Efficacy and Safety of Low-Dose Blinatumomab in the Treatment of Refractory Autoimmune Encephalitis and Autoimmune Cerebellitis

Обзор

This is a multicenter, single-arm, continuous, prospective, interventional registry study designed to systematically evaluate the efficacy and safety of low-dose blinatumomab in patients with antibody-mediated refractory autoimmune encephalitis (AE) and autoimmune cerebellitis. Eligible participants will be patients with a confirmed diagnosis of refractory AE or autoimmune cerebellitis who have provided written informed consent. All enrolled patients will receive blinatumomab treatment according to a unified protocol, consisting of two cycles: Cycle 1 (Week 1): Continuous intravenous infusion at 9 µg/day for 5 consecutive days (total dose: 45 µg). Cycle 2 (Week 3): Continuous intravenous infusion at 9 µg/day for 5 consecutive days (total dose: 45 µg). If there is no improvement in the modified Rankin Scale (mRS) score at Week 3 and the proportion of peripheral blood B cells (CD3-/CD19+) remains \>1%, the dose may be optimized to 15 µg/m²/day (maximum 28 µg/day). During the study, all patients will undergo regular follow-up visits to collect data on clinical symptoms, functional scores, immunological biomarkers, and adverse events, to comprehensively assess the efficacy and safety of the treatment. This study uses a non-randomized, open-label design with no blinding or control group.

Вмешательства

• Препарат Blinatumomab
  Low-dose blinatumomab administered intravenously in two cycles: Cycle 1 (Week 1) at 9 μg/day for 5 consecutive days, and Cycle 2 (Week 3) at 9 μg/day for 5 consecutive days (45 μg per cycle). If no clinical improvement is observed at Week 3 and peripheral blood B-cell proportion (CD3-/CD19+) remains \>1%, the dose may be optimized to 15 µg/m²/day (maximum 28 µg/day).

Первичные конечные точки

• Proportion of participants with mRS score 0-2 [Срок оценки: Week 3 (±1 day), Week 4 (±1 day), Week 5 (±1 day), Week 6 (±1 day), Week 8 (±1 day), Week 12 (±1 day), Week 24 (±3 days), Week 36 (±5 days), Week 48 (±10 days)]
• Distribution of mRS scores [Срок оценки: Week 3 (±1 day), Week 4 (±1 day), Week 5 (±1 day), Week 6 (±1 day), Week 8 (±1 day), Week 12 (±1 day), Week 24 (±3 days), Week 36 (±5 days), Week 48 (±10 days)]
• Proportion of participants with mRS improvement ≥1 point [Срок оценки: Week 3 (±1 day), Week 4 (±1 day), Week 5 (±1 day), Week 6 (±1 day), Week 8 (±1 day), Week 12 (±1 day), Week 24 (±3 days), Week 36 (±5 days), Week 48 (±10 days)]
• Change in CASE score from baseline [Срок оценки: Week 3 (±1 day), Week 4 (±1 day), Week 5 (±1 day), Week 6 (±1 day), Week 8 (±1 day), Week 12 (±1 day), Week 24 (±3 days), Week 36 (±5 days), Week 48 (±10 days)]
• Relapse rate within 48 weeks [Срок оценки: Up to Week 48 (±10 days)]

Вторичные конечные точки (7)

• Changes in MMSE scores from baseline [Срок оценки: Week 3 (±1 day), Week 8 (±1 day), Week 12 (±1 day), Week 24 (±3 days), Week 36 (±5 days), Week 48 (±10 days)]
• Changes in MoCA scores from baseline [Срок оценки: Week 8 (±1 day), Week 12 (±1 day), Week 24 (±3 days), Week 36 (±5 days), Week 48 (±10 days)]
• Changes in PSQI scores from baseline [Срок оценки: Week 3 (±1 day), Week 4 (±1 day), Week 5 (±1 day), Week 6 (±1 day), Week 8 (±1 day), Week 12 (±1 day), Week 24 (±3 days), Week 36 (±5 days), Week 48 (±10 days)]
• Changes in NPI scores from baseline [Срок оценки: Week 3 (±1 day), Week 4 (±1 day), Week 5 (±1 day), Week 6 (±1 day), Week 8 (±1 day), Week 12 (±1 day), Week 24 (±3 days), Week 36 (±5 days), Week 48 (±10 days)]
• Changes in SDMT scores from baseline [Срок оценки: Week 3 (±1 day), Week 4 (±1 day), Week 5 (±1 day), Week 6 (±1 day), Week 8 (±1 day), Week 12 (±1 day), Week 24 (±3 days), Week 36 (±5 days), Week 48 (±10 days)]
• Changes in serum and CSF autoantibody titers from baseline [Срок оценки: Week 3 (±1 day), Week 4 (±1 day), Week 5 (±1 day), Week 6 (±1 day), Week 8 (±1 day), Week 12 (±1 day), Week 24 (±3 days), Week 36 (±5 days), Week 48 (±10 days)]
• Changes in peripheral blood lymphocyte subsets from baseline [Срок оценки: Week 3 (±1 day), Week 4 (±1 day), Week 5 (±1 day), Week 6 (±1 day), Week 8 (±1 day), Week 12 (±1 day), Week 24 (±3 days), Week 36 (±5 days), Week 48 (±10 days)]

Критерии участия

Критерии включения

• Aged ≥18 years, male or female.
• Confirmed diagnosis of antibody-positive autoimmune encephalitis (AE) or autoimmune cerebellitis (ACA).
• Refractory AE/ACA defined as antibody-positive disease meeting all of the following:
• Modified Rankin Scale (mRS) score >3 (stable for at least 24 hours) at baseline.
• Received first-line acute therapy more than 6 weeks prior to baseline visit, defined as at least 3 days of intravenous methylprednisolone (≥500 mg/day) or equivalent oral corticosteroids, and/or at least 3 days of IVIG and/or plasma exchange (PE), or any combination thereof.
• Received additional immunotherapy beyond the first acute course, meeting the following:

• For rituximab: treatment initiated at least 2 months prior to screening, last dose at least 4 weeks prior to baseline, and no improvement in mRS score for 2 months before baseline.
• For other immunosuppressive therapies (IST; e.g., mycophenolate mofetil, cyclophosphamide, azathioprine): treatment for at least 2 months prior to screening, stable dose for at least 4 weeks prior to baseline, and no improvement in mRS score for 4 weeks before baseline.
• For oral corticosteroids: stable dose >20 mg/day prednisone equivalent, no dose increase for 4 weeks prior to baseline, and no improvement in mRS score for 4 weeks before baseline.
• For repeated first-line therapy courses: completed at least 2 weeks prior to baseline visit.
• For patients on oral corticosteroids: stable dose ≥20 mg/day prednisone equivalent, no dose increase for 4 weeks prior to enrollment, and no improvement in mRS score for 4 weeks before enrollment.
• For patients on rituximab: treatment initiated at least 2 months prior to enrollment, last dose at least 4 weeks prior to enrollment, and no improvement in mRS score for 4 weeks before enrollment.
• For patients on other IST (e.g., azathioprine, mycophenolate mofetil): treatment for at least 2 months prior to enrollment, stable dose for at least 4 weeks prior to enrollment, and no improvement in mRS score for 4 weeks before enrollment.
• For patients on repeated first-line therapy courses: completed at least 2 weeks prior to enrollment.
• Patient or legally authorized representative provides written informed consent.
• For females of childbearing potential: agreement to abstain from heterosexual intercourse or use adequate contraception during treatment and for at least 3 months after the last dose. Post-menopausal females (≥12 consecutive months of amenorrhea without other cause) or those permanently sterilized by surgery (e.g., bilateral oophorectomy, hysterectomy) are not considered of childbearing potential. Acceptable contraceptive methods include bilateral tubal ligation, male sterilization, hormonal contraceptives, hormonal IUDs, copper IUDs, male/female condoms with spermicide, and contraceptive diaphragms/caps with spermicide. Periodic abstinence and withdrawal are not considered adequate.

Diagnostic Criteria for Antibody-Positive Autoimmune Encephalitis (AE):

A. Clinical presentation: Acute or subacute onset (<3 months) with ≥1 neuropsychiatric symptom:

• Limbic encephalitis: memory impairment, seizures, psychiatric symptoms.
• Encephalopathy syndrome: diffuse or multifocal brain dysfunction.
• CSF pleocytosis (>5×10⁶/L), lymphocytic inflammation, or oligoclonal bands.

B. Investigations: ≥1 of the following or associated tumors:

• CSF abnormalities as above.
• Neuroimaging/EEG: MRI T2/FLAIR hyperintensity in limbic system or other regions (excluding non-specific white matter changes/stroke); PET hypermetabolism in limbic system or multifocal cortex/basal ganglia; EEG with focal epileptiform discharges or diffuse/multifocal slowing.
• Specific tumors associated with AE. C. Confirmatory test: Positive anti-neuronal antibodies. D. Other causes excluded. All criteria A-D must be met.

Diagnostic Criteria for Autoimmune Cerebellitis (ACA):

• Acute or subacute onset with predominant cerebellar syndrome.
• No significant cerebellar/brainstem atrophy on brain MRI within 3 months of onset.
• Meets either 3.1 or 3.2:

3.1 Positive anti-cerebellar antibodies in serum and/or CSF detected by cell-based assay (CBA).

3.2 At least two of the following: personal or first-degree family history of autoimmune disease; CSF pleocytosis (>5×10⁶/L) or oligoclonal bands; characteristic immunofluorescence pattern of anti-Purkinje cell antibodies on tissue-based assay (TBA); presence of systemic autoimmune disease-related antibodies.

• Other causes excluded.

Критерии исключения

• Systemic or central nervous system tumors (e.g., gliomatosis cerebri), history of cancer (excluding ovarian/extra-ovarian teratoma, skin squamous cell carcinoma, or basal cell carcinoma with documented cure ≥3 months prior to enrollment); hereditary diseases (e.g., mitochondrial encephalopathy); neurodegenerative diseases (e.g., Lewy body dementia); prior epilepsy with ongoing seizures; severe traumatic brain injury; metabolic/toxic encephalopathy (e.g., Wernicke encephalopathy).
• Infectious diseases (e.g., viral encephalitis); active or uncontrolled infection requiring systemic treatment within 1 week prior to screening; history of severe recurrent or chronic infections, especially respiratory infections.
• Positive hepatitis B surface antigen/核心 antigen and/or positive hepatitis C PCR at screening.
• Active tuberculosis at screening.
• Diseases requiring long-term corticosteroid or immunosuppressive therapy.
• Known history of primary immunodeficiency (congenital or acquired) or conditions predisposing to infection (e.g., HIV infection, splenectomy).
• History of solid organ or hematopoietic stem cell transplantation within 3 months prior to screening.
• Live or attenuated vaccine within 3 weeks prior to enrollment (inactivated vaccines are allowed); BCG vaccine within 1 year prior to enrollment.
• Congenital heart disease, acute myocardial infarction within 6 months prior to screening, severe arrhythmias (e.g., polymorphic ventricular tachycardia), moderate to large pericardial effusion, severe myocarditis, hemodynamic instability requiring vasopressors, left ventricular ejection fraction (LVEF) ≤55%, or significant ECG abnormalities.
• Any of the following laboratory abnormalities:
• Absolute lymphocyte count (ALC) ≤0.5×10⁹/L
• Absolute neutrophil count (ANC) ≤0.5×10⁹/L
• Immunoglobulin G (IgG) ≤5.0 g/L
• CD4 T-cell count <300 cells/µL
• Hemoglobin ≤80 g/L
• Platelet count ≤75×10⁹/L
• Estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73m²
• AST/ALT ≥3× upper limit of normal (ULN); total bilirubin ≥2×ULN
• Pregnant or breastfeeding females, or those planning pregnancy during the trial.
• Incomplete medical records or refusal to participate in the registry.
• Known allergy or hypersensitivity to any component of the study drug or to any biologic therapy.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Beijing Tiantan Hospital, Capital Medical University — Пекин

Идентификаторы

NCT: NCT07686042 · BTHospital

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗