Safety and Efficacy of Fecal Microbiota Transplantation on Cognitive Function in T1DM: a Randomized Controlled, Triple-blind Clinical Study
Overview
- Phase
- Not Applicable
- Intervention
- fecal microbiota transplantation
- Conditions
- Type 1 Diabetes
- Sponsor
- Second Xiangya Hospital of Central South University
- Enrollment
- 40
- Locations
- 1
- Primary Endpoint
- Cognition: Comparison of the average change in Auditory Verbal Learning Test between the experimental and control groups from baseline to week 24.
- Status
- Recruiting
- Last Updated
- last year
Overview
Brief Summary
This study is a prospective, single-center, parallel-design,1:1 randomized controlled trial with triple blinding. It aims to investigate the effects of fecal microbiota transplantation (FMT) on cognitive function in patients with long-term type 1 diabetes (T1D), as well as its effects on other complications, glycemic control, insulin dosage, insulin resistance, peripheral blood immune cells, serum metabolites, and safety. This study is divided into two phases for recruiting participants. The first phase recruits 10 individuals (experimental group: 5, control group: 5), while the second phase recruits 30 individuals (experimental group: 15, control group: 15).The main research objectives are as follows:
- To observe the difference in cognitive function between the FMT group and the placebo group, with the indicators including cognitive scale scores, changes in brain MRI imaging indicators and brain age at week 24 compared to baseline.
- To observe the difference in other complications between the FMT group and the placebo group, with the indicators including changes in urinary albumin/creatinine ratio, fundus photography, carotid intima-media thickness, and arterial pulse wave velocity at week 24 compared to baseline.
- To observe the difference in glycemic control, insulin dosage, insulin resistance, peripheral blood immune cells, gut microbiota, and serum metabolites between the FMT group and the placebo group.
- To evaluate the safety of FMT.
Investigators
Xia Li
Professor, Department of Endocrinology, Institute of of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Second Xiangya Hospital of Central South University
Second Xiangya Hospital of Central South University
Eligibility Criteria
Inclusion Criteria
- •According to the definition of type 1 diabetes mellitus (T1DM) by the World Health Organization (WHO), the diagnostic criteria are as follows: (i) clinically diagnosed as T1D by endocrinologists; (ii) insulin dependence from disease onset and diabetic ketoacidosis (DKA)/diabetic ketosis (DK) at diagnosis; (iii) positive for at least one of islet autoantibodies for glutamic acid decarboxylase antibody \[GADA\], insulinoma-associated protein 2 antibody \[IA-2A\], and zinc transporter 8 antibody \[ZnT8A\]; or negative for all three islet autoantibodies, but diagnosed before age
- •Age between 18 and 60 years, with a diabetes duration of 10 years or more
- •Glycated hemoglobin levels ranging from 6.5% to 9.0%.
Exclusion Criteria
- •Use of any hypoglycemic medication other than insulin in the two months prior to randomization.
- •Participation in other clinical trials within the two months prior to randomization.
- •Use of antimicrobial drugs, probiotics, intestinal microbiota regulators, and other drugs with significant impact on gut microbiota within the two months prior to randomization.
- •Gastrointestinal diseases: celiac disease, irritable bowel syndrome, Crohn's disease, etc.
- •Severe infections, severe heart, liver, kidney diseases, tumors, and other inflammatory or autoimmune diseases.
- •Pregnant or lactating women, or women planning pregnancy during the study period.
- •Severe mental health disorders such as schizophrenia, major depression, bipolar disorder, alcohol or substance abuse, etc.
- •Neurological disorders such as Parkinson's disease, progressive supranuclear palsy, epilepsy, multiple sclerosis, traumatic brain injury, stroke, etc.
- •Post-implantation of metal materials or contraindications for other MRI examinations.
- •Severe episodes of unconscious hypoglycemia within the past two months.
Arms & Interventions
fecal microbiota transplantation
On the basis of baseline medication, high-dose fecal microbiota transplantation (FMT) will be administered, with subjects taking 50 fecal microbiota capsules. Subsequently, maintenance doses will be administered at week 2, 4, 8, 12, and 20, with 10 capsules taken each time. Fasting is required 4 hours before and 1 hour after capsule ingestion, and subjects are instructed to maintain a stable diet and physical activity pattern throughout the 24-week study period. Capsules will be transported on ice and warmed for 10 minutes at 37°C before FMT administration.
Intervention: fecal microbiota transplantation
placebo
Different from the experimental group, the control group will receive placebo capsules that have the same appearance as the fecal microbiota capsules, while other procedures remain the same as those in the experimental group.
Intervention: Placebo
Outcomes
Primary Outcomes
Cognition: Comparison of the average change in Auditory Verbal Learning Test between the experimental and control groups from baseline to week 24.
Time Frame: from baseline to week 24
The Auditory Verbal Learning Test (AVLT) is a neuropsychological assessment tool used to evaluate an individual's verbal learning and memory skills. This test involves the presentation of a list of words to the test subject, who is then asked to recall as many words as possible from the list after a single exposure. The process is typically repeated several times, allowing the examiner to assess the subject's ability to learn new information and retain it over time.
Cognition:Comparison of the average change in Z-scores for memory and executive domain-related assessments between the experimental and control groups from baseline to week 24.
Time Frame: from baseline to week 24
The Z-scores of memory and executive domain assessments-related assessments are indicators that can comprehensively reflect cognitive function.
Cognition: Comparison of the average change in Trail Making Test Part A and Part B between the experimental and control groups from baseline to week 24.
Time Frame: from baseline to week 24
The Trail Making Test is a neuropsychological test of visual attention and task switching. It consists of two parts, A and B. Participant is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. The test can provide information about visual search speed, scanning, speed of processing, mental flexibility, as well as executive functioning. Results for both TMT A and B are reported as the number of seconds required to complete the task; therefore, higher scores reveal greater impairment.
Cognition: Comparison of the average change in Stroop Color- Word Association Test between the experimental and control groups from baseline to week 24.
Time Frame: from baseline to week 24
The Stroop Color- Word Association Test is particularly useful in assessing executive functions, such as selective attention and cognitive flexibility. It is sensitive to the effects of various conditions that impact cognitive control, including attention deficit hyperactivity disorder (ADHD), Alzheimer's disease, Parkinson's disease, and substance abuse disorders. The test can also be used to evaluate the effectiveness of cognitive training programs and to monitor changes in cognitive function over time.
Cognition: Comparison of the average change in Verbal Fluency Test between the experimental and control groups from baseline to week 24.
Time Frame: from baseline to week 24
The Verbal Fluency Test (VFT) is a common neuropsychological assessment used to evaluate an individual's cognitive flexibility and generative language abilities. It typically involves asking the participant to produce as many words as possible within a certain time limit, usually one minute, that fit a specific criterion.
Cognition: Comparison of the average change in Boston Naming Test between the experimental and control groups from baseline to week 24.
Time Frame: from baseline to week 24
The Boston Naming Test (BNT) is a widely used neuropsychological instrument designed to assess an individual's confrontational naming abilities, which is a critical aspect of language function. The test consists of a series of line drawings of objects, animals, and people, each paired with a prompt that encourages the participant to name the item.
Cognition: Comparison of the average change in Subjective Cognitive Decline 9 between the experimental and control groups from baseline to week 24.
Time Frame: from baseline to week 24
Subjective Cognitive Decline 9 (SCD9) is a tool designed to assess an individual's perception of changes in their cognitive abilities over time. It is particularly useful for identifying early signs of cognitive decline that may be indicative of the onset of neurodegenerative diseases such as Alzheimer's disease. The development of the SCD9 questionnaire aims to provide a localized, sample-assisted, multi-domain instrument that can be used to evaluate subjective cognitive decline in the elderly population over the past 1-2 years. The scale has demonstrated good reliability and validity, with a confirmatory factor analysis supporting a 4-factor model that includes memory, attention, executive function, and language domains.
Cognition: Comparison of the average change in Symbol Digit Modalities Test between the experimental and control groups from baseline to week 24.
Time Frame: from baseline to week 24
The Symbol Digit Modalities Test (SDMT) is a brief neuropsychological screening tool designed to assess cognitive processing speed and attention. The SDMT is scored based on the number of correct responses within the time frame, providing a quantitative measure of cognitive performance. It is particularly sensitive to changes in cognitive function that may occur with aging, as well as in conditions such as multiple sclerosis, Parkinson's disease, traumatic brain injury, and Alzheimer's disease. The test is often used to monitor the progression of cognitive decline and to evaluate the effectiveness of treatments. The SDMT is also valuable in differentiating between different types of cognitive impairments and can be used as part of a comprehensive neuropsychological assessment to provide a more detailed picture of an individual's cognitive strengths and weaknesses. Its brevity and ease of administration make it a practical tool for repeated assessments over time.
Cognition: Comparison of the average change in Clock drawing test between the experimental and control groups from baseline to week 24.
Time Frame: from baseline to week 24
The Clock Drawing Test (CDT) is a widely used neuropsychological screening tool that assesses an individual's cognitive function, particularly in the areas of executive function, visual-spatial skills, and constructional praxis. It is a simple yet effective test that requires participants to draw a clock face and then set the hands to indicate a specific time, often 10 minutes past 11.
Cognition: Comparison of the average change in MOCA between the experimental and control groups from baseline to week 24.
Time Frame: from baseline to week 24
The Montreal Cognitive Assessment (MOCA) is a rapid screening tool for mild cognitive dysfunction, particularly useful in identifying early signs of cognitive impairment associated with conditions such as Alzheimer's disease and other forms of dementia.The test is sensitive to changes in cognitive function that may not be detected by less detailed assessments, making it a valuable tool for both clinical and research settings.
Cognition: Comparison of the average change in Brain MRI between the experimental and control groups from baseline to week 24.
Time Frame: from baseline to week 24
Brain MRI, particularly structural Structural MRI, Diffusion MRI(DTI), and Functional MRI (fMRI), plays a crucial role in understanding cognitive functions. Structural MRI can identify anatomical correlates of cognitive deficits, while DTI provides insights into the integrity of neural pathways essential for cognitive processing. fMRI allows researchers to observe brain activity during various cognitive tasks, offering a direct link between brain function and cognition. This comprehensive approach enables clinicians and researchers to explore the neural basis of cognitive functions and disorders, enhancing diagnosis and treatment strategies.
Secondary Outcomes
- microvascular complications：Comparison of the average change in Neuropathy lmpairment Score in the Lower Limbs between the experimental and control groups from baseline to week 24.(from baseline to week 24)
- Blood lipid：Comparison of the average change in total cholesterol between the experimental and control groups from baseline to week 24.(from baseline to week 24)
- Blood lipid：Comparison of the average change in high-density lipoprotein cholesterol between the experimental and control groups from baseline to week 24.(from baseline to week 24)
- Safety: Proportion of participants with treatment-related adverse events, serious adverse events, or adverse events of special interest.(from baseline to week 24)
- microvascular complications：Comparison of the average change in Albumin-to-Creatinine Ratio between the experimental and control groups from baseline to week 24.(from baseline to week 24)
- Glycemic control：Comparison of the average change in Time Above Range between the experimental and control groups from baseline to week 24.(from baseline to week 24)
- macrovascular complications：Comparison of the average change in Carotid Intima-Media Thickness between the experimental and control groups from baseline to week 24.(from baseline to week 24)
- macrovascular complications：Comparison of the average change in Arterial Pulse Wave Velocity between the experimental and control groups from baseline to week 24.(from baseline to week 24)
- macrovascular complications：Comparison of the average change in Ankle-Brachial Index between the experimental and control groups from baseline to week 24.(from baseline to week 24)
- microvascular complications：Comparison of the average change in Estimated Glomerular Filtration Rate between the experimental and control groups from baseline to week 24.(from baseline to week 24)
- microvascular complications：Compare the differences in the proportion of abnormal fundus photography and the severity of progression between the experimental and control groups during the follow-up period.(from baseline to week 24)
- Glycemic control：Comparison of the average change in Hemoglobin A1c between the experimental and control groups from baseline to week 24.(from baseline to week 24)
- Blood lipid：Comparison of the average change in triglycerides between the experimental and control groups from baseline to week 24.(from baseline to week 24)
- Glycemic control：Comparison of the average change in Time in Range between the experimental and control groups from baseline to week 24.(from baseline to week 24)
- Glycemic control：Comparison of the average change in Time Below Range between the experimental and control groups from baseline to week 24.(from baseline to week 24)
- Glycemic control：Comparison of the average change in Glucose Management Indicato between the experimental and control groups from baseline to week 24.(from baseline to week 24)
- Glycemic control：Comparison of the average change in Mean Amplitude of Glycemic Excursions between the experimental and control groups from baseline to week 24.(from baseline to week 24)
- Body Mass Index：Comparison of the average change in body mass index between the experimental and control groups from baseline to week 24.(from baseline to week 24)
- Insulin resistance: Comparison of the average change in estimated Glucose Disposal Rate between the experimental and control groups from baseline to week 24.(from baseline to week 24)
- Insulin dose: Comparison of the average change in insulin dose between the experimental and control groups from baseline to week 24.(from baseline to week 24)
- Glycemic control：Comparison of the average change in Glycemia risk index between the experimental and control groups from baseline to week 24.(from baseline to week 24)
- Glycemic control：Comparison of the average change in Coefficient of Variation between the experimental and control groups from baseline to week 24.(from baseline to week 24)
- Blood pressure：Comparison of the average change in blood pressure between the experimental and control groups from baseline to week 24.(from baseline to week 24)
- Blood lipid：Comparison of the average change in low-density lipoprotein cholesterol between the experimental and control groups from baseline to week 24.(from baseline to week 24)
- Change in gut composition: Engraftment of fecal microbial transplant as assessed by 16S rRNA sequencing of recipient stool sample(from baseline to week 24)
- Changes in peripheral blood metabolites: Assessing the impact of fecal microbiota transplantation on peripheral blood metabolites using metabolomics.(from baseline to week 24)
- Changes in peripheral blood mononuclear cells: Assessing the effects of fecal microbial transplant on peripheral blood mononuclear cells by flow cytometry.(from baseline to week 24)