Phase III Clinical Study of NPB-01 in Patients With Autoimmune Encephalitis

Study Overview
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Brief Summary
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To compare the efficacy and safety of NPB-01 in patients with autoimmune encephalitis refractory to steroid pulse therapy using steroid pulse therapy as a control.

Official Title
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Phase III Study to Evaluate the Efficacy and Safety of NPB-01 in Patients With Autoimmune Encephalitis Refractory to Steroid Pulse Therapy

Conditions
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Autoimmune Encephalitis

Intervention / Treatment
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* Drug: NPB-01
* Drug: NPB-01-ME


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria < At 1st registration > Patients meeting the possible diagnostic criteria for autoimmune encephalitis < At 1st registration > Patients with a CASE score of 5 to 22 during the screening period < At 1st registration > Patients with autoimmune encephalitis in progress (active and requiring therapeutic intervention) < At 1st registration > IVIG therapy and steroid pulse therapy are considered necessary by the investigator. < At 1st registration > Patients aged 15 years or older at the time of informed consent < At 2nd registration > Patients who meet any of the following (1) to (6): Definite diagnostic criteria for autoimmune limbic encephalitis MRI evidence of demyelination (probable autoimmune encephalitis) Probabilistic diagnostic criteria for anti-NMDAR encephalitis Probabilistic diagnostic criteria for Bickerstaff brainstem encephalitis Probabilistic diagnostic criteria for Hashimoto's encephalopathy Diagnostic Criteria for Autoimmune Encephalitis with Negative but Probable Autoantibodies < At 2nd registration > CASE score of 5 to 22 on Day 8 of the previous treatment period < At 2nd registration > Patients who have had an inadequate response to steroid pulse therapy Exclusion Criteria: < At 1st registration > Patients with strongly suspected infectious encephalitis < At 1st registration > Patients who received immunoglobulin preparations within 8 weeks prior to informed consent < At 1st registration > Patients who received plasma exchange within 4 weeks prior to informed consent < At 1st registration > Patients who received immunosuppressants (Rituximab, cyclophosphamide, etc.) within 4 weeks prior to informed consent < At 1st registration > Patients who have had tumor resection associated with autoimmune encephalitis within 4 weeks prior to informed consent < At 1st registration > Patients with a history of shock or hypersensitivity to the ingredients of NPB-01 < At 1st registration > Patients with known IgA deficiency < At 1st registration > Patients with renal disorder < At 1st registration > Patients with a current or previous history of cerebral or cardiovascular disorders (Asymptomatic cerebral infarction and myocardial infarction that occurred more than 5 years ago are not applicable.) < At 1st registration > Patients at high risk of thromboembolism < At 1st registration > Patients with haemolytic/blood loss anaemia < At 1st registration > Immunosuppressed/immunocompromised patients < At 1st registration > Patients with decreased cardiac function < At 1st registration > Pregnant, expected (desired or planned) pregnant, or breastfeeding patients < At 1st registration > Use of prohibited medications or treatment in this study < At 1st registration > Patients who received investigational product in this study (re-enrollment prohibited) < At 1st registration > Patients who have received treatment with investigational product other than this study within 4 months prior to informed consent < At 1st registration > Patients with a history of hypersensitivity to methylprednisolone sodium succinate < At 1st registration > Patients who have a tumor associated with autoimmune encephalitis and are considered to require resection during the study period. < At 1st registration > Patients receiving intravenous general anesthetics or sedative hypnotics < At 1st registration > Patients in coma < At 1st registration > Ventilated patients < At 1st registration > Patients who cannot undergo protocol-specified tests/assessments < At 1st registration > Other patients considered ineligible for the study by the investigator < At 2nd registration > Positive herpes simplex virus DNA qualitative test in the screening period. < At 2nd registration > Serum creatinine ≥ 2 times the upper limit of normal during the screening period. < At 2nd registration > Total protein ≥ 9 g/dL during the screening period. < At 2nd registration > Patients with hematocrit ≥ 55% during the screening period < At 2nd registration > Patients who meet any of the exclusion criteria at the time of first registration

Ages Eligible for Study
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Minimum Age: 15 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: NPB-01<br>Intravenous immunoglobulin | Drug: NPB-01<br>* NPB-01 will be administered for the treatment of autoimmune encephalitis<br>* Other names: Intravenous immunoglobulin;|
| Active Comparator: NPB-01-ME<br>methylprednisolone sodium succinate | Drug: NPB-01-ME<br>* NPB-01-ME will be administered for the treatment of autoimmune encephalitis<br>* Other names: methylprednisolone sodium succinate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of responders in CASE (Clinical Assessment Scale in Autoimmune Encephalitis) | A responder is defined as a patient whose CASE score at Week 4 of the post-treatment follow-up period after treatment with investigational product improved by 40% or more compared to the pre-treatment period. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CASE | The change in CASE score at each time point after the start of treatment with investigational product compared with that on Day 8 of the pretreatment period will be compared between the arms. Changes in CASE scores divided into three segments (0 -4: excellent, 5 -9: moderate, 10 -27: poor) will also be compared. In addition, the period until CASE score becomes 4 points or less after the start of treatment with investigational product will be checked. | 1, 2, 3, 4, 6, 8, 12 weeks | 
| mRS | Changes in mRS at each time point after the start of investigational product treatment compared with Day 8 of the pretreatment period will be compared between the arms. | 1, 2, 3, 4, 6, 8, 12 weeks | 
| GCS | To compare the change in GCS at each time point after the start of investigational product with that on Day 8 of the pretreatment period between the arms. | 1, 2, 3, 4, 6, 8, 12 weeks | 
| MMSE-J | The change in MMSE-J at each time point after the start of investigational product as compared with Day 8 of the pretreatment period will be compared between the arms. | 4, 8, 12 weeks | 
| FAB | The change in FAB at each time point after the start of investigational product as compared with Day 8 of the pretreatment period will be compared between the arms. | 4, 8, 12 weeks | 
| Disappearance of abnormal EEG findings | The proportion of subjects in whom abnormal findings in EEG disappeared at each time point after the start of investigational product as compared with Day 8 of the pretreatment period will be compared between the arms. | 4, 12 weeks | 
| Disappearance of abnormal head MRI findings | The proportion of subjects in whom abnormal findings in head MRI disappeared at each time point after the start of investigational product as compared with Day 8 of the pretreatment period will be compared between the arms. | 4, 12 weeks | 
| Cerebrospinal fluid test | The proportion of subjects in whom the cell count returned to within the reference range (≤ 5/μl) and the proportion of subjects in whom the protein count returned to within the reference range (15.0   45.0 mg/dL) at each time point after the start of investigational product treatment as compared with Day 8 of the pretreatment period will be checked. | 4, 12 weeks | 
| Duration of hospitalization | Duration of hospitalization after the start of treatment with investigational product to be compared between the arms. | 12 weeks | 
| mRS proportion | The proportions of subjects with an mRS score of ≤ 2, subjects with an improvement of ≥ 1 point, and subjects with an improvement of ≥ 2 points will also be compared. Also, the time to mRS improvement after the start of treatment with investigational product (≤ 2 points, ≥ 1 point improvement, ≥ 2 points improvement) . | 1, 2, 3, 4, 6, 8, 12 weeks | 
| GCS proportion | Changes in GCS when divided into three segments (15-13: Mild, 12-9: Moderate, 8-3: Severe) will also be compared. In addition, the period until the GCS score reaches 13 or higher after the start of treatment with investigational product will be checked. | 1, 2, 3, 4, 6, 8, 12 weeks |