Efficacy and Safety of Calculus Bovis Sativus (CBS) for Adult Encephalitis (CBSinEncephalitis)
NCT Number: NCT06584045
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: NA
Conditions: Encephalitis|Encephalitis, Viral|Autoimmune Encephalitis Caused by N-Methyl D-Aspartate Receptor Antibody|Autoimmune Encephalitis
Interventions: DRUG: Calculus bovis sativus (CBS)
Sponsor: Tongji Hospital
Collaborators: Wuhan Jianmin DAPENG Pharmaceutical Co., Ltd.
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 250
Study Design: Allocation: NON_RANDOMIZED|Intervention Model: PARALLEL|Masking: NONE|Primary Purpose: TREATMENT
Start Date: 2024-09
Completion Date: 2029-12
Locations: Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, 430000, China

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.

Primary Outcome Measures: 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 Outcome Measures: 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., The score of MMSE ranges from 0 to 30, and 30 represents the best., Up to 12 weeks after treatment initiation|Montreal cognitive assessment scale (MoCA) at week 12 compared with baseline (visit 1) and control group., The score of MoCA ranges from 0 to 30, and 30 represents the best., Up to 12 weeks after treatment initiation|The score of Hamilton Anxiety Scale at week 12 compared with baseline (visit 1) and control group., The score of Hamilton Anxiety Scale ranges from 0 to 56, and 56 represents the worst., Up to 12 weeks after treatment initiation|The score of Hamilton Depression Scale at week 12 compared with baseline (visit 1) and control group., The score of Hamilton Depression Scale ranges from 0 to 81, and 81 represents the worst., Up to 12 weeks after treatment initiation|The score of 36-item Short-Form (SF-36) at week 12 compared with baseline (visit 1) and control group., The score of SF-36 ranges from 0 to 100, and 100 represents the best., Up to 12 weeks after treatment initiation|The incidence of Columbia-Suicide Severity Rating Scale (C-SSRS) events at week 14 compared with baseline (visit 1) and control group., Up to 14 weeks after treatment initiation
Other Outcome Measures: 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|The value of SUVmax and ratio of T/B of inflammatory lesion in 18F-DPA-714 PET/MR imaging examinations at week 12 compared with baseline (visit 1)., To evaluate the degree of inflammation related to microglia in brain through 18F-DPA-714 PET/MR., Up to 12 weeks after treatment initiation|Concentration of inflammatory factors (IL-1β/IL-2R/IL-6/IL-8/IL-10/TNF-α) in cerebrospinal fluid at week 12 compared with baseline (visit 1)., Up to 12 weeks after treatment initiation