Efficacy and Safety of Bifidobacterium Quadruple Live Tablets in Patients With T2DM and Constipation

Study Overview
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Brief Summary
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Constipation is one of the common complication of diabetes mellitus, whose pathogenesis was previously recognized as decreased gastrointestinal motility caused by diabetic autonomic neuropathy. It is always treated with gastrointestinal motility drugs or laxatives which may have side effects such as gut microbiota dysbiosis and withdraw symptoms. Recently, researches have indicated that the risk of developing type 2 diabetes mellitus is associated with alterations in the structure of the gut microbiota and have begun to treat diabetic constipation by improving gut microbiota of these patients. The rational use of microecological preparation for the prevention and treatment of diabetic constipation has received increasing attention. This trial is aimed to evaluate the efficacy and safety of Combined Bifidobacterium, Lactobacillus, Enterococcus and Bacillus Cereus Tablets, Live (Siliankang) in the treatment of patients with type 2 diabetes and constipation, and to analyze its influence on gut microbiota and blood glucose.

Detailed Description
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This is a 16 week, 1:1 randomised, controlled, open label, two-arm, parallel-group trial evaluating efficacy and safety of Combined Bifidobacterium, Lactobacillus, Enterococcus and Bacillus Cereus Tablets, Live (Siliankang) in patients with type 2 diabetes and constipation. Patients will be randomized into experimental group or control group treated with Siliankang or placebo tablets respectively. Total trial duration for the individual subject will be approximately 16 weeks including screening, 12-weeks treatment and 4-weeks follow-up. Patients will attend at 2-week, 8-week, 12-week and 16-week throughout the trial taking physical examination, having blood test, collecting faecal specimen and completing the questionnaire of constipation under the direction of doctors.

Official Title
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Efficacy and Safety of Combined Bifidobacterium, Lactobacillus, Enterococcus and Bacillus Cereus Tablets, Live (Siliankang) in Patients With Type 2 Diabetes and Constipation: a Randomized, Double-blind, Placebo-controlled, Multicenter Trial

Conditions
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Type 2 Diabetes Mellitus With Complication

Intervention / Treatment
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* Drug: Bifidobacterium, Lactobacillus, Enterococcus and Bacillus Cereus Tablets, Live
* Drug: Siliankang simulating tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: According to the diagnostic criteria of World Health Organization (WHO) in 1999, type 2 diabetes mellitus was diagnosed clinically. The duration of T2DM was no more than 8 years (including 8 years). According to the ROME III diagnostic criteria of functional constipation or guideline for diagnosis and treatment of chronic constipation in China (2013 edition), chronic constipation was diagnosed clinically. The duration of constipation was more than 6 months (including 6 months). The age ranged from 18 to 70 years (including 18 and 70 years) with no restriction of sex. Fasting blood glucose was no more than 8mmol/L and glycosylated hemoglobin ranged from 7.0% to 10.0% (including 7.0% and 10.0%). Sign written consent form voluntarily. Exclusion Criteria: Other types of diabetes mellitus. History of diabetic ketoacidosis and hyperosmolar hyperglycemic syndrome. Constipation induced by drugs[i.e. antidepressants, calcium antagonists, diuretics, sympathetic agents, antacids with aluminum or calcium, calcium agents, iron agents, antidiarrhetics]. Organic constipation [i.e. intestinal diseases，endocrine and metabolic diseases (except diabetes), nervous system and muscle disease]. Gastrointestinal diseases [i.e. colitis, mesenteric lymphadenitis, with a history of intestinal surgery]. Using drugs that may affect clinical outcome evaluation in the past 2 weeks, such as antibiotics (penicillin, amoxicillin, erythromycin, azithromycin and cephalosporin, etc.), microecological preparations, laxative drugs (magnesium sulfate and lactulose, etc.); anthraquinones (rhubarb, aloe and senna, etc.); Gastrointestinal motility drugs (metoclopramide, domperidone, cisapride, etc). History of myocardial infarction or stroke within 6 months, or existing severe cardiovascular disease and risk. Abnormal liver function [i.e. serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) is 1.5 times higher than the upper limit of normal value]. Abnormal renal function [Creatinine exceeds the upper limit of normal value]. Severe hypertension that defined as systolic blood pressure ≥160 mmHg, diastolic blood pressure ≥90 mmHg with drug therapy, or hypotension (resting seat blood pressure < 90/50 mmHg). History of acute and chronic gastroenteritis or gastrointestinal surgery Psychosis, alcohol dependence or history of drug abuse. Lactating women, pregnant women and patients who have pregnancy plan during the trial or within 3 months after the trial. Participation in other studies three months before the trial. Allergic constitution or allergic to a variety of drugs. Those researchers think inappropriate to the research.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental group<br>Patients will be instructed to continue current antidiabetic treatment, which should be kept unchanged throughout the trial, and start treatment with Bifidobacterium, Lactobacillus, Enterococcus and Bacillus Cereus Tablets, Live (Siliankang) 3 tablets p.o. tid for 12 weeks. | Drug: Bifidobacterium, Lactobacillus, Enterococcus and Bacillus Cereus Tablets, Live<br>* Patients will be instructed to continue current antidiabetic treatment, which should be kept unchanged throughout the trial, and start treatment with Bifidobacterium, Lactobacillus, Enterococcus and Bacillus Cereus Tablets, Live (Siliankang) 3 tablets p.o. tid for 12 weeks.<br>* Other names: Siliankang;|
| Placebo Comparator: Control group<br>Patients will be instructed to continue current antidiabetic treatment, which should be kept unchanged throughout the trial, and start treatment with Siliankang simulative tablets 3 tablets p.o. tid for 12 weeks. | Drug: Siliankang simulating tablets<br>* Patients will be instructed to continue current antidiabetic treatment, which should be kept unchanged throughout the trial, and start treatment with Siliankang simulative tablets 3 tablets p.o. tid for 12 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of bowel movements | Changes from baseline in the number of completely spontaneous bowel movements (CSBMs) and number of spontaneous bowel movements (SBMs). Effectiveness is defined as CSBMs more than 3 times weekly (including 3 times) with increase from baseline, while ineffectiveness is defined as CSBMs less than 3 times weekly or with no increase from baseline. | Baseline, Week 2, Week 4, Week 8, Week 12, Week 16 | 
| Glycosylated hemoglobin | Changes from baseline in glycosylated hemoglobin. | Baseline, Week 12, Week 16 | 
| Glycosylated albumin | Changes from baseline in glycosylated albumin. | Baseline, Week 2, Week 4, Week 8, Week 12, Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gut micobiota | Changes from baseline in gut microbiota. | Baseline, Week 4, Week 8, Week 12, Week 16 | 
| The ratio of CSBMs to SBMs | Changes from baseline in the ratio of CSBMs to SBMs. | Baseline, Week 2, Week 4, Week 8, Week 12, Week 16 | 
| Bristol Stool Scale | Proportions whose stool characters recover to Type III and IV by Bristol Stool Scale. | Baseline, Week 2, Week 4, Week 8, Week 12, Week 16 | 
| Bowel Function Index (BFI) | Changes from baseline in the score of Bowel Function Index (BFI). | Baseline, Week 2, Week 4, Week 8, Week 12, Week 16 | 
| Patient Assessment of Constipation symptom (PAC-SYM) | Changes from baseline in the scale of Patient Assessment of Constipation symptom (PAC-SYM). | Baseline, Week 2, Week 4, Week 8, Week 12, Week 16 | 
| Patient global impression of changes (PGIC) | Difference in the Patient global impression of changes (PGIC) between experimental group and control group. | Week 16 | 
| The first time of CSBM | Difference in the first time of completely spontaneous bowel movement (CSBM) between the experimental group and control group. | Week 1 to Week 16 | 
| Fasting blood glucose | Changes from baseline in fasting blood glucose. | Baseline, Week 2, Week 4, Week 8, Week 12, Week 16 | 
| Serum lipid spectrum | Changes from baseline in serum lipid spectrum. | Baseline, Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 diabetes;Constipation;Gut microbiota;Bifidobacterium