Clinical trial NCT06474520: Efficacy and Safety of Calculus Bovis Sativus (CBS) for Idiopathic Inflammatory Demyelinating Disease (CBSinIIDD)
Official title: An Open Label Clinical Trial to Evaluate the Efficacy and Safety of Calculus Bovis Sativus (CBS) for Idiopathic Inflammatory Demyelinating Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Idiopathic Inflammatory Demyelinating Disease
Multiple Sclerosis
Neuromyelitis Optica Spectrum Disorder
Myelin Oligodendrocyte Glycoprotein Antibody-associated Disease
Acute Disseminated Encephalomyelitis
Lead sponsor: Tongji Hospital
Sponsor class: OTHER
Collaborators: name: Jianmin Pharmaceutical Group Co., LTD.
First posted: 2024-06-25
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: According to the records of traditional Chinese medicine, CBS has the following functions: clearing the heart, resolving phlegm, promoting bile secretion, and calming the nerves. It can treat fever, coma, delirium, epilepsy, convulsions in children, dental caries, throat swelling, oral sores, carbuncle, and furuncle.

The significant pathophysiological process of primary inflammatory demyelinating disease of the central nervous system (hereinafter referred to as IIDD) is the activation of the immune system of the central nervous system and the enhancement of inflammation. It includes several common diseases: multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody-related disease (MOGAD), acute disseminated encephalomyelitis (ADEM), concentric sclerosis, tumor-like inflammatory demyelinating disease, etc.

Combined with the inspiration brought to us by the above background research, especially bilirubin and bile acid are closely related to intestinal digestive function, and CBS is clinically effective through oral administration by subjects, the investigators speculate that CBS is likely to exert its immune, anti-inflammatory and neuroprotective effects on the brain by changing the intestinal flora and regulating the brain-gut axis. In terms of symptoms, CBS is likely to have the effect of improving the clinical symptoms of IIDD subjects and reducing disability.


Eligibility criteria: Inclusion Criteria:

* IIDD cohort:

  * Subjects are capable of understanding the purpose and risks of the study, providing informed consent and authorizing the use of confidential health information in accordance with national and local privacy regulations.
  * Both men and women are welcome, and the age at the time of providing informed consent is 18-65 years (inclusive).
  * All women of childbearing age and all men must use contraceptive measures 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.
  * Must be diagnosed with

    ① Multiple sclerosis, meet the 2017 revised McDonald criteria, and enter the MS cohort;

    ② Aquaporin Protein-4-positive (AQP4) neuromyelitis optica spectrum disease, meet the 2015 international consensus diagnostic criteria for neuromyelitis optica spectrum disease (NMOSD), and AQP4 antibody positive, enter the AQP4-NMOSD cohort;

    ③ Myelin oligodendrocyte glycoprotein antibody-related disease, clinically diagnosed as MOGAD according to the 2023 international MOGAD diagnostic criteria, and positive MOG autoantibody test by cell-based-assay method;

    ④ Acute disseminated encephalomyelitis, clinically diagnosed as ADEM according to the 2013 International Pediatric Multiple Sclerosis Study Group (IPMSSG) diagnostic criteria, characterized by multifocal neurological deficits, must have encephalopathy manifestations (behavioral changes and/or changes in consciousness that cannot be explained by fever, including irritability), and exclude other specific antibody-positive IIDD.
  * EDSS score ≤ 4 points at baseline (visit 1).
  * Stable neurological examination within 30 days prior to Baseline (Visit 1).
* 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: Expanded Disability Status Scale (EDSS)
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 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: Quantitative and qualitative changes in 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 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: Fecal flora abundance 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 cell subtypes 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
Locations:
city: Wuhan
country: China
facility: Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology
state: Hubei
Study officials:
affiliation: Tongji Hospital
name: Wei Wang, MD
role: PRINCIPAL_INVESTIGATOR
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