Efficacy and Safety of Calculus Bovis Sativus (CBS) for Adult Encephalitis (CBSinEncephalitis)

NCT06584045 | Recruiting

• 1 other identifier: CBSinEncephalitis
• Study Type: interventional
• Target: 250
• Locations: 1 country
• Sites: 1

Brief Summary

Based on the records of traditional Chinese medicine, CBS has the functions of purifying the heart, eliminating phlegm, stimulating bile secretion, and soothing the nerves. It has the ability to alleviate fever, coma, delirium, epilepsy, convulsions in youngsters, dental caries, throat swelling, mouth ulcers, carbuncle, and furuncle. Encephalitis is a neurological condition characterized by widespread or multiple inflammation of brain tissue. The causes of encephalitis are many and can stem from infectious organisms or be induced by autoimmune reactions, the latter being referred to as autoimmune encephalitis (AE). The yearly occurrence rate of encephalitis is 12.6 per 100,000 individuals. Among these cases, approximately 40-50% are caused by infectious factors, whereas 20-30% are attributed to autoimmune encephalitis (AE). The development of viral encephalitis involves the direct invasion of brain tissue by the virus and the immune response of the body to viral antigens. The virus multiplies extensively, leading to the degeneration of neurons, necrosis, the proliferation of glial cells, and the infiltration of inflammatory cells. These severe tissue reactions can result in the formation of demyelinating lesions and damage to blood vessels and the areas surrounding them. Additionally, vascular lesions affect the circulation in the brain and worsen the damage to brain tissue. The development of AE involves several factors, including molecular mimicry, the activation of latent antigen epitopes, the spread of antigen epitopes, and the disruption of the innate immune system caused by persistent pathogen infection. The mechanisms that are clearer can be summarized as follows: (1) Decrease in the number of receptors on the surface due to cross-linking and internalization: Anti-NMDAR antibodies have the ability to attach to NMDAR on the postsynaptic membrane, resulting in a reduction of NMDAR surface density through cross-linking and internalization. This reduction leads to a decrease in NMDAR-mediated current, which in turn causes learning and memory defects. (2) Protein-protein interaction disruption: Anti-LGI1 antibodies can disrupt the binding between LGI1 and ADAM23 on the presynaptic membrane and ADAM22 on the postsynaptic membrane. This disruption leads to a decrease in the density of anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). According to the aforementioned background processes, along with the most recent research, there was a decrease in the abundance of gut flora in patients with AE. Transplanting the fecal bacteria of individuals with anti-NMDAR encephalitis into mice's intestines resulted in cognitive impairment in the animals. This indicates that the brain-gut axis may have a significant role in the development of anti-NMDAR encephalitis. From a clinical perspective, patients consume CBS orally in order to achieve its therapeutic benefits. The primary constituents, bilirubin and bile acid, have been documented to possess regulatory effects on the gut microbiota. Thus, we hypothesize that CBS is probable to have neuroprotective and anti-inflammatory impacts on the brain through alterations in the intestinal microbiota and regulation of the brain-gut connection. CBS is expected to decrease the occurrence of symptomatic seizures and enhance the patient's level of consciousness and cognitive abilities.

Conditions

Encephalitis; Encephalitis, Viral; Autoimmune Encephalitis Caused by N-Methyl D-Aspartate Receptor Antibody; Autoimmune Encephalitis

Outcome Measures

Primary Outcomes (3)

• The Modified Rankin Scale (mRS)

  To assess mRS of subjects within 12 weeks after treatment initiation. The score ranges from 0 to 5. 5 represents the worst.

  Up to 12 weeks after treatment initiation

• Clinical Assessment Scale in Autoimmune Encephalitis (CASE)

  To assess CASE of subjects within 12 weeks after treatment initiation. The score ranges from 0 to 27. 27 represents the worst.

  Up to 12 weeks after treatment initiation

• Incidence and Severity of Adverse Effects (AEs) and Severe Adverse Effects (SAEs)

  To evaluate the AEs and SAEs occurred within 14 weeks after treatment initiation

  Up to 14 weeks after treatment initiation

Secondary Outcomes (10)

• The number of newly increased inflammatory lesions on T2 flair weighted imaging at week 12 compared with baseline (visit 1) and control group.

  Up to 12 weeks after treatment initiation

• The number of newly increased inflammatory lesions on gadolinium-enhanced T1 weighted imaging at week 12 compared with baseline (visit 1) and control group.

  Up to 12 weeks after treatment initiation

• The quantity of epileptiform abnormalities on electroencephalograph at week 12 compared with baseline (visit 1) and control group.

  Up to 12 weeks after treatment initiation

• The quantity of background deterioration on electroencephalograph at week 12 compared with baseline (visit 1) and control group.

  Up to 12 weeks after treatment initiation

• The score of Mini-mental State Examination (MMSE) at week 12 compared with baseline (visit 1) and control group.

  Up to 12 weeks after treatment initiation

Other Outcomes (5)

• The abundance of fecal flora at week 12 compared with baseline (visit 1).

  Up to 12 weeks after treatment initiation

• Quantitative and qualitative changes in fecal metabolomics analysis at week 12 compared with baseline (visit 1).

  Up to 12 weeks after treatment initiation

• Profiling of lymphocytes subtypes in serum, including absolute counting and ratio of each type of lymphocyte, at week 12 compared with baseline (visit 1).

  Up to 12 weeks after treatment initiation

Study Arms (3)

CBS therapy, CBS dosage: 100mg per day from day 1 to day 84, in encephalitis cohort

EXPERIMENTAL

Subjects in encephalitis cohort of this arm will receive general therapy plus CBS.

Drug: Calculus bovis sativus (CBS)

Control therapy: no intervention, in encephalitis cohort

NO INTERVENTION

Subjects in encephalitis cohort of this arm will only receive general therapy.

CBS therapy, CBS dosage: 100mg per day from day 1 to day 84, in healthy cohort

EXPERIMENTAL

Subjects in healthy cohort of this arm will only receive CBS.

Drug: Calculus bovis sativus (CBS)

Interventions

Calculus bovis sativus (CBS) DRUG

Subjects will orally receive 100mg CBS per day from day 1 to day 84.

CBS therapy, CBS dosage: 100mg per day from day 1 to day 84, in encephalitis cohort; CBS therapy, CBS dosage: 100mg per day from day 1 to day 84, in healthy cohort

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects must meet the following eligibility criteria at screening to participate in this study.
• Tumors or malignancies can be reasonably excluded before the baseline visit (randomization), and screening guidelines for thymoma, teratoma, and malignant tumors should be followed.
• Both men and women are welcome, and the age at the time of providing informed consent is 18-80 years old (inclusive).
• Meet the diagnosis of AE (according to the Chinese Autoimmune Encephalitis Diagnosis and Treatment Expert Consensus 2022 Edition): A. Clinical manifestations: acute or subacute onset (\<3 months), with one or more of the following neurological and psychiatric symptoms or clinical syndromes.
• a. Limbic system symptoms: recent memory loss, epileptic seizures, mental and behavioral abnormalities, one or more of the three symptoms.
• b. Encephalitis syndrome: clinical manifestations of diffuse or multifocal brain damage.
• c. Clinical manifestations of involvement of the basal ganglia and/or diencephalon/hypothalamus.
• d. Mental disorder, and the psychiatric specialist believes that it does not meet the non-organic disease.
• B. Auxiliary examination: one or more of the following auxiliary examination findings, or combined with related tumors.
• a. Abnormal cerebrospinal fluid: cerebrospinal fluid leukocytosis (\>5×106/L), or cerebrospinal fluid cytology shows lymphocytic inflammation, or specific oligoclonal bands are positive.
• b. Neuroimaging or electrophysiological abnormalities: MRI limbic system T2 or FLAIR abnormal signals, unilateral or bilateral, or other areas of T2 or FLAIR abnormal signals (excluding nonspecific white matter changes and stroke); or PET imaging limbic system hypermetabolism changes, or multiple cortical and/or basal ganglia hypermetabolism. Figure 1 shows the typical neuroimaging manifestations of AE patients. Abnormal electroencephalogram, manifested as focal epilepsy or epileptiform discharge (located in the temporal lobe or outside the temporal lobe), or diffuse or multifocal slow wave rhythm. In adult patients with anti-NMDAR encephalitis, abnormal delta brush waves (extreme delta brush) often correspond to prolonged hospitalization and poor prognosis.
• c. Specific types of tumors associated with AE, such as limbic encephalitis combined with small cell lung cancer, anti-NMDAR encephalitis combined with ovarian teratoma.
• C. Confirmatory experiments: positive anti-neuronal antibodies. Including NMDA-R, LGI-1, CASPR2, IgLON5, GABAA/BR, GlyR, AMPAR and axonal protein-3α and intracellular substance antibodies anti-Hu, anti-Ma2, anti-CRMP5, anti-Yo, anti-double carrier protein, anti-GAD, etc.
• D. Reasonably exclude other causes (refer to the differential diagnosis section of the consensus).
• Diagnostic criteria: including possible AEs and confirmed AEs:

You may not qualify if:

• Any clinically significant cardiac, endocrine, hematologic, hepatic, immune, infectious, metabolic, urologic, pulmonary, neurological, dermatologic, psychiatric, and renal disease or other major medical history that the investigator determines would preclude participation in the clinical trial.
• Any untreated teratoma or thymoma at the baseline visit (randomization)
• Other causes of symptoms, including central nervous system infection, septic encephalopathy, metabolic encephalopathy, epileptic disorders, mitochondrial disease, Klein-Levin syndrome, Creutzfeldt-Jakob disease, rheumatic disease, Reyes syndrome, or inborn errors of metabolism.
• History of herpes simplex encephalitis within the previous 24 weeks. 1.5. Any surgical procedure within 4 weeks prior to baseline, except laparoscopic surgery or minor surgery (defined as surgery requiring only local anesthesia or conscious sedation, i.e., surgery that does not require general, neuraxial, or regional anesthesia and can be performed on an outpatient basis; e.g., toenail surgery, mole surgery, wisdom tooth extraction), excluding thymoma or teratoma removal.
• Planned surgery during the study (except minor surgery).
• History of severe allergic or anaphylactic reactions, or any allergic reaction that the investigator believes may be exacerbated by any component of study treatment.
• Current or history of malignant disease, including solid tumors and hematologic malignancies (except for basal cell carcinoma and squamous cell carcinoma that have been completely resected and considered cured for at least 12 months prior to Day -1). Subjects with cancer remission for more than 5 years prior to baseline (Visit 1) may be included after discussion with the sponsor/sponsor approval.
• A history of gastrointestinal surgery (except appendectomy or cholecystectomy performed more than 6 months before screening), irritable bowel syndrome, inflammatory bowel disease (Crohn's disease, ulcerative colitis), or other clinically significant active gastrointestinal diseases in the opinion of the investigator.
• A history of clinically significant recurrent or active gastrointestinal symptoms (e.g., nausea, diarrhea, dyspepsia, constipation) within 90 days before screening, including the need to start symptomatic treatment (e.g., start medication for gastroesophageal reflux disease) or a change in symptomatic treatment within 90 days before screening (e.g., dose increase).
• A history of diverticulitis or concurrent severe gastrointestinal (GI) abnormalities (e.g., symptomatic diverticular disease) because the investigator believes that this may lead to an increased risk of complications such as GI perforation.
• A history of blood donation (1 unit or more), plasma donation, or platelet donation within 90 days before screening.
• Active suicidal ideation within 6 months before screening, or a history of suicide attempt within 3 years before screening.
• Based on the investigator's judgment, there are serious diseases or abnormalities in the clinical laboratory test results that prevent the patient from completing the study or participating in the study safely.
• Pregnant or lactating, or planning to become pregnant during the study or within 3 months after the last dose of the study drug; women of childbearing potential must have a negative serum pregnancy test result at screening and a negative urine pregnancy test result before the start of the study.
• The subject's mental or physical condition will hinder the evaluation of efficacy and safety.

Sponsors & Collaborators

• Tongji Hospital: lead
• Jianmin Pharmaceutical Group Co., LTD.: collaborator

Study Sites (1)

Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology

Wuhan, Hubei, 430000, China

RECRUITING

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MeSH Terms

Conditions

Encephalitis; Encephalitis, Viral; Autoimmune Diseases of the Nervous System

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuroinflammatory Diseases; Central Nervous System Viral Diseases; Central Nervous System Infections; Infections; Infectious Encephalitis; Virus Diseases; Autoimmune Diseases; Immune System Diseases

Central Study Contacts

Ke Shang, MD

CONTACT

86-27-83663337; kay_sang@qq.com

Ke Shang, MD

CONTACT

86-27-83663477; kay_sang@hust.edu.cn

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Neurology

Study Record Dates

• First Submitted: August 26, 2024
• First Posted: September 4, 2024
• Study Start: September 30, 2024
• Primary Completion (Estimated): July 1, 2029
• Study Completion (Estimated): December 1, 2029
• Last Updated: April 8, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)