Effect of Akkermansia Muciniphila WST01 Strain in Overweight or Obese Patients With Type 2 Diabetes

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to conduct a randomized, double-blinded, placebo-controlled, multicenter clinical trial, evaluating the glucose-lowering and weight-loss effects of Akkermansia muciniphila WST01 strain in overweight or obese patients with Type 2 Diabetes.

Detailed Description
-----------------
In the present study, about 60 overweight/obese and drug naïve type 2 diabetes patients will be enrolled from multiple centers in China. After screening, eligible subjects will be randomized (1:1) into two groups, taking either Akkermansia muciniphila WST01 strain product or placebo product for 12 weeks. Blood, feces and urine samples will be collected before and after treatment. Metabolic parameters including waist and hip circumference, area of visceral and subcutaneous fat, glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), insulin, glucagon-like peptide 1 (GLP-1), inflammation factors and lipid levels will be measured. Furthermore, the change of gut microbiota and metabolites will be evaluated too. The primary objective is to determine whether Akkermansia muciniphila WST01 strain has a positive effect in patients with Type 2 Diabetes. The secondary objective is to explore the effect of Akkermansia muciniphila WST01 strain on safety, intestinal flora, insulin sensitivity, and other metabolic indicators and metabolites in the patients.

Official Title
-----------------
A Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Trial to Evaluate the Effect of Akkermansia Muciniphila WST01 Strain in Patients With Type 2 Diabetes

Conditions
-----------------
Obese, Overweight, Type 2 Diabetes

Intervention / Treatment
-----------------
* Drug: WST01 strain product
* Drug: placebo powder


Participation Criteria
=================
Eligibility Criteria
-----------------
Main Inclusion Criteria: Subjects with type 2 diabetes mellitus; Age 18-60 years; Overweight / obesity (24.0 ≤ BMI ≤ 40.0 kg/m2)； Subjects with or without other obesity related metabolic complications (hypertension, dyslipidemia, hyperuricemia, etc.); Subjects with screening HbA1c ≥ 7.0% and ≤ 10.0%, and the fasting blood glucose ≥ 7.0 mmol/l and ≤ 13.3 mmol/l； Subjects who are not taking any medications to control blood glucose; Subjects control blood glucose only by lifestyle intervention (diet and exercise) for at least 2 months before the screening period; Subjects understand the nature, significance, potential benefits, inconvenience, and risks of the study before it starts； Subjects fully understand the study produces and voluntarily sign the informed consent form. Main Exclusion Criteria: Subjects with a history of taking hypoglycemic drugs; Subjects who are pregnant or in lactation; Subjects with type 1 diabetes, single gene mutation diabetes, diabetes due to pancreatic injury or other secondary diabetes (such as Cushing's syndrome, thyroid dysfunction or acromegaly, etc.); Subjects who were or are using oral hypoglycemic agents or insulin or incretin to control diabetes; Subjects with liver and kidney dysfunction (alanine transaminase(ALT) / aspartate aminotransferase(AST)≥2.5×the upper limit of normal(ULN) set by the hospital, serum creatinine>1×ULN set by the hospital, or eGFR<60mL/min/1.73m2); Surgery with serious cardiovascular and cerebrovascular diseases (such as heart failure, myocardial infarction, cerebral infarction, acute myocarditis, severe arrhythmia, patients receiving interventional therapy, etc.) or stage III hypertension (systolic blood pressure cannot be controlled below 160 mmHg with three antihypertensive drugs); Subjects with acute diabetic complications such as diabetic ketoacidosis or diabetic hyperosmolar coma in the past 3 months; Subjects with a medical history of malignant tumor (except local skin basal cell carcinoma) in the past 5 years; Subjects with a medical history of intestine, or other digestive tract surgery (such as cholecystectomy) within one year, or other non-gastrointestinal surgery within 6 months; Any condition that in the judgement of the investigator precludes participation. Details please see the study protocol.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

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

Accepts Healthy Volunteers
-----------------
No

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental<br> | Drug: WST01 strain product<br>* orally given WST01 strain product, added onto lifestyle. The specific ingredients are the optimized Akkermansia muciniphila WST01 strain powder with maximum live bacteria of 5*10^10 CFU/g (1 g/pack, 3 packs QD, 20-30 min after breakfast)<br>|
| Placebo Comparator: Placebo comparator<br> | Drug: placebo powder<br>* orally given placebo powder (the specific ingrdients are the excipients of the WST01 strain powder), added onto lifestyle. (3 packs of placebo powder QD, 20-30 min after breakfast)<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body weight | change of body weight from baseline | 12 weeks | 
| Fasting plasma glucose levels | change of fasting plasma glucose from baseline | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gut microbiome | including fecal intestinal flora metagenome | 12 weeks | 
| Glycated haemoglobin (HbA1c) |  | 12 weeks | 
| 2-hour post-prandial plasma glucose levels |  | 12 weeks | 
| Fasting serum insulin levels |  | 12 weeks | 
| 2-hour post-prandial serum insulin levels |  | 12 weeks | 
| Fasting glucagon-like peptide-1 (GLP-1) levels |  | 12 weeks | 
| 2-hour post-prandial GLP-1 levels |  | 12 weeks | 
| Serum triglycerides |  | 12 weeks | 
| Serum total cholesterol |  | 12 weeks | 
| Serum LDL-c |  | 12 weeks | 
| Serum HDL-c |  | 12 weeks | 
| Area of visceral and subcutaneous fat |  | 12 weeks | 
| Waist and hip circumference |  | 12 weeks | 
| Energy expenditure | using metabolic chamber to measure energy expenditure | 12 weeks | 
| Blood metabolomics profile measurement | In aid of LC/MS and GC/MS technique, etc, we will measure the metabolomics molecular profile in blood samples before and after treatment. The metabolomics measurement will help to detect the profile of all kinds of bile acid species, lipids species and amino acid species, etc. The composition change of all these biological molecular induced by the treatment is our major interest rather than single molecular quantification. | 12 weeks | 
| Inflammation markers | including hs-CRP, TNF-alfa, IL-6, and IL-8, etc | 12 weeks | 
| Systolic and diastolic blood pressure | Safety outcomes | 12 weeks | 
| Body temperature | Safety outcomes | 12 weeks | 
| Pulse rate | Safety outcomes | 12 weeks | 
| White blood cell (WBC) count | Safety outcomes | 12 weeks | 
| Red blood cell (RBC) count | Safety outcomes | 12 weeks | 
| Hemoglobin levels | Safety outcomes | 12 weeks | 
| Platelet count | Safety outcomes | 12 weeks | 
| Hepatic function | including alanine aminotransferase, aspartate aminotransferase，ɣ-glutamyltransferase, and alkaline phosphatase | 12 weeks | 
| Renal function | including serum urea nitrogen, serum creatinine, and serum urinary acid | 12 weeks | 
| Adverse events | Safety outcomes | 12 weeks | 
| Fasting serum C peptide levels |  | 12 weeks | 
| 2-hour post-prandial serum C peptide levels |  | 12 weeks | 
| Lean mass | using DEXA scan to measure lean mass | 12 weeks | 
| Fat mass | using DEXA scan to measure fat mass | 12 weeks |