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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 (Multicenter, Randomized, Double-blind, Active-controlled, Parallel Group Study)

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

40

Demographic data were well balanced between the NPB-01 group and the NPB-01-ME group. Overall, there were more female than male participants (57.5% vs 42.5%). The mean (SD) age was 53.9 (20.10) years overall. The majority of participants (28 participants [70.0%]) were < 65 years and 12 participants (30.0%) were >= 65 years of age.

A total of 77 participants were screened in Japan. 69 participants were eligible for first enrollment into the trial and received steroid pulse therapy as pre-treatment for 5 days. Finally, 40 participants were eligible for second enrollment and randomized to trial intervention (NPB-01 or NPB-01-ME: 20 participants for each group). All randomized participants in each treatment group completed the trial intervention treatment period. 7 participants each in the NPB-01 group and the NPB-01-ME group received an additional dose of NPB-01. The majority of randomized participants in the NPB-01 group (19 participants, 95.0%) and 14 participants (70.0%) in NPB-01-ME group completed the post-treatment observation period. The reported reasons for discontinuation from the post-treatment observation period by treatment group were voluntary withdrawal in the NPB-01 group (1 participant, 100%), and need or use of prohibited concomitant medication or therapy (3 participants, 50.0%), adverse events (1 participant, 16.7%), and lost to follow-up (1 participant, 16.7%) in the NPB-01-ME group.

The results of the trial demonstrated that NPB-01 was safe and well tolerated with TEAEs that were manageable and generally reversible. The frequency of TEAEs by PT was similar between intervention groups. The reported TEAEs with 15% or more in the NPB-01 group were rash, headache, deep vein thrombosis, and hepatic function abnormal (3 participants [15.0%] each). All TEAEs were mild or moderate in severity, with the exception of a participant who had a severe SAE of pyelonephritis in the NPB-01 group and a participant who had a severe SAE of cardiac failure acute in the NPB-01-ME group. The percentages of participants with TEAEs assessed as related to trial intervention by the investigator were similar between intervention groups (50.0% in the NPB-01 group and 65.0% in the NPB-01-ME group). The most frequently reported intervention-related TEAE in the NPB-01 group was rash, white blood cell count decreased, and hepatic function abnormal (2 participants [10.0%] each). No deaths were reported in the NPB-01 group. 1 participant (5.0%) in the NPB-01-ME group had a TEAE resulting in death. The percentages of participants with a treatment-emergent SAE were the same between intervention groups (20.0%, 4 participants each). 2 SAEs (gastric ulcer haemorrhage and pyelonephritis) in the NPB-01 group were assessed as related to trial intervention by the investigator. The percentages of participants with TEAEs leading to discontinuation of trial intervention were the same between intervention groups (5.0%, 1 participant each).

In all FAS participants who tested positive for any cell-surface antigen antibodies, the proportion of responders based on the CASE score at Week 4 was 57.1% (4 of 7 participants, 95% CI: 18.405, 90.101) in the NPB-01 group and 0% (0 of 3 participants, 95% CI: 0.000, 70.760) in the NPB-01-ME group. The difference in the proportion of responders based on the CASE score at Week 4 was 57.1 (95%CI: -22.884, 90.570). The proportion of responders in the NPB-01 group was higher than that in the NPB-01-ME group. The mean (SD) change from baseline in CASE score at the each timepoint (Week 1, 2, 3, 4, 6, 8, and 12) was -1.1 (0.90), -1.9 (1.86), -2.0 (2.00), -2.3(1.89), -3.1 (1.86), -3.1 (2.19), and -3.4 (2.15) in the NPB-01 group and -0.7 (2.08), -1.7 (2.08), -2.0 (2.65), -2.3 (1.53), -3.3 (1.53), -4.7 (2.89), -5.3 (4.04) the NPB-01-ME group respectively in all FAS participants who tested positive for any cell-surface antigen antibodies. The percentages of categorized CASE scores (excellent [0-4], moderate [5-9], and poor [10-27]) in the NPB-01 group were 100% 'moderate'(all 7 participants) and in the NPB-01-ME group were 66.7% 'moderate' (2 of 3 participants) at baseline in all FAS participants who tested positive for any cell-surface antigen antibodies. The percentages of categorized CASE scores (excellent/moderate/poor) at each timepoint (Week 1, 2, 3, 4, 6, 8,and 12) was 28.57/71.43/0% (Week 1),42.86/57.14/0%(Week 2),57.14/42.86/0% (Week 3), 57.1/42.9/0% (Week 4),85.71/14.29/0% (Week 6), 85.71/14.29/0% (Week 8), 85.71/14.29/0% (Week 12) in the NPB-01 group and 0%/66.67/33.33% (Week 1), 0%/66.67/33.33% (Week 2), 0/100/0% (Week 3), 33.33/33.33/33.33% (Week 4), 33.33/66.67/0% (Week 6), 33.33/66.67/0% (Week 8), 66.67/33.33/0% (Week 12) the NPB-01-ME group respectively in all FAS participants who tested positive for any cell-surface antigen antibodies. The estimated median time to CASE score improvement (decrease to 4 or less) was 20.0 days (95% CI: 8.0, NA) in the NPB-01 group in all FAS participants who tested positive for any cell-surface antigen antibodies. It was not possible to estimate median time to CASE score improvement in the NPB-01-ME group due to the small number of participants and cumulative rate of improvement of less than 50%. The mean (SD) change from baseline in mRS at the each timepoint (Week 1, 2, 3, 4, 6, 8,and 12) was 0.0 (0.58), -0.7 (0.76), -0.9 (1.07), -0.9 (0.69), -0.9 (0.69), -1.0 (0.58), -1.3 (0.95) in the NPB-01 group and 0.0 (0.00), 0.0 (0.00), 0.0 (0.00), -0.3 (0.58), -0.3 (0.58), -0.7 (0.58), -0.7 (0.58) the NPB-01-ME group respectively in all FAS participants who tested positive for any cell-surface antigen antibodies. The mean (SD) change from baseline in GCS at each timepoint (Week 1, 2, 3, 4, 6, 8,and 12) was 0.1 (1.82), 0.3 (1.30), 0.1 (2.02), 0.4 (1.31), 0.6 (0.98), 0.4 (2.19), 0.6 (1.50) in the NPB-01 group and 0.1 (1.07), 0.3 (1.45), 0.3 (1.40), 0.7 (0.90), 0.6 (0.83), 0.7 (0.98), 0.6 (1.09) the NPB-01-ME group respectively in FAS. The mean (SD) change from baseline in MMSE-J at each timepoint (Week 4, 8,and 12) was 1.7 (2.60), 2.4 (2.34), 2.1 (2.29) in the NPB-01 group and (1.4 (8.80), 4.5 (6.51), 5.1 (6.59) the NPB-01-ME group respectively in FAS. The mean (SD) change from baseline in FAB at each timepoint (Week 4, 8,and 12) was 1.3 (2.23), 1.7 (2.58), 1.4 (2.06) in the NPB-01 group and 1.3 (4.52), 2.8 (4.83), 3.0 (4.71) the NPB-01-ME group respectively in FAS. The number of participants with abnormal EEG findings at baseline which returned to normal at Week 4 in FAS was 4 of 16 participants in the NPB-01 group and 2 of 15 participants in the NPB-01-ME group. Although the difference between the treatment groups was not so large, the proportion of participants in the NPB-01 group who resolved to normal EEG at Week 4 was greater than the NPB-01-ME group. Among participants with abnormal EEG findings at baseline, the number of participants who resolved to normal EEG at Week 12 was 4 of 15 participants in the NPB-01 group and 5 of 11 participants in the NPB-01-ME group. The number of participants with abnormal head MRI findings at baseline which returned to normal at Week 4 in FAS was 4 of 20 participants in the NPB-01 group and 1 of 19 participants in the NPB-01-ME group. Although the difference between the treatment groups was not so large, the proportion of participants in the NPB-01 group who resolved to normal MRI at Week 4 was greater than that of the NPB-01-ME group. Among participants with abnormal head MRI findings at baseline (pre-treatment), the number of participants who resolved to normal MRI at Week 12 was 4 of 18 participants in the NPB-01 group and 2 of 15 participants in the NPB-01-ME group. Among participants whose CSF examination (cell count) was not within normal limits (greater than 5/mcrL) at baseline, the number of participants who returned to within normal limits (5/mcrL or less) at Week 4 in FAS was 1 of 4 participants in the NPB-01 group and 2 of 7 participants in the NPB-01-ME group. The number of participants who returned to within normal limits (5/mcrL or less) at Week 12 was all 3 participants in the NPB-01 group and 4 of 5 participants in the NPB-01-ME group. Among participants whose CSF examination (protein count) was not within normal limits (outside of range 15.0 to 45.0 mg/dL) at baseline, the number of participants who returned to within normal limits (15.0 to 45.0 mg/dL) at Week 4 was 1 of 7 participants in the NPB-01 group and 2 of 4 participants in the NPB-01-ME group. The number of participants who returned to within normal limits (15.0 to 45.0 mg/dL) at Week 12 was 1 of 6 participants in the NPB-01 group and 0 of 4 participants in the NPB-01-ME group. The estimated median time to discharge in FAS was 62.0 days (95% CI: 22.0, 90.0) in the NPB-01 group. It was not possible to estimate the median time to discharge in the NPB-01-ME group due to the small number of participants and the cumulative rate of hospitalization staying greater than 50%. Spearman's rank correlation coefficient at baseline (pre-treatment) and each timepoint (Week 1, 2, 3, 4, 6, 8, 12) on FAS in the NPB-01 group were 0.8198, 0.7787, 0.8510, 0.8472, 0.8720, 0.8539, 0.9039, 0.9510. Spearman's rank correlation coefficient at baseline (pre-treatment) and each timepoint (Week 1, 2, 3, 4, 6, 8, 12) in the NPB-01-ME group were 0.7239, 0.6491, 0.7218, 0.7532, 0.6793, 0.7783, 0.7781, 0.8559, respectively. The mean (SD) serum IgG concentration in all FAS participants who tested positive for any cell-surface antigen antibodies at baseline, Week 1, 2, 3, 4, 6, 8,and 12 were 983.7 (126.69), 775.0 (258.05), 1106.3 (610.75), 1386.0 (1034.18), 1447.7 (1113.17), 1507.0 (989.93), 1255.0 (513.15), 1135.3 (230.56) mg/dL in the NPB-01-ME group, respectively. Refer to the attached document on this record for the results of the following outcome measures: - Number of Participants With mRS Score of 2 or Less - Number of Participants With Improvement to a mRS Score of 2 or Less From Baseline - Number of Participants With Improvement in mRS Score by 1 or More From Baseline - Number of Participants With Improvement in mRS Score by 2 or More From Baseline - Time to Improvement in mRS Score - Number of Participants With Categorized GCS Scores - Time to Improvement in GCS Score Brief Summary (Cont') The primary efficacy endpoint of the proportion of responders based on the CASE score at week 4 in the surface antibody positive participants was met; the response rate was higher in the NPB-01 group than in the NPB-01-ME group. Secondary endpoints using different outcome metrics generally supported the primary endpoint findings.

NPB-01 at 400 mg/kg/day for 5 consecutive days confirmed clinical benefit in participants with autoimmune encephalitis refractory to steroid pulse therapy. Overall, NPB-01 has a favorable benefit/risk profile and was shown to be safe and well tolerated in this participant population. No new safety signals were identified and data obtained was consistent with already well-established safety profile of NPB-01.

Yes

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

https://jrct.mhlw.go.jp/latest-detail/jRCT2061210070

Ota Mamoru

Nihon Pharmaceutical Co., Ltd.

8-1, Akashi-cho, Chuo-ku, Tokyo 104-0044 JAPAN

kaihatsu@nihon-pharm.co.jp

Nihon Pharmaceutical Co., Ltd. Research and Development division

Nihon Pharmaceutical Co., Ltd.

8-1, Akashi-cho, Chuo-ku, Tokyo 104-0044 JAPAN

+81-3-5148-7570

kaihatsu@nihon-pharm.co.jp

Complete

Mar. 03, 2022

Interventional

randomized controlled trial

double blind

active control

parallel assignment

treatment purpose

1) Patients aged 15 years or older at the time of informed consent
2) Patients who meet any of the following (1) to (6):
(1) Definite diagnostic criteria for autoimmune limbic encephalitis
(2) MRI evidence of demyelination (probable autoimmune encephalitis)
(3) Probabilistic diagnostic criteria for anti-NMDAR encephalitis
(4) Probabilistic diagnostic criteria for Bickerstaff brainstem encephalitis
(5) Probabilistic diagnostic criteria for Hashimoto's encephalopathy
(6) Diagnostic Criteria for Autoimmune Encephalitis with Negative but Probable Autoantibodies
3) CASE score of 5 to 22
4) Patients who have had an inadequate response to steroid pulse therapy

1) Patients with strongly suspected infectious encephalitis
2) Patients who received immunoglobulin preparations within 8 weeks prior to informed consent
3) Patients who received plasma exchange within 4 weeks prior to informed consent
4) Patients who received immunosuppressants (Rituximab, cyclophosphamide, etc.) within 4 weeks prior to informed consent
5) Patients who have had tumor resection associated with autoimmune encephalitis within 4 weeks prior to informed consent
6) Patients with a history of shock or hypersensitivity to the ingredients of NPB-01
7) Patients with known IgA deficiency
8) Patients with renal disorder
9) 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.)
10) Patients at high risk of thromboembolism
11) Patients with haemolytic/blood loss anaemia
12) Immunosuppressed/immunocompromised patients
13) Patients with decreased cardiac function
14) Pregnant, expected (desired or planned) pregnant, or breastfeeding patients
15) Use of prohibited medications or treatment in this study
16) Patients who received investigational product in this study (re-enrollment prohibited)
17) Patients who have received treatment with investigational product other than this study within 4 months prior to informed consent
18) Patients with a history of hypersensitivity to methylprednisolone sodium succinate
19) Patients who have a tumor associated with autoimmune encephalitis and are considered to require resection during the study period.
20) Patients receiving intravenous general anesthetics or sedative hypnotics
21) Patients in coma
22) Ventilated patients
23) Patients who cannot undergo protocol-specified tests/assessments
24) Other patients considered ineligible for the study by the investigator or subinvestigator
25) Positive herpes simplex virus DNA qualitative test in the screening period.
26) Serum creatinine 2 times or more the upper limit of normal during the screening period.
27) Total protein 9 g/dL or more during the screening period.
28) Patients with hematocrit 55% or more during the screening period

Both

Autoimmune Encephalitis

- Experimental: NPB-01: Intravenous immunoglobulin
- 400 mg(8mL) /kg/d (max 1g/d) , 5 consecutive days, IV administration
- Active Comparator: NPB-01-ME: Methylprednisolone sodium succinate
- 30 mg/kg/d (max 1g/d) 5 consecutive days, IV administration

D004660

1. Percentage of Responders Based on Clinical Assessment Scale in Autoimmune Encephalitis (CASE) Score at Week 4 of the Post-Treatment Observation Period
Timeframe: Week 4
A responder was defined as a participant whose CASE (Clinical Assessment Scale in Autoimmune Encephalitis) score at Week 4 of the post-treatment observation period after study treatment with investigational product improved by 40% or more compared to the pre-treatment. The CASE score is an assessment index created to evaluate the symptoms of autoimmune encephalitis and consists of 9 items (seizures, memory dysfunction, psychiatric symptoms, consciousness, language problems, dyskinesia/dystonia, gait instability and ataxia, brainstem dysfunction, and weakness). Each item is assigned a value of up to 3 points, and the total score ranges from 0 to 27. A higher score indicates greater severity of autoimmune encephalitis.

1. Change From Baseline in CASE Score
Timeframe: Pre-treatment (Baseline), Week 1, 2, 3, 4, 6, 8, 12

2. Number of Participants in Each Categorized CASE Score
Timeframe: Pre-treatment (Baseline), Week 1, 2, 3, 4, 6, 8, 12
Number of participants in each category of CASE score (0 - 4: excellent, 5 - 9: moderate, 10 - 27: poor) at each time point was reported.

3. Time to CASE Score Improvement
Timeframe: Up to 12 weeks from the start of treatment period
Time from the start of treatment with study drug until CASE score improvement was reported. CASE score improvement was defined as decrease to 4 or less of the CASE score.

4. Change From Baseline in Modified Rankin Scale (mRS) Score
Timeframe: Pre-treatment (Baseline), Week 1, 2, 3, 4, 6, 8, 12
The mRS score is a general prognostic scale for stroke patients and consists of 7 scales (0: Completely asymptomatic to 6: Death) and the total score ranges from 0 to 6. A higher score indicates greater severity of stroke.

5. Change from Baseline in Glasgow Coma Scale (GCS) Score
Timeframe: Pre-treatment (Baseline), Week 1, 2, 3, 4, 6, 8, 12
The GCS score was used as an assessment index for level of consciousness. GCS quantifies three components: eye opening, verbal response, and motor response, and evaluates consciousness levels based on the total score. Total score ranges from 0 to 15. Lower scores indicate greater severity, and a score of 8 or less is considered severe.

6. Change From Baseline in Mini-Mental State Examination-Japanese (MMSE-J) Score
Timeframe: Pre-treatment (Baseline), Week 4, 8, 12
MMSE-J is the Japanese version of the MMSE (Mini-Mental State Examination), used dementia screening test. MMSE-J consists of questions related to 11 categories measuring cognitive function: orientation to time, orientation to place, registration, attention and calculation, recall, naming, repetition, comprehension, reading, writing, and drawing. Scores range from 0 to 30 with lower values indicating greater impairment.

7. Change From Baseline in Frontal Assessment Battery (FAB) Score
Timeframe: Pre-treatment (Baseline), Week 4, 8, 12
FAB is a test that evaluates frontal lobe functions, particularly executive function, attention, and language abilities. FAB consists of six items that evaluate similarities, language fluency, motor programming, sensitivity to interference, inhibitory control, and comprehension actions. Scores range from 0 to 18 (0 to 3 for each category) with lower values indicating greater impairment.

8. Number of Participants with Abnormal Electroencephalography (EEG) Findings at Baseline which Returned to Normal
Timeframe: Week 4, 12

9. Number of Participants with Abnormal Head Magnetic Resonance Imaging (MRI) Findings at Baseline which Returned to Normal
Timeframe: Week 4, 12

10. Number of Participants With Cell Count from Cerebrospinal Fluid (CSF) Examination Outside of Normal Limits at Baseline Who Returned to Within Normal Limits
Timeframe: Week 4, 12
Number of participants with cell count from CSF examination outside of normal limits (greater than 5/microliter) at baseline who returned to within normal limits (5/microliter or less) at Week 4 and Week 12 was reported.

11. Number of Participants With Protein Count from Cerebrospinal Fluid (CSF) Examination Outside of Normal Limits at Baseline Who Returned to Within Normal Limits
Timeframe: Week 4, 12
Number of participants with protein count from CSF examination outside of normal limits at baseline who returned to within normal limits (15.0 to 45.0 mg/dL) at Week 4 and Week 12 was reported.

12. Length of Hospitalization
Timeframe: Up to 12 weeks from the start of treatment period
Length of hospitalization (days) was calculated as the day the participant left the hospital (if the participant was still hospitalized after completing the study, then the last day of observation) minus day of first dose of double-blind study drug administration plus 1. If the participant continued to be hospitalized until the last day of observation or if the participant died before leaving the hospital, the participant was censored on the last day of observation or on the date of death.

13. Correlation Between CASE Score and mRS
Timeframe: Baseline, Week 1, 2, 3, 4, 6, 8, 12
Spearman's rank correlation coefficient at baseline (pre-treatment), Week 4 and Week 12 of the Post-Treatment Observation Period were reported as correlation between CASE Score and mRS. Spearman's rank correlation coefficient is represented within the range from -1 to 1, where values closer to 1 indicate a strong positive correlation, and values closer to -1 indicate a strong negative correlation.

14. Serum IgG Concentration
Timeframe: Pre-treatment (Baseline), Week 1, 2, 3, 4, 6, 8, 12

15. Number of Participants With mRS Score of 2 or Less
Timeframe: Pre-treatment (Baseline), Week 1, 2, 3, 4, 6, 8, 12
Number of participants with mRS score of 2 or Less at each time point was reported.

16. Number of Participants With Improvement to a mRS Score of 2 or Less From Baseline
Timeframe: Pre-treatment (Baseline), Week 1, 2, 3, 4, 6, 8, 12
Number of participants with improvement to a mRS score of 2 or less at each time point from baseline was reported.

17. Number of Participants With Improvement in mRS Score by 1 or More From Baseline
Timeframe: Pre-treatment (Baseline), Week 1, 2, 3, 4, 6, 8, 12
Number of participants with improvement in mRS score by 1 or more at each time point from baseline was reported.

18. Number of Participants With Improvement in mRS Score by 2 or More From Baseline
Timeframe: Pre-treatment (Baseline), Week 1, 2, 3, 4, 6, 8, 12
Number of participants with improvement in mRS score by 2 or more at each time point from baseline was reported.

19. Time to Improvement in mRS Score
Timeframe: Up to 12 weeks from the start of treatment period
Time to improvement in mRS score (improvement to a score of 2 or less, improvement in score by 1 or more, and improvement in score by 2 or more) from baseline (the start of treatment with investigational product) was reported.

20. Number of Participants in Each Categorized GCS Score
Timeframe: Pre-treatment (Baseline), Week 1, 2, 3, 4, 6, 8, 12
Number of participants in each category of GCS score (13 - 15: mild, 9 - 12: moderate, 3 - 8: severe) at each time point was reported.

21. Time to Improvement in GCS Score
Timeframe: Up to 12 weeks from the start of treatment period
Time to improvement in GCS score (increase in GCS score to 13 or more) from baseline (the start of treatment with investigational product) was reported.

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