CPI Combination Therapy for Autoimmune Encephalitis (CPI)

Combination Therapy of Pulse Corticosteroid and Plasma Exchange Followed by Intravenous Immunoglobulin in Patients With Severe Antibody- Associated Autoimmune Encephalitis: a Randomized Controlled Trial

Corticosteroids, intravenous immunoglobulin (IVIG), and plasma exchange (PE) are the first-line therapies for autoimmune encephalitis (AE) patients, but optimal first-line treatment strategy for different AE patients remains undetermined. The study is to compare the efficacy between pulse corticosteroid plus PE initially followed by IVIG (CPI therapy) and pulse corticosteroid plus IVIG followed by PE two weeks later (CIP therapy) in patients with severe antibody-associated autoimmune encephalitis (AE).

Study Overview

• Status: Completed
• Conditions: Autoimmune Encephalitis
• Intervention / Treatment: Procedure: Plasma exchange (PE); Drug: intravenous immunmoglobulin (IVIG), intravenous methylprednisolone (IVMP)

Detailed Description

Patients with AE will be randomly divided into the CPI and CIP group according to the random table. All patients will receive tumour screening, symptomatic supportive treatment, and immunotherapy. The immunotherapy includes intravenous methylprednisolone (IVMP), intravenous immunoglobulin (IVIG; 0.4 g/kg/d for each course for 5 d), PE and immunosuppressants. Patients in the CPI group received IVMP and PE treatment without delay, followed by IVIG immediately after PE treatment. Patients in the CIP group were given IVMP and IVIG and IVMP immediately, followed by PE at least 2 weeks after IVIG treatment. The patients received long-term immunotherapy involving a combination of oral corticosteroids and immunosuppressants (such as mycophenolate mofetil at a dose of 1-2g/d) for 6-12 months if no contraindications. The primary outcome is the proportion of patients achieving functional improvement [a decrease of at least 1 point in modified Rankin Scale (mRS) score] at 3 months after immunotherapy.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100053
      • Xuanwu Hospital of Capital Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

1. 14-65 years old;
2. met all the three following diagnostic criteria of AE: (i) subacute onset (rapid progress of less than 3 months) of working memory deficits, altered mental status, or psychiatric symptoms; (ii) at least one of the followings: new focal CNS findings, seizures not explained by a previously known disease, cerebrospinal fluid (CSF) pleocytosis (white blood cell count 5 cells/mm3), magnetic resonance imaging (MRI) features suggestive of encephalitis, and (iii) reasonable exclusion of alternative causes;
3. the presence of antibody against neuronal surface antigen in serum or CSF indicating a positive diagnosis of AE using a cell-based assay;
4. critically ill with a modified Rankin scale (mRS) score of 4 to 5;
5. within 3 months of onset;
6. no immunotherapy previously.

Exclusion criteria:

1. relative contraindications of TPE treatment: serious underlying diseases such as severe active hemorrhage, disseminated intravascular coagulation, severe hypotension or shock, unstable cardiac failure, cerebral herniation, severe infection or other endangered conditions;
2. allergic to immunoglobulin;
3. contraindications of glucocorticoid therapy: glucocorticoid allergy, active gastric or duodenal ulcer, severe osteoporosis, diabetes, hypertension after recent gastrointestinal anastomosis, and serious infection that cannot be controlled by antibiotics;
4. serious underlying diseases, such as cardiac dysfunction, arrhythmia, and coagulation disorders;
5. premorbid mRS ≥ 3.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CPI group; Intravenous methylprednisolone (IVMP) combined with PE (5 times in each course) and IVIG after PE.	Procedure: Plasma exchange (PE); PE is performed every other day using a multi-filtrate apheresis device (Fresenius, Bad Homburg, Germany), and 5 times in total for each course. The plasma removed during PE is replaced with an equal volume of substitution (half 5% albumin with normal saline and half plasma). The plasma volume to be replaced was estimated according to the following formula: plasma volume (L) = 7.5%×weight (kg)×(1-hematocrit)×1000ml. Heparin was added to the exchange circuit to prevent blood clotting. The exchange rate was monitored, recorded, and balanced to prevent cardiovascular instability. Blood pressure and other vital signs were closely monitored every 15 minutes throughout the exchange.; Drug: intravenous immunmoglobulin (IVIG), intravenous methylprednisolone (IVMP); IVIG is given 0.4 g/kg/d for each course for 5 days. IVMP is 1,000 mg or 500 mg methylprednisolone for 3 or 5 days, and the dosage of glucocorticoid will gradually decrease.
Active Comparator: CIP group; IVMP and IVIG (0.4g/kg/d for 5 days) immediately, followed by PE at least 2 weeks after IVIG treatment.	Procedure: Plasma exchange (PE); PE is performed every other day using a multi-filtrate apheresis device (Fresenius, Bad Homburg, Germany), and 5 times in total for each course. The plasma removed during PE is replaced with an equal volume of substitution (half 5% albumin with normal saline and half plasma). The plasma volume to be replaced was estimated according to the following formula: plasma volume (L) = 7.5%×weight (kg)×(1-hematocrit)×1000ml. Heparin was added to the exchange circuit to prevent blood clotting. The exchange rate was monitored, recorded, and balanced to prevent cardiovascular instability. Blood pressure and other vital signs were closely monitored every 15 minutes throughout the exchange.; Drug: intravenous immunmoglobulin (IVIG), intravenous methylprednisolone (IVMP); IVIG is given 0.4 g/kg/d for each course for 5 days. IVMP is 1,000 mg or 500 mg methylprednisolone for 3 or 5 days, and the dosage of glucocorticoid will gradually decrease.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
proportion of subjects achieving functional improvement	Functional improvement is defined as a decrease of at least 1 point in mRS score, modified Rankin Scale: 0 - No symptoms. 1 - No significant disability. Able to carry out all usual activities, despite some symptoms.2 - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. 3 - Moderate disability. Requires some help, but able to walk unassisted. 4 - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. 5 - Severe disability. Requires constant nursing care and attention, bedridden, incontinent. 6 - Dead.	3 months following Immunotherapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
modified Rankin Scale	modified Rankin Scale: 0 - No symptoms. 1 - No significant disability. Able to carry out all usual activities, despite some symptoms.2 - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. 3 - Moderate disability. Requires some help, but able to walk unassisted. 4 - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. 5 - Severe disability. Requires constant nursing care and attention, bedridden, incontinent. 6 - Dead.	3 months following Immunotherapy
modified Rankin Scale	modified Rankin Scale: 0 - No symptoms. 1 - No significant disability. Able to carry out all usual activities, despite some symptoms.2 - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. 3 - Moderate disability. Requires some help, but able to walk unassisted. 4 - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. 5 - Severe disability. Requires constant nursing care and attention, bedridden, incontinent. 6 - Dead.	6 months following Immunotherapy
modified Rankin Scale	modified Rankin Scale: 0 - No symptoms. 1 - No significant disability. Able to carry out all usual activities, despite some symptoms.2 - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. 3 - Moderate disability. Requires some help, but able to walk unassisted. 4 - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. 5 - Severe disability. Requires constant nursing care and attention, bedridden, incontinent. 6 - Dead.	12 months following Immunotherapy
modified Rankin Scale	modified Rankin Scale: 0 - No symptoms. 1 - No significant disability. Able to carry out all usual activities, despite some symptoms.2 - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. 3 - Moderate disability. Requires some help, but able to walk unassisted. 4 - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. 5 - Severe disability. Requires constant nursing care and attention, bedridden, incontinent. 6 - Dead.	24 months following Immunotherapy
proportion of favorable outcome	A mRS score of 0-2 was considered a favorable outcome, whereas a mRS score of 3-6 was graded as an unfavorable one. modified Rankin Scale: 0 - No symptoms. 1 - No significant disability. Able to carry out all usual activities, despite some symptoms.2 - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. 3 - Moderate disability. Requires some help, but able to walk unassisted. 4 - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. 5 - Severe disability. Requires constant nursing care and attention, bedridden, incontinent. 6 - Dead.	3 months following Immunotherapy
proportion of favorable outcome	A mRS score of 0-2 was considered a favorable outcome, whereas a mRS score of 3-6 was graded as an unfavorable one. modified Rankin Scale: 0 - No symptoms. 1 - No significant disability. Able to carry out all usual activities, despite some symptoms.2 - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. 3 - Moderate disability. Requires some help, but able to walk unassisted. 4 - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. 5 - Severe disability. Requires constant nursing care and attention, bedridden, incontinent. 6 - Dead.	6 months following Immunotherapy
proportion of favorable outcome	A mRS score of 0-2 was considered a favorable outcome, whereas a mRS score of 3-6 was graded as an unfavorable one. modified Rankin Scale: 0 - No symptoms. 1 - No significant disability. Able to carry out all usual activities, despite some symptoms.2 - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. 3 - Moderate disability. Requires some help, but able to walk unassisted. 4 - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. 5 - Severe disability. Requires constant nursing care and attention, bedridden, incontinent. 6 - Dead.	12 months following Immunotherapy
proportion of favorable outcome	A mRS score of 0-2 was considered a favorable outcome, whereas a mRS score of 3-6 was graded as an unfavorable one. modified Rankin Scale: 0 - No symptoms. 1 - No significant disability. Able to carry out all usual activities, despite some symptoms.2 - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. 3 - Moderate disability. Requires some help, but able to walk unassisted. 4 - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. 5 - Severe disability. Requires constant nursing care and attention, bedridden, incontinent. 6 - Dead.	24 months following Immunotherapy
CASE score	Clinical Assessment Scale in Autoimmune Encephalitis	3 months following Immunotherapy
CASE score	Clinical Assessment Scale in Autoimmune Encephalitis	6 months following Immunotherapy
CASE score	Clinical Assessment Scale in Autoimmune Encephalitis	12 months following Immunotherapy
CASE score	Clinical Assessment Scale in Autoimmune Encephalitis	24 months following Immunotherapy
Length of ICU stay	Length of ICU stay (days)	before discharge

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events	Adverse events related with PE	within 24 months following immunotherapy

Collaborators and Investigators

• Sponsor: Xuanwu Hospital, Beijing
• Investigators: Study Chair: Yan Zhang, MD, Phd, Xuanwu Hospital, Beijing

Study record dates

Study Major Dates

• Study Start (Actual): November 25, 2020
• Primary Completion (Actual): December 12, 2022
• Study Completion (Actual): September 12, 2024

Study Registration Dates

• First Submitted: May 18, 2018
• First Submitted That Met QC Criteria: May 18, 2018
• First Posted (Actual): May 31, 2018

Study Record Updates

• Last Update Posted (Actual): June 27, 2025
• Last Update Submitted That Met QC Criteria: June 26, 2025
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: corticosteroid; Autoimmune encephalitis, Plasma exchange, Immunotherapy, Outcome; immunoglobulin
• Additional Relevant MeSH Terms: Neuroinflammatory Diseases; Endocrine System Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Autoimmune Diseases; Immune System Diseases; Thyroid Diseases; Thyroiditis, Autoimmune; Thyroiditis; Encephalitis; Autoimmune Diseases of the Nervous System; Hashimoto Disease; Antineoplastic Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protective Agents; Neuroprotective Agents; Methylprednisolone Acetate; Prednisolone; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate
• Other Study ID Numbers: AE-CPI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No