A Study on the Efficacy and Gut Microbiota of Berberine and Probiotics in Patients With Newly Diagnosed Type 2 Diabetes

Probiotics and BeRberine on the Efficacy and Change of Gut MicrObiota in paTients With Newly Diagnosed Type 2 diabEtes（PREMOTE Study）

The purpose of this study is to conduct a multicenter randomized, double-blind, placebo-controlled clinical trial, evaluating the effects and change of gut microbiota after berberine and/or probiotics administration in patients with newly diagnosed type 2 diabetes

Study Overview

• Status: Unknown
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: 1. Berberine hydrochloride tablets ; 2. ProMetS probiotics powder; Drug: 1. Berberine placebo tablets ; 2. ProMetS probiotics powder; Drug: 1. Berberine hydrochloride tablets; 2. Probiotics placebo powder; Drug: 1. Berberine placebo tablets; 2. Probiotics placebo powder

Detailed Description

In the present study, about 400 newly-diagnosed type 2 diabetes patients will be enrolled from multiple centers in China. Randomisation was computer generated and stratified by age. After screening, eligible subjects will be given Gentamycin Sulfate Sustained-release Tablets 80mg bid po for a week at the washout period, then all participants will be randomly assigned into one of the following four groups: Berberine hydrochloride tablets（0.6g bid po）and ProMetS probiotics powder（4g qN po), Berberine placebo tablets（6 pills bid po) and ProMetS probiotics powder (4g qN po), Berberine hydrochloride tablets（0.6g bid po）and Probiotics placebo powder (2 strips qN po), Berberine placebo tablets（6 pills bid po) and Probiotics placebo powder (2 strips qN po) for 3 months.

The primary objective is to determine whether a combination of probiotics and berberine is preferable to either berberine alone or probiotics alone, in comparison with placebo in improving 1). glycemic control, as measured by change in HbA1c level from baseline to 13-week follow-up, and 2). glycemic control, as measured by change in HbA1c level from baseline to 13-week follow-up in participants aged ≥ 50 years.

Blood, feces and urine samples will be collected before and after treatment. HbA1C, fasting plasma glucose (FPG), postprandial plasma glucose (PPG), GLP-1 , lipids, amino acids, bile acids and other metabolic related components and parameters will be measured. Furthermore, the change of gut microbiota will be evaluated too.

• Study Type: Interventional
• Enrollment (Anticipated): 400
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China
      • Ruijin Hospital，Shanghai Jiao Tong University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 69 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Main Inclusion Criteria:

1. Newly diagnosed type 2 diabetes defined as WHO (1999) diagnostic criteria ; Both Genders Eligible;
2. Age: ≥20 and <70 years;
3. BMI: 19.0 ~ 35.0kg/m2;
4. Not receive previously with anti-diabetic agents (oral agents, GLP-1 or insulin);
5. Have at least 2 months of life style intervention to control blood glucose before screening;
6. HbA1c ≥6.5% and ≤10.0%, and fasting plasma glucose≥7.0 mmol/L and ≤13.3mmol/L at screening.

Details please see the study protocol. -

Main Exclusion Criteria:

1. Significant impaired liver function (defined as alanine transaminase (ALT)> 2.5 times upper limit of normal); Impaired renal function (defined as serum-creatinine> 132μmol/L or eGFR <60 mL/min/1.73m2 ); Mental disease, severe infection, severe anemia, neutropenia disease;
2. Other severe heart disease, such as congenital heart disease, rheumatic heart disease, hypertrophic or dilated cardiomyopathy, defined as New York Heart Association class III or IV;
3. Allergic to gentamicin or other amino glycosides antibiotics;
4. Histories of acute diabetic complications including diabetic ketoacidosis or hyperosmolar hyperglycemic non-ketotic coma within 3 months;
5. Pregnancy;
6. Acute and chronic diarrhea or severe constipation of the digestive tract diseases;
7. Medical history of malignant tumor (except local skin basal cell carcinoma) in the past 5 years;
8. Medical history of intestine, or other digestive tract surgery (such as cholecystectomy) within one year, or other non gastrointestinal surgery within 6 months.

Details please see the study protocol.

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Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A	Drug: 1. Berberine hydrochloride tablets ; 2. ProMetS probiotics powder; 0.6g (6 pills) of Berberine tablets administered twice a day orally before meal ;; 4g (2 strips) of ProMetS probiotics powder administered orally every night
Experimental: Group B	Drug: 1. Berberine placebo tablets ; 2. ProMetS probiotics powder; 6 pills of Berberine placebo tablets administered twice a day orally before meal;; 4g (2 strips) of ProMetS probiotics powder administered orally every night
Experimental: Group C	Drug: 1. Berberine hydrochloride tablets; 2. Probiotics placebo powder; 0.6g (6 pills) of Berberine tablets administered twice a day orally before meal;; 2 strips of probiotics placebo powder administered orally every night
Placebo Comparator: Group D	Drug: 1. Berberine placebo tablets; 2. Probiotics placebo powder; 6 pills of Berberine placebo tablets administered twice a day orally before meal;; 2 strips of probiotics placebo powder administered orally every night

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
HbA1c	13 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gut microbiome		13 weeks
Fasting glucose levels		13 weeks
2-hour postprandial glucose levels		13 weeks
Fasting insulin levels		13 weeks
2-hour postprandial insulin levels		13 weeks
Serum Triglycerides		13 weeks
Serum total Cholesterol		13 weeks
Serum HDL-c		13 weeks
Serum LDL-c		13 weeks
Blood metabolomics profile measurement	In aid of LC/MS and GC/MS technique, 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. The composition change of all these biological molecular induced by the treatment is our major interest rather than single molecular quantification	13 weeks
Blood Incretin	In aid of multiple ELISA based on xMAP Luminex technology, we will measure gut hormones, including Glp-1, GIP and PYY in ng/ml.	13 weeks
Inflammation markers (hs-CRP, TNF-alfa, IL-6, and IL-8 etc. in ng/ml)		13 weeks

Collaborators and Investigators

• Sponsor: Shanghai Jiao Tong University School of Medicine

Publications and helpful links

General Publications

• Zhang Y, Gu Y, Ren H, Wang S, Zhong H, Zhao X, Ma J, Gu X, Xue Y, Huang S, Yang J, Chen L, Chen G, Qu S, Liang J, Qin L, Huang Q, Peng Y, Li Q, Wang X, Kong P, Hou G, Gao M, Shi Z, Li X, Qiu Y, Zou Y, Yang H, Wang J, Xu G, Lai S, Li J, Ning G, Wang W. Gut microbiome-related effects of berberine and probiotics on type 2 diabetes (the PREMOTE study). Nat Commun. 2020 Oct 6;11(1):5015. doi: 10.1038/s41467-020-18414-8.

Study record dates

Study Major Dates

• Study Start (Actual): August 18, 2016
• Primary Completion (Actual): December 1, 2017
• Study Completion (Anticipated): May 1, 2019

Study Registration Dates

• First Submitted: August 1, 2016
• First Submitted That Met QC Criteria: August 5, 2016
• First Posted (Estimate): August 10, 2016

Study Record Updates

• Last Update Posted (Actual): February 12, 2019
• Last Update Submitted That Met QC Criteria: February 9, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Sensory System Agents; Anesthetics; Antiemetics; Gastrointestinal Agents; Dermatologic Agents; Hypnotics and Sedatives; Anesthetics, Local; Anti-Allergic Agents; Sleep Aids, Pharmaceutical; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Antipruritics; Diphenhydramine; Promethazine
• Other Study ID Numbers: CCEMD-20160301