Clinical trial NCT06584045: Efficacy and Safety of Calculus Bovis Sativus (CBS) for Adult Encephalitis (CBSinEncephalitis)
Official title: An Open Label Clinical Trial to Evaluate the Efficacy and Safety of Calculus Bovis Sativus (CBS) for Adult Encephalitis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Encephalitis
Encephalitis, Viral
Autoimmune Encephalitis Caused by N-Methyl D-Aspartate Receptor Antibody
Autoimmune Encephalitis
Lead sponsor: Tongji Hospital
Sponsor class: OTHER
Collaborators: name: Jianmin Pharmaceutical Group Co., LTD.
First posted: 2024-09-04
Enrollment: 250
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

* Subjects must meet the following eligibility criteria at screening to participate in this study.

1.1 Inclusion criteria for subjects with autoimmune encephalitis (hereinafter referred to as AE) of all subtypes 1.1.1 Subjects are able to understand the purpose and risks of the study, provide informed consent, and authorize the use of confidential health information in accordance with national and local privacy regulations.

1.1.2. Tumors or malignancies can be reasonably excluded before the baseline visit (randomization), and screening guidelines for thymoma, teratoma, and malignant tumors should be followed.

1.1.3. Both men and women are welcome, and the age at the time of providing informed consent is 18-80 years old (inclusive).

1.1.4. 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:

1. Possible AEs: meet the three diagnostic criteria of A, B and D.
2. Confirmed AEs: meet the four diagnostic criteria of A, B, C and D. 1.1.5. AE symptoms occurred ≤9 months before randomization 1.1.6. Subjects meet new AEs

   - New onset: defined as subjects with NMDA-R or LGI-1 AEs and meeting the following criteria:
   * The mRS score measured at baseline is stable (at least 24 hours) and is ≥2 points.
   * Received the first acute first-line treatment within 6 weeks before randomization (baseline visit).

   1.1.7. All females of childbearing potential and all males must use contraception during the study and for at least 30 days after the last dose of study treatment. In addition, subjects should not donate sperm or eggs during the study and for at least 30 days after the last dose of study treatment.

   1.1.8. Stable neurological examination within 30 days before baseline (Visit 1).

   1.2 Additional inclusion criteria for the NMDA-R AE cohort

   In addition to the criteria outlined in Section 1.1, only subjects who met all of the following criteria were eligible for inclusion in the NMDA-R AE cohort:
   * Age ≥ 18 years at the time of informed consent
   * Informed consent, as appropriate based on patient age, specific site, and national criteria
   * Suspected or definite NMDAR AE diagnosis as follows:

   1.2.1. Suspected NMDAR encephalitis was diagnosed when all three of the following criteria were met: 1.2.1.1 Rapid onset (less than 3 months) of at least four of the following six cardinal symptoms:
   * Abnormal (psychiatric) behavior or cognitive dysfunction
   * Speech dysfunction (rushing speech, hypospeech, mutism)
   * Seizures
   * Ataxia, dyskinesia, or rigid/abnormal posture
   * Decreased level of consciousness
   * Autonomic dysfunction or central hypoventilation 1.2.1.2. At least one of the following laboratory results:
   * Abnormal EEG (focal or diffuse slow or disorganized activity, epileptic activity, or extreme delta brushes)
   * CSF with pleocytosis or oligoclonal bands 1.2.1.3. Reasonable exclusion of other etiologies and other clear encephalitis syndromes: for example, Bickerstaff brainstem encephalitis, acute disseminated encephalomyelitis, Hashimoto encephalopathy, primary angiitis of the central nervous system (CNS), Rasmussen encephalitis.

   Note: If the above three groups of symptoms in criterion 1.2.1.1 are present and accompanied by systemic teratoma, suspected NMDAR encephalitis can also be diagnosed.

   1.2.2 Definite NMDAR encephalitis can be diagnosed when the following three criteria are met at the same time: 1.2.2.1. The presence of one or more of the six main symptoms described in criterion 1.2.1.1 for suspected NMDAR encephalitis.

   1.2.2.2. History of anti-NMDAR (GluN1) IgG antibodies detected in CSF using a cell-based assay.

   1.2.3. Reasonable exclusion of other etiologies and other well-defined encephalitis syndromes: e.g., Bickerstaff brainstem encephalitis, acute disseminated encephalomyelitis, Hashimoto encephalopathy, primary angiitis of the central nervous system (CNS), Rasmussen encephalitis.

   1.3 Other inclusion criteria for the LGI-1 AE cohort

   In addition to the criteria outlined in Section 1.1, only subjects who meet all of the following criteria are eligible for inclusion in the LGI1 AE cohort:

   1.3.1 Age ≥ 18 years at the time of signing the informed consent For subjects who are unable to provide informed consent due to the severity of their illness, the informed consent may be signed by their legally authorized representative at the time of obtaining the subject's consent, according to local requirements.

   1.3.2 Diagnosis of LGI-1 AE

   The diagnosis of LGI-1 encephalitis can be made when both of the following criteria are met:

   1.3.2.1 Documented history of anti-LGI-1 IgG antibodies (in serum or CSF) using a cell-based assay.

   1.3.2.2 Subacute onset (less than 4 months of development) of working memory deficits, seizures (including faciobrachial dystonic seizures), or psychiatric symptoms suggestive of limbic system involvement.

   1.3.2.3 Diagnosis of LGI1 AE is reasonable when other etiologies and other well-defined encephalitis syndromes are excluded: e.g., Bickerstaff brainstem encephalitis, acute disseminated encephalomyelitis, Hashimoto encephalopathy, primary CNS vasculitis, Rasmussen encephalitis.

   1.4 Other inclusion criteria for the AA AE cohort

   In addition to the criteria outlined in Section 1.1, only subjects who meet all of the following criteria are eligible for inclusion in the AA AE cohort:
   * Aged ≥ 18 years at the time of signing the informed consent form For subjects who are unable to provide informed consent due to the severity of their illness, the informed consent form may be signed by their legally authorized representative when the subject agrees, according to local requirements.
   * Diagnosis of AA AE Meet the diagnosis of AE in 1.1, negative for anti-NMDA antibodies and anti-LGI-1 antibodies, and positive for at least one of the other anti-neuronal antibodies.

   1.5 Inclusion criteria for viral encephalitis (hereinafter referred to as VE) cohort

   The following four conditions must be met simultaneously for diagnosis of VE:
   * Primary condition: altered mental status, including decreased level of consciousness, drowsiness, or abnormal mental behavior lasting ≥24 h; or new onset of epileptic seizure
   * Secondary condition: fever ≥38 °C (before or within 72 h after onset), or new focal manifestations of the nervous system, or cerebrospinal fluid leukocytes ≥5×10\^6/L, or cerebrospinal fluid cytology showing lymphocytic inflammation, or imaging showing brain parenchymal lesions consistent with encephalitis, or abnormal electroencephalogram consistent with encephalitis
   * Confirmatory laboratory test: positive cerebrospinal fluid viral nucleic acid (polymerase chain reaction or metagenomic next-generation sequencing), or positive cerebrospinal fluid and/or serum antiviral antibody IgM
   * Reasonable exclusion of other causes

   1.6 Healthy cohort:
   * Age ≥ 18 years old when signing the informed consent form
   * Healthy adult subjects without underlying diseases

     * Exclusion Criteria:

       * 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.
       * Systolic blood pressure \>150 mmHg or \<90 mmHg after sitting still for 5 minutes or before dosing at screening. If out of range, it can be measured again at screening and before dosing. If the repeated measurement value is still out of range, the subject shall not receive the drug.
       * Subjects with second or third degree atrioventricular block or sick sinus syndrome, poorly controlled atrial fibrillation, severe or unstable angina, congestive heart failure, myocardial infarction, or significant ECG abnormalities, including corrected QT interval \>450 msec (male) or 470 msec (female), where corrected QT interval is determined based on the Fridericia correction method, within 3 months prior to the screening visit.
       * Planned elective procedures or surgeries at any time after signing the Informed Consent Form by follow-up visit.
       * Any condition that affects the absorption of study treatment (e.g., gastrectomy).
       * History of hypersensitivity to heparin or history of heparin-induced thrombocytopenia.
       * Subjects with abnormalities in medical history, physical examination, ECG, or diagnostic laboratory tests that the investigator considers to be clinically relevant.
       * History of human immunodeficiency virus (HIV) or positive test results at screening.
       * Current infection with hepatitis C (defined as positive hepatitis C virus (HCV) antibodies and detectable HCV RNA). Subjects with positive HCV antibodies and HCV RNA below the limit of detection are eligible to participate in the study.
       * Current infection with hepatitis B (defined as positive HBsAg and/or positive total anti-HBc).
       * Chronic, recurrent, or severe infection (e.g., pneumonia, sepsis) within 90 days prior to baseline (visit 1).
       * History of tuberculosis (TB) diagnosis or positive latent TB test result.
       * Symptoms of bacterial, fungal, or viral infection (including upper respiratory tract infection) within 28 days prior to baseline (visit 1). Subjects with localized fungal infection (e.g., candidiasis, tinea) are eligible for rescreening after successful treatment of the infection.
       * Infection requiring hospitalization or IV anti-infective medication within 4 weeks prior to baseline visit.
       * Any live or live attenuated vaccine within 28 days prior to baseline (visit 1) or planned during the study.
       * Contraindications to all of the following salvage therapies: rituximab, intravenous immunoglobulin, high-dose corticosteroids, or IV cyclophosphamide.
       * History of or receipt of the following treatments: Total lymphoid irradiation, cladribine, T-cell or T Cell recipient vaccination, total body irradiation, or total lymphoid irradiation at any time. Stem cell transplantation at any time.
       * Abnormal laboratory values determined by the investigator to be clinically significant at Screening or Baseline (Visit 1).
       * Any of the following blood test abnormalities at Screening: a. White blood cell count \< 3.0 × 10\^3/µL. b. Absolute neutrophil count \< 2.0 × 10\^3/µL. c. Absolute lymphocyte count \< 0.5 × 10\^3/µL. d. Platelet count \< × 10 × 10\^4/µL. e. glutamic-pyruvic transaminase, glutamic oxaloacetic transaminase, or γ-glutamyl transpeptidase ≥ 3 x upper limit of normal (ULN) or bilirubin \> 2 x ULN. f. glomerular filtration rate ≤ 60 mL/min/1.73 m2. g. Lymphocyte count \< lower limit of normal
       * Any of the following urine test abnormalities at Screening: a. β-2-microglobulin\>0.3 μg/mL. b. Albumin/creatinine ratio\>22.6 mg/mmol.
       * Previous participation in this study.
       * Blood donation (1 unit or more) within 90 days before screening, plasma donation within 1 week before screening, and platelet donation within 6 weeks before screening.
       * History of alcohol or drug abuse in the past year (determined by the investigator).
       * Pregnant or lactating subjects, as well as subjects planning to become pregnant or start breastfeeding at any time during the study and within 30 days after completion of study treatment.
       * Participating in a clinical trial or having participated in a clinical trial within 90 days before screening.
       * History of clinically significant suicidal thoughts or behaviors in the past 12 months as assessed by Columbia-Suicide Severity Rating Scale at screening.
       * Unwilling or unable to comply with protocol requirements.
       * The patient has obvious hearing or vision impairment, language barriers, claustrophobia, etc., which makes the patient unable to cooperate with the neuropsychological scale assessment and MRI examination.
       * The researcher or sponsor believes that there are other unknown reasons that make the subject unsuitable for inclusion.

Primary outcomes:
measure: The Modified Rankin Scale (mRS)
timeFrame: Up to 12 weeks after treatment initiation
measure: Clinical Assessment Scale in Autoimmune Encephalitis (CASE)
timeFrame: Up to 12 weeks after treatment initiation
measure: Incidence and Severity of Adverse Effects (AEs) and Severe Adverse Effects (SAEs)
timeFrame: Up to 14 weeks after treatment initiation
Secondary outcomes:
measure: The number of newly increased inflammatory lesions on T2 flair weighted imaging at week 12 compared with baseline (visit 1) and control group.
timeFrame: Up to 12 weeks after treatment initiation
measure: The number of newly increased inflammatory lesions on gadolinium-enhanced T1 weighted imaging at week 12 compared with baseline (visit 1) and control group.
timeFrame: Up to 12 weeks after treatment initiation
measure: The quantity of epileptiform abnormalities on electroencephalograph at week 12 compared with baseline (visit 1) and control group.
timeFrame: Up to 12 weeks after treatment initiation
measure: The quantity of background deterioration on electroencephalograph at week 12 compared with baseline (visit 1) and control group.
timeFrame: Up to 12 weeks after treatment initiation
measure: The score of Mini-mental State Examination (MMSE) at week 12 compared with baseline (visit 1) and control group.
timeFrame: Up to 12 weeks after treatment initiation
measure: Montreal cognitive assessment scale (MoCA) at week 12 compared with baseline (visit 1) and control group.
timeFrame: Up to 12 weeks after treatment initiation
measure: The score of Hamilton Anxiety Scale at week 12 compared with baseline (visit 1) and control group.
timeFrame: Up to 12 weeks after treatment initiation
measure: The score of Hamilton Depression Scale at week 12 compared with baseline (visit 1) and control group.
timeFrame: Up to 12 weeks after treatment initiation
measure: The score of 36-item Short-Form (SF-36) at week 12 compared with baseline (visit 1) and control group.
timeFrame: Up to 12 weeks after treatment initiation
measure: The incidence of Columbia-Suicide Severity Rating Scale (C-SSRS) events at week 14 compared with baseline (visit 1) and control group.
timeFrame: Up to 14 weeks after treatment initiation
Other outcomes:
measure: The abundance of fecal flora at week 12 compared with baseline (visit 1).
timeFrame: Up to 12 weeks after treatment initiation
measure: Quantitative and qualitative changes in fecal metabolomics analysis at week 12 compared with baseline (visit 1).
timeFrame: Up to 12 weeks after treatment initiation
measure: Profiling of lymphocytes subtypes in serum, including absolute counting and ratio of each type of lymphocyte, at week 12 compared with baseline (visit 1).
timeFrame: Up to 12 weeks after treatment initiation
measure: 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).
timeFrame: Up to 12 weeks after treatment initiation
measure: 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).
timeFrame: Up to 12 weeks after treatment initiation
Locations:
city: Wuhan
country: China
facility: Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology
state: Hubei
Study officials:
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