Effects Of Berberine Plus Inulin On Diabetes Care in Patients With LADA

Study Overview
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Brief Summary
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The primary purpose of this study is to evaluate the effects of oral berberine (BBR) and inulin combined with insulin therapy on diabetes care in patients with LADA.

Detailed Description
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Latent autoimmune diabetes in adults (LADA) is a hybrid form of diabetes, characterized by autoimmune destruction of pancreatic β-cells as well as insulin resistance and is triggered by environmental factors in the context of genetic susceptibility. Meanwhile，blood glucose management is the cornerstone of diabetes care and poor glycemic control will cause a series of diabetes complications. This study will focus on improving the quality of life of LADA patients and blood glucose management as the starting point to explore the improvement effects of combined drugs on the development of diabetes. Inulin is a common prebiotic that has been shown to improve glycemic control, alter the gut microbiota and suppress inflammation. Berberine(BBR), a small alkaloid isolated from medicinal plants, has been reported to have many therapeutic effects, including anti-bacteria, anti-diabetes, and lipid-lowering. Besides, studies revealed that BBR exerts antidiabetic effects by modulating gut microbiota. In a multicentre, randomized, double-blinded, placebo-controlled 12-week clinical trial conducted in 409 drug-naive T2D patients, Wang et al. confirmed the hypoglycaemic effect of BBR in Chinese participants and demonstrated the BBR-induced changes in the human gut microbiome in comparison with the placebo. Moreover, Ho et al. conducted a randomized, placebo-controlled trial in 38 children with type 1 diabetes using placebo or prebiotic oligofructose-enriched inulin for 12 weeks, and found that oral supplement of the prebiotic could improve glycemic status and β cell function. So we speculate that BBR and inulin combination can also improve glycemic control in the patients with LADA. This study is a prospective, randomized, double-blind, placebo-controlled trial. The study comprises once screening, the 1-month run-in period, the 3-month treatment period and the 9-month follow-up period. After obtaining the informed consent from the patient who is willing to participate the 3-month treatment will enter to the 1-month run-in period. According to the inclusion/exclusion criteria, the eligible patients will be randomized to the 3-month treatment period. Patients will be randomized into four groups : BBR-alone, inulin+BBR, inulin-alone, or placebo. The primary outcome is to assess the change in glycated hemoglobin levels. Dynamic blood glucose parameters, β-cell function and gut microbiota, as well as adverse events and quality of life will be monitored.

Official Title
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Effects of Berberine Plus Inulin on Diabetes Care in Patients With Latent Autoimmune Diabetes in Adults: A Randomized Controlled Trial

Conditions
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Type 1 Diabetes Mellitus, Autoimmune Diabetes

Intervention / Treatment
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* Drug: Berberine
* Drug: Inulin
* Drug: Berberine placebo tablets
* Drug: Inulin placebo tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diabetes diagnosed according to the report of WHO in 1999； Meet the Chinese Diabetes Society diagnostic criteria (2012) for LADA: (1)glutamic acid decarboxylase antibody (GADA) positive; (2) age at diagnosis ≧ 18 years old; (3) independent on insulin for more than 6 months after diagnosis; Aged between 18 and 70 years old; 7.0%≤HbA1c ≤10.0%; BMI ≥ 18.5 kg/m2, and no more than 37.5 kg/m2; Written informed consent from the patient or family representative. Exclusion Criteria: Severe liver dysfunction (ALT and AST greater than 3 times the upper limit of detection); eGFR < 50ml/(min • 1.73 m2); Evidence of acute or chronic infection affecting glycemic control within 4 weeks prior to the first visit; History of any malignancy; Pregnancy, breastfeeding, or planned pregnancy during the study period; Secondary diabetes; Presence of acute complications (ketoacidosis, lactic acidosis or hyperosmolar coma); Severe organic heart disease, including but not limited to congenital heart disease, rheumatic heart disease, hypertrophic or dilated cardiomyopathy, etc., New York Heart Association (NYHA) heart function classification ≥Grade III; Chronic use of systemic glucocorticoids or other immunosuppressive agents for over 3 months，or use of antibiotic medications or other interventions that could affect the gastrointestinal tract for 2 months before the screening and during the whole study period. History of hemolytic anemia or glucose-6-phosphate dehydrogenase deficiency. Allergic to berberine or any components in the combinations.

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>LADA patients are assigned to receive berberine and inulin for 3-month. | Drug: Berberine<br>* 0.6g (6 pills) of Berberine tablets administered twice a day orally before meal for 3 months<br>Drug: Inulin<br>* 0.6g (6 pills) of Inulin tablets administered twice a day orally before meal for 3 months<br>|
| Experimental: Group B<br>LADA patients are assigned to receive berberine and placebo(for inulin) for 3-month. | Drug: Berberine<br>* 0.6g (6 pills) of Berberine tablets administered twice a day orally before meal for 3 months<br>Drug: Inulin placebo tablets<br>* 0.6g (6 pills) of Inulin placebo tablets administered twice a day orally before meal for 3 months<br>|
| Experimental: Group C<br>LADA patients are assigned to receive placebo(for berberine) and inulin for 3-month. | Drug: Inulin<br>* 0.6g (6 pills) of Inulin tablets administered twice a day orally before meal for 3 months<br>Drug: Berberine placebo tablets<br>* 0.6g (6 pills) of Berberine placebo tablets administered twice a day orally before meal for 3 months<br>|
| Placebo Comparator: Group D<br>LADA patients are assigned to receive placebo(for berberine) and placebo(for inulin) for 3-month. | Drug: Berberine placebo tablets<br>* 0.6g (6 pills) of Berberine placebo tablets administered twice a day orally before meal for 3 months<br>Drug: Inulin placebo tablets<br>* 0.6g (6 pills) of Inulin placebo tablets administered twice a day orally before meal for 3 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c | The primary outcome measure is the change in mean HbA1c level, reflecting the blood glucose management status of the patients. | 1 year after start of trial | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in C-peptide | C-peptide are measured before and after a mixed meal tolerance test. | 1 year after start of trial | 
| Incidence of acute and chronic diabetes complications | In this study, the chronic diabetes complications recorded mainly include diabetic macrovascular disease, diabetic nephropathy, diabetic retinopathy and peripheral neuropathy. | 1 year after start of trial | 
| Change in gut permeability | Gut permeability is measured by amount of mannitol and lactulose in urine. | 1 year after start of trial | 
| Change in gut microbiota composition | The changes of gut microbiota are mainly detected by multi omics technology. | 1 year after start of trial | 
| Assessment of quality of life | Quality of life will be assessed by the Chinese version of the Audit of Diabetes Dependent Quality of Life (ADDQoL-19). | 1 year after start of trial | 
| Gastrointestinal side effects and other drug-related side effects | The gastrointestinal side effects need to be self-reported by the patient, such as nausea, vomiting, diarrhea, constipation, flatulence, etc. | 1 year after start of trial | 
| Hypoglycemic events | Hypoglycemia events are divided into mild hypoglycemia and severe hypoglycemia. | 1 year after start of trial | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Inulin, LADA, Berberine, Diabetes Care