Effect of Gut Microbiome Intervention on Aging Via Oral FMT

Study Overview
=================
Brief Summary
-----------------
A severe public health issue facing global population is aging. Increasing preclinical and clinical data indicate the contribution of gut microbiome on aging and aging-related diseases such as cardiovascular disease, Alzheimer Disease, and diabetes. Interventions on microbiota are developed including prebiotics, probiotics, and fecal microbial transplantation (FMT). FMT via oral capsules also advances in recent with limited safety concerns compared with invasive routes. A hypothesis is thus raised that gut microbiome intervention via oral FMT can be a potential safe approach to encourage healthy aging, with multiple aspects evaluated for clinical phenotype of frailty, anthropometric measurement, cognitive function, cardiovascular aging, physical function, living activity, hippocampal volume, telomere length, cognitive biomarkers, inflammatory biomarkers, altered microbial composition and metabolites.

Detailed Description
-----------------
Objective: To explore the effect, safety and underlying mechanisms of gut microbiome intervention via FMT on aging. Study Design: A multi-center, randomized, blinded, placebo-controlled pilot study. Data quality control and statistical analysis: The investigators have invited professional statistic analysts to assist analyzing data and a third party to supervise data quality. Ethics: The Ethics Committee of Fuwai Hospital approved this study. Informed consents before patient enrollment are required.

Official Title
-----------------
Effect of Fecal Microbiota Transplantation on Aging and the Underlying Mechanism of Gut Microbiome Restoration: a Randomized Clinical Trial

Conditions
-----------------
Aging, Frailty

Intervention / Treatment
-----------------
* Biological: FMT capsules
* Other: Placebo capsules


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 70-85 years. Patients with informed consent after thorough explanation. Exclusion Criteria: Participants of other clinical trials; Antibiotics or probiotics usage within last 4 weeks; Severe hepatic or renal diseases ((ALT >3 times the upper limit of normal value, or end stage renal disease on dialysis or eGFR <30 mL/min/1.73 m2, or serum creatinine >2.5 mg/dl [>221 μmol/L]); History of large atherosclerotic cerebral infarction or hemorrhagic stroke (not including lacunar infarction and transient ischemic attack [TIA]); Hospitalization for myocardial infarction within last 6 months; Coronary revascularization (PCI or CABG) within last 12 months; Planned for PCI or CABG in the next 6 months; NYHA class III-IV heart failure; Hospitalization for chronic heart failure exacerbation within last 6 months; Severe valvular diseases; Potential for surgery or percutaneous valve replacement within the study period; Dilated cardiomyopathy; Hypertrophic cardiomyopathy; Rheumatic heart disease; Congenital heart disease; History of dementia, Parkinson's disease, intracranial infection, intracranial tumor, schizophrenia, anxiety, depression; History of neurosurgical operation; History of gastrointestinal tumor, gastrointestinal surgery, inflammatory bowel disease; Hospitalization for peptic ulcer disease exacerbation within last 6 months or anticipated hospitalization for peptic ulcer disease the next 6 months; Hypertension with uncontrolled blood pressure ≥180/110mmHg; Diabetes Mellitus with uncontrolled fasting glucose level ≥200mg/dl (11.1mmol/L), or HbA1C>8%; Addicted to alcohol; Use of medication influencing cognitive function(i.e., antihistamine, antipsychotic); General anesthesia within last 3 months; Other severe diseases influencing the entry or survival of participants, such as malignant tumor or acquired immune deficiency syndrome, life expectancy <1 year; Impaired verbal communication who are incapable of providing their own informed consent, or incapable of self-care; Special diet influencing microbiota (i.e. vegetarian); Other conditions inappropriate for recruitment according to the investigators.

Ages Eligible for Study
-----------------
Minimum Age: 70 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FMT capsules<br>FMT capsules containing extensively screened donor stool. FMT capsules will be orally taken on week 0, week 4, week 8, week 12, week 24, week 36, week 48, week 60, week 72, week 84. | Biological: FMT capsules<br>* FMT capsules containing extensively screened donor stool.<br>|
| Placebo Comparator: Placebo capsules<br>Placebo capsules that do not contain donor stool or any active drug. Placebo capsules will be orally taken on week 0, week 4, week 8, week 12, week 24, week 36, week 48, week 60, week 72, week 84. | Other: Placebo capsules<br>* Placebo capsules that do not contain donor stool or any active drug.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with reduced frailty score at week 96 follow-up | Frailty score via CHS criteria of five frailty components, compared with baseline | week 96 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with reduced frailty score at week 12 follow-up | Frailty score via CHS criteria of five frailty components, compared with baseline | week 12 | 
| Proportion of participants with reduced frailty score at week 24 follow-up | Frailty score via CHS criteria of five frailty components, compared with baseline | week 24 | 
| Proportion of participants with reduced frailty score at week 48 follow-up | Frailty score via CHS criteria of five frailty components, compared with baseline | week 48 | 
| Proportion of participants with reduced frailty score at week 72 follow-up | Frailty score via CHS criteria of five frailty components, compared with baseline | week 72 | 
| Change from baseline in Frailty score | Frailty score via CHS criteria of five frailty components, ranging from 0 to 5, with higher score indicating worse outcome | week 12, week 24, week 48, week 72, week 96, compared with baseline | 
| Change from baseline in telomere length | Change from baseline in telomere length | week 48, week 96 | 
| Change from baseline in Cognitive assessment via Mini Mental State Examination(MMSE) | MMSE (Mini Mental State Examination) ranging from 0 to 30, with lower score indicating worse outcome | week 24, week 48, week 72, week 96, compared with baseline | 
| Change from baseline in Cognitive assessment via Montreal Cognitive Assessment(MoCA) | MoCA (Montreal Cognitive Assessment) ranging from 0 to 30, with lower score indicating worse outcome | week 24, week 48, week 72, week 96, compared with baseline | 
| Change from baseline in Hippocampal volumes | Hippocampal volumes evaluated by Magnet Resonance Imaging | week 48, week 96 | 
| Change from baseline in cognitive biomarkers | plasma levels of cognitive biomarkers for BDNF、tau、Aβ-40、Aβ42 | week 12, week 24, week 48, week 72, week 96 | 
| Change from baseline in inflammatory biomarkers | plasma levels of inflammatory biomarkers for hs-C-reactive protein (hs-CRP)、 interleukin 6(IL-6)、interleukin 1 β(IL-1 β) 、interleukin10 (IL-10)、tumor necrosis factor α(TNF-α) | week 12, week 24, week 48, week 72, week 96 | 
| Change from baseline in Intestinal Microbiota Composition Pre- and Post-intervention via Metagenomic Analysis | Change in Intestinal Microbiota Composition Pre- and Post-intervention (FMT or Placebo) via Metagenomic Analysis, stratified by: Randomisation Change in Office SBP | week 12, week 24, week 48, week 72, week 96 | 
| Change from baseline in Intestinal Microbiota Function assessed by KEGG Orthology (KO) Pre- and Post-intervention via Metagenomic Analysis | Change in Intestinal Microbiota Function assessed by KEGG Orthology (KO) Pre- and Post-intervention (FMT or Placebo) via Metagenomic Analysis, stratified by: Randomisation Change in Office SBP | week 12, week 24, week 48, week 72, week 96 | 
| Change from baseline in Plasma Metabolite Composition Pre- and Post-intervention via Metabolomic Analysis | Change in Plasma Metabolite Composition Pre-and Post-intervention (FMT or Placebo) via Metabolomic Analysis | week 12, week 24, week 48, week 72, week 96 | 
| Change from baseline in Ankle-Brachial Blood Pressure Index(ABI) | Change for ABI as an objective measurement of arterial insufficiency based on the ratio of ankle systolic pressure to brachial systolic pressure. | week 48, week 96 | 
| Change from baseline in Pulse wave velocity(PWV) | Change for Pulse wave velocity(PWV) | week 48, week 96 | 
| Number of Participants with Adverse Events (AEs) as a Measure of Safety | Number of Participants with Adverse Events (AEs) as a Measure of Safety | week 12, week 24, week 48, week 72, week 96 | 
| Change from baseline in Body Mass Index (BMI) | Change for Body Mass Index | week 4, week 8, week 12, week 24, week 48, week 72, week 96 | 
| Change from baseline in office SBP | change for office systolic blood pressure(SBP) | week 4, week 8, week 12, week 24, week 48, week 72, week 96 | 
| Change from baseline in office DBP | change for office diastolic blood pressure(DBP) | week 4, week 8, week 12, week 24, week 48, week 72, week 96 | 
| Change from baseline in Blood Lipid Level | Change for Blood Lipid Level (Total Cholesterol, Total Triglyceride, Low Density Lipoprotein Cholesterol, High Density Lipoprotein Cholesterol) | week 12, week 24, week 48, week 96 | 
| Change from baseline in blood fasting glucose level | Change for blood fasting glucose level | week 12, week 24, week 48, week 96 | 
| Change from baseline in blood HbA1c level | Change for blood glycosylated hemoglobin, type A1C (HbA1c) level | week 12, week 24, week 48, week 96 | 
| Change from baseline in physical function assessment via 6MWT | 6-minute walking test(6MWT) | week 12, week 24, week 48, week 72, week 96 | 
| Change from baseline in daily function assessment via Activity of Daily Living (ADL) | Activity of Daily Living (ADL) ranging from 0 to 100, with lower score indicating worse outcome | week 12, week 24, week 48, week 72, week 96 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Aging, Frailty, Microbiome, Treatment, Fecal Microbiota Transplantation