To Evaluate the Beneficial Effect of Probiotics on DKD Patients and the Role of Gut Microbiota Modulation

Sponsor

GenMont Biotech Incorporation (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05674981

Collaborator

Chung Shan Medical University (Other)

Enrollment

Location

Arms

Anticipated Duration (Months)

4.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

To evaluate the efficacy of probiotics in the treatment of diabetic kidney disease, this study is designed to explore after consumption of probiotics lactobacillus reuteri ADR-1 and lactobacillus rhamnosus GM-020 composite strain powder sachets for 6 months, whether the improvement of blood sugar, kidney related indicators can further improve the course of diabetic kidney disease. The clinical trial predicted that probiotics can improve diabetic kidney disease by changing the intestinal flora by inhibiting harmful bacteria, reduction of systemic oxidative stress, balance carbohydrate and fat metabolism, further preventing the progress of diabetic kidney disease.

Condition or Disease	Intervention/Treatment	Phase
Diabetic Kidney Disease	Dietary Supplement: Probiotic group Other: Placebo group	N/A

Detailed Description

WHO predicts that diabetes will become the seventh leading cause of death in 2030. This disease usually causes complications including hypertension, diabetic kidney disease, neuropathy, skin infection, and a high risk of blindness and so on. It demonstrated that probiotics have beneficial effects on several disorders; these beneficial effects include a reduction in allergic symptoms, a decrease in serum cholesterol levels, the prevention of obesity, and an improvement of the digestive system. In recent years, many studies have pointed out that Lactobacillus affects the progression of diabetes kidney disease by controlling blood sugar. From 2017 to 2020, 8 clinical trials conducted related research to explore the clinical benefits of probiotics on diabetic kidney disease. It was found that the indicators related to kidney function have ameliorated significantly, including improving glomerular function, blood sugar control, insulin metabolism, inflammatory substances in serum, and even oxidative stress factors, etc.

In a previous study, Lactobacillus strain ADR-1 was selected to verify the efficacy by utilizing HFD (High-fructose-fed) rats model, the result shows reductions in serum HbA1c and liver injury after oral gavage for 14 weeks. Afterward, a double-blind, randomized, placebo-group human clinical trial was conducted, recruiting 68 subjects with type 2 diabetes to evaluate the intestinal flora and blood sugar-related indicators, among which the metabolic indicators had significant changes. After taking it for 3 and 6 months, HbA1c and cholesterol were significantly reduced compared to the Placebo group, it was also found that the L.reuteri flora had a significant increase in the intestinal flora while the same pattern was found in the Bifidobacterium flora accordingly. This result represents the development of a positive correlation between Lactobacillus and Bifidobacterium for the intestinal flora. Furthermore, GM-020 has been proved by mouse model experiments to slow down kidney diseases, including the improvement of related indicators of renal function, serum urea nitrogen (BUN), and creatinine (Creatinine), and it shows dose-dependent variation. The combination of these two strains of probiotics is predicted to improve the metabolical index of diabetic kidney disease.

This clinical trial will explore the health-promoting effect of probiotics on patients with diabetic kidney disease, and fully explore how probiotics can improve the good bacteria and reduce the bad bacteria by changing the intestinal flora to achieve anti-inflammatory effects, Chronic inflammation, reduce systemic oxidative stress, balances carbohydrate and fat metabolism, and prevents the progression of diabetic kidney disease.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

50 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Parallel Assignment, Randomized Controlled TrialParallel Assignment, Randomized Controlled Trial

Masking:

Double (Participant, Investigator)

Primary Purpose:

Supportive Care

Official Title:

To Evaluate the Clinical Efficacy of Probiotic in Patients With DKD

Anticipated Study Start Date :

Feb 1, 2023

Anticipated Primary Completion Date :

Jan 31, 2024

Anticipated Study Completion Date :

Jan 31, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Probiotic group Subjects received two probiotic sachets per day	Dietary Supplement: Probiotic group Two-strain probiotic supplement includes Lactobacillus reuteri ADR-1 (alive) and Lactobacillus rhamnosus GM-020 ( alive). Other Names: Test group
Placebo Comparator: Placebo group Subjects received two placebo sachets per day	Other: Placebo group Same additives to Probiotic group but replace probiotics with corn starch and Maltodextrin. Other Names: Control group

Arm

Intervention/Treatment

Experimental: Probiotic group

Subjects received two probiotic sachets per day

Dietary Supplement: Probiotic group

Two-strain probiotic supplement includes Lactobacillus reuteri ADR-1 (alive) and Lactobacillus rhamnosus GM-020 ( alive).

Other Names:

Test group

Placebo Comparator: Placebo group

Subjects received two placebo sachets per day

Other: Placebo group

Same additives to Probiotic group but replace probiotics with corn starch and Maltodextrin.

Other Names:

Control group

Outcome Measures

Primary Outcome Measures

Change from baseline in Cys-C (Cystatin C) level at 3 months [3 months]
Blood samples will be collected to examine the variation of Cys-C (Cystatin C) from baseline at 3 months.
Change from baseline in Cys-C (Cystatin C) level at 6 months [6 months]
Blood samples will be collected to examine the variation of Cys-C from baseline at 6 months.

Secondary Outcome Measures

Change from baseline in BMI (Body Mass Index) at 3 months [3 months]
BMI will be calculated with weight and height combined in kg/m^2.
Change from baseline in BMI (Body Mass Index) at 6 months [6 months]
BMI will be calculated with weight and height combined in kg/m^2.
Change from baseline in Waist and hip circumference at 3 months [3 months]
Waist and hip circumference will take down in centimeters.
Change from baseline in Waist and hip circumference at 6 months [6 months]
Waist and hip circumference will take down in centimeters.
Change from baseline in blood pressure at 3 months [3 months]
The unit of measurement of blood pressure is mmHg. Both systolic and diastolic blood pressure will be measured.
Change from baseline in blood pressure at 6 months [6 months]
The unit of measurement of blood pressure is mmHg. Both systolic and diastolic blood pressure will be measured.
Change from baseline in levels of FPG (Fasting Plasma Glucose) at 3-months [3 months]
Fasting blood samples will be collected to examine variation in FPG in uIU/mL.
Change from baseline in levels of FPG at 6-months [6 months]
Fasting blood samples will be collected to examine variation in FPG in uIU/mL.
Change from baseline in levels of serum insulin at 3-months [3 months]
Fasting blood samples will be collected to examine variation in serum insulin in uIU/mL.
Change from baseline in levels of serum insulin at 6-months [6 months]
Fasting blood samples will be collected to examine variation in serum insulin in uIU/mL.
Change from baseline in levels of HbA1c (Hemoglobin A1C) at 3-months [3 months]
Fasting blood samples will be collected to investigate the levels of HbA1c in %.
Change from baseline in levels of HbA1c at 6-months [6 months]
Fasting blood samples will be collected to investigate the levels of HbA1c in %.
Change from baseline in levels of HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) at 3-months [3 months]
The equation of HOMA-IR=(insulin (mIU/L) and glucose (mg/dL))/405)
Change from baseline in levels of HOMA-IR at 6-months [6 months]
The equation of HOMA-IR=(insulin (mIU/L) and glucose (mg/dl))/405)
Change from baseline in levels of HOMA-β (Homeostatic Model Assessment for β-cell function) at 3-months [3 months]
The equation of HOMA-β=20 × fasting insulin (μIU/ml)/fasting glucose (mmol/ml) - 3.5
Change from baseline in levels of HOMA-β (Homeostatic Model Assessment for β-cell function) at 6-months [6 months]
The equation of HOMA-β=20 × fasting insulin (μIU/ml)/fasting glucose (mmol/ml) - 3.5
Change from baseline in levels of QUICKI (Quantitative Insulin Sensitivity Check Index) at 3-months [3 months]
The equation of QUICKI=1 / [log(Fasting Insulin (µU/ml) + log(Fasting Glucose (mg/dL))]
Change from baseline in levels of QUICKI (Quantitative Insulin Sensitivity Check Index) at 6-months [6 months]
The equation of QUICKI=1 / [log(Fasting Insulin (µU/ml) + log(Fasting Glucose (mg/dL))]
Change from baseline in the level of GA (Glycated albumin) at 3-months [3 months]
Blood samples will be collected to examine changes in GA in mg/dL.
Change from baseline in the level of GA (Glycated albumin) at 6-months [6 months]
Blood samples will be collected to examine changes in GA in mg/dL.
Change from baseline in the level of CRE (Creatinine) at 3-months [3 months]
Blood samples will be collected to examine changes in CRE in mg/dL.
Change from baseline in the level of CRE at 6-months [6 months]
Blood samples will be collected to examine changes in CRE in mg/dL.
Change from baseline in the level of BUN (Blood Urea Nitrogen) at 3-months [3 months]
Blood samples will be collected to examine changes in BUN in mg/dL.
Change from baseline in the level of BUN at 6-months [6 months]
Blood samples will be collected to examine changes in BUN in mg/dL.
Change from baseline in the level of K+ (Potassium) at 3-months [3 months]
Blood samples will be collected to examine changes from baseline in K+ in mg/dL.
Change from baseline in the level of K+ at 6-months [6 months]
Blood samples will be collected to examine changes from baseline in K+ in mg/dL.
Change from baseline in the level of Urine protein/albumin at 3-months [3 months]
Urine samples will be collected to examine changes in Urine protein/albumin in mg/dL.
Change from baseline in the level of Urine protein/albumin at 6-months [6 months]
Urine samples will be collected to examine changes in Urine protein/albumin in mg/dL.
Change from baseline in the level of Urine microalbuminuria/creatinine at 3-months [3 months]
Urine samples will be collected to examine changes from baseline in Urine protein/albumin in mg/dL.
Change from baseline in the level of Urine microalbuminuria/creatinine at 6-months [6 months]
Urine samples will be collected to examine changes from baseline in Urine protein/albumin in mg/dL.
Change from baseline in the level of Urine acid at 3-months [3 months]
Urine samples will be collected to examine changes in Urine protein/albumin in mg/dL.
Change from baseline in the level of Urine acid at 6-months [6 months]
Urine samples will be collected to examine changes in Urine protein/albumin in mg/dL.
Change from baseline in the level of CG (The Cockcroft and Gault formula) at 3-months [3 months]
CG will be calculated with creatinine, age, weight, gender. The equation of CG = (((140 - age in years) x (weight in kg)) x 1.23) / (serum creatinine in micromol/l).
Change from baseline in the level of CG at 6-months [6 months]
CG will be calculated with creatinine, age, weight, gender. The equation of CG = (((140 - age in years) x (weight in kg)) x 1.23) / (serum creatinine in micromol/l).
Change from baseline in the level of eGFR (Estimated Glomerular Filtration Rate) at 3-months [3 months]
eGFR will be estimated according to the CKD-EPI Creatinine Equation (2021) which is calculated with serum creatinine, Cystatin C, age, gender.
Change from baseline in the level of eGFR (Estimated Glomerular Filtration Rate) at 6-months [6 months]
eGFR will be estimated according to the CKD-EPI Creatinine Equation (2021) which is calculated with serum creatinine, Cystatin C, age, gender.
Change from baseline in levels of blood lipid-related Index at 3 months [3 months]
Blood samples will be collected to examine variation in TG (Triglyceride), TC (Total Cholesterol), VLDL (Very-Low-Density Lipoprotein), LDL (Low-density lipoprotein), HDL (High-density lipoprotein).
Change from baseline in levels of blood lipid-related Index at 6 months [6 months]
Blood samples will be collected to examine variation in TG (Triglyceride), TC (Total Cholesterol), VLDL (Very-Low-Density Lipoprotein), LDL (Low-density lipoprotein), HDL (High-density lipoprotein).
Change from baseline in levels of cytokines Index at 3 months [3 months]
Blood samples will be collected to examine variation in hs-CRP (high-sensitivity C-reactive protein), IL-6 (Interleukin-6), IL-18 (Interleukin-18), IL -1-α (Interleukin-1-α), IL-1β (Interleukin-1 β), TNF-α (Tumor necrosis factor-α), NGAL (Neutrophil Gelatinase-Associated Lipocalin), sTNFR1 (Soluble tumour necrosis factor receptor-1), PGRN (Progranulin). All the indexes will be recorded in in pg/mL.
Change from baseline in levels of cytokines Index at 6 months [6 months]
Blood samples will be collected to examine variation in hs-CRP, IL-6, IL-18, IL-1-α, IL-1β, TNF-α, NGAL, sTNFR1, PGRN. All the indexes will be recorded in in pg/mL.
Change from baseline in levels of TIBC (Total Iron-Binding Capacity) at 3-months [3 months]
TIBC will be calculated by summing the values of serum iron and UIBC(unsaturated iron-binding capacity) which is examed from blood samples.
Change from baseline in levels of TIBC at 6-months [6 months]
TIBC will be calculated by summing the values of serum iron and UIBC which is examed from blood samples.
Change from baseline in the level of SCFA (Short Chain Fatty Acids) at 6 months [6 months]
Stool samples will be collected to examine variation in SCFA (Short Chain Fatty Acids).
Change from baseline in the level of TMAO (Trimethylamine N-oxide) at 3-months [3 months]
Blood samples will be collected to examine variation in TMAO in μmol/L.
Change from baseline in the level of TMAO at 6-months [6 months]
Blood samples will be collected to examine variation in TMAO in μmol/L.
Change from baseline in self-record of the International physical activity questionary (IPAQ) in physical assessment at 6 months [6 months]
The questionnaire will be recorded the laborious activity by the subject himself/herself before and after the treatment.
Change from baseline in gut microbiota at 6 months [6 months]
The analysis of Gut microbiota will utilize DNA sequencing to investigate the intestinal microbiota through stool samples.

Eligibility Criteria

Criteria

Ages Eligible for Study:

25 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age between 25 and 80 years old
Suffering from type 2 diabetes and stable medication for 3 months
Detection of HbA1c before meals between 7% and 10%
Stage 1-3a diabetic nephropathies (eGFR > 45 mL/min)
Microalbuminuria estimated between 30 to 300 mg/day

Exclusion Criteria:

Patients with Type I Diabetes Mellius
Patients with inflammatory bowel disease, liver disease, liver cirrhosis, systemic lupus erythematosus, malignancy, and high blood pressure.
Patients with hypoglycemic coma, Diabetic ketoacidosis, hyperosmolar non-ketotic diabetic coma, or diabetes mellitus acute complications.
Acute infection medical history in past 3 month
Fasting blood glucose >13.3 mmol/L
GPT>100U/L (2.5 times than usual situation)
Vulnerable population (Including breeding or pregnant women, prisoner, aboriginal, disabled population)
Smoker or Alcoholic
Taking Antibiotics in past 1 month
Stably taking probiotics supplements in past 1 months (Yogurt or dairy products were excluded)
Taking immunosuppressive drug, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers in past 3 months