + components of Delis-Kaplan Executive Function System (D-KEFS). | 24 weeks | 
| Survival as measured by a Kaplan-Meier analysis. | Survival as measured by a Kaplan-Meier analysis. | 96 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Inebilizumab, NMDAR encephalitis, Autoimmune Encephalitis, Rare Disease