Prognostic Predictors of Response to Hypoglycemic Therapy

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

Search for Highly Specific Predictors of Response to Different Hypoglycemic Therapy for Cardiovascular Prognosis

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03804411
• Other study ID #: 11/2017
• Status: Recruiting
• Phase: Phase 4
• Start date: August 1, 2017
• Est. completion date: May 2020

Study information

• Verified date: February 2020
• Source: Federal State Budgetary Institution, V. A. Almazov Federal North-West Medical Research Centre, of the Ministry of Health
• Contact: Alina Babenko, MD, PhD
• Phone: 0078127025586
• Email: alina_babenko[@]mail.ru
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a randomized controlled trial aimed to determine highly specific personified predictors of response to the therapy by different groups of hypoglycemic drugs (SGLT-2 inhibitors, DPP-4 inhibitors, GLP-1 receptor agonists, sulfonylureas) in patients with type 2 diabetes mellitus, develop an algorithm of personalized therapy based on them, design an organizational and methodological model for prevention of the cardiovascular complications, and create an automated decision-making system for therapy selection to reduce the incidence of cardiovascular events and related adverse outcomes compared to the traditional approach. This is an interventional, randomized controlled trial, open-label study.

Description:

The study aims to determine highly specific personified predictors of response to the therapy by different groups of hypoglycemic drugs in patients with type 2 diabetes mellitus, to develop on their basis a mathematical model that allows to objectify the choice of therapy for each patient, and validate it in clinical practice with assessment of dynamic of cardiovascular risk markers (vascular wall condition, markers of fibrosis and inflammation, molecular-genetic markers of vascular damage, dynamic of intestinal microbiota, clinical outcomes, psychological parameters of quality of life, eating, treatment satisfaction) and pharmaco-economic component. Patients with type 2 diabetes mellitus and non-target HbA1c will be randomized to receive antidiabetic drugs (SGLT-2 inhibitors, DPP-4 inhibitors, GLP-1 receptor agonists, sulfonylureas) in open prospective study according to: 1) standard recommendations; 2) predictors chosen with automated decision-making system developed on the literature analysis. At baseline and 3, 6, 12, and 24 months into the study patients will be asked to complete the questionnaires on eating behavior, appetite, propensity to alcohol consumption, smoking, level of physical activity, general health condition, level of anxiety and depression, cognitive functions, adherence to treatment and treatment satisfaction. At baseline and 3, 6, 12, and 24 months into the study there will be physical examination and laboratory tests, including: fasting and 1.5 hours post meal glucose, glycated hemoglobin, insulin with calculation of HOMA-IR index, indicators of lipid metabolism (total cholesterol, TG, LDL, calculation of HDL and VLDL), markers of kidney function (serum creatinine with GFR calculation, urine albumin-to-creatinine ratio), biochemical parameters of therapy safety (ALT, AST, bilirubin, uric acid, fibrinogen, alkaline phosphatase, amylase 5), levels of orexigenic / anorexigenic hormones (GLP1, GIP, ghrelin, leptin, glucagon, adiponectin, C-peptide). The study will also include the evaluation of endothelial dysfunction (using EndoPAT 2000), state of the vascular wall (using the SphygmoCor), thickness of intima-media complex of carotid arteries, echocardiographic study, estimation of the global longitudinal strain (2-D Speckle-tracking echocardiographic analysis), MRI of the heart, biomarkers of inflammation (CRP level by the ultrasensitive method, adhesion molecules E-selectin and sICAM-1), markers of oxidative stress (myeloperoxidase, paraoxanase-1), markers of fibrosis (PICP, PIIINP, CITP, MMP / TIMP, TGF-β, galectin-3), markers of heart failure (NT-proBNP, sST2). The investigators will conduct immunophenotyping of circulating progenitor cells (CD45 + / CD34 + / collagen-I +) by flow cytometry, and assess molecular-genetic markers of endothelial damage (microRNA-126, microRNA-21, microRNA-27, miRNA-125 and miRoRNA-155).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 800
• Est. completion date: May 2020
• Est. primary completion date: March 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

1. Male and female aged 17-70 years

2. Type 2 diabetes mellitus with non-target HbA1c exciding less than 1% (<1%)

3. Initiation of the treatment by SGLT- 2 inhibitors, dipeptidyl peptidase-4 inhibitors, GLP-1 analogues

4. Stable hypoglycemic therapy for 12 weeks before enrollment

5. Signed informed consent

Exclusion Criteria:

1. Type 1 diabetes mellitus

2. Recent acute coronary syndrome or acute disturbance of cerebral blood circulation (less than 2 months ago)

3. Decompensation of chronic heart failure, chronic heart failure class IV (NYHA), acute heart failure

4. Confirmed non-diabetic kidney disease (glomerulonephritis, pyelonephritis, amyloidosis)

5. Chronic kidney disease requiring hemodialysis and/or urinary albumin concentration (morning spot) >1000 mg/L

6. Regular nephrotoxic drugs intake (long-term intake of NSAIDs, aminoglycosides, sulfonamides, cyclosporine, lithium preparations)

7. Anamnesis of malignancy.

8. Diabetic foot ulcer and neuropathic osteoarthropathy

9. Anamnesis of bariatric surgery or surgical interventions on the gastrointestinal tract leading to malabsorption.

10. Treatment with drugs reducing body weight less than 3 months ago or any other drugs use that can lead to a change in body weight.

11. Liver disorders with elevation of ALT/AST exceeding three-fold the upper limit of normal

12. Immunosuppressive therapy or regular nonsteroidal anti-inflammatory drugs intake

13. Change in the dosage of thyroid hormones less than 6 weeks ago.

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2

Intervention

Drug:
• Automatic system guided treatment
Addition of: 1A -vildagliptin 100 mg/day 2A - sitagliptin 100 mg/day, 3A- dapagliflozin 10 mg/day 4A- empagliflozin 10 mg/day 5A- liraglutide 1,2-1,8 mg/day 6A- exenatide 20 µg/day 7A - glimepiride 8A - gliclazide
• Standard treatment
Addition of: B -vildagliptin 100 mg/day B - sitagliptin 100 mg/day, B- dapagliflozin 10 mg/day B- empagliflozin 10 mg/day B- liraglutide 1,2-1,8 mg/day B- exenatide 20 µg/day B - glimepiride B - gliclazide

Locations

Country	Name	City	State
Russian Federation	Alina Babenko	Saint-Petersburg

Sponsors (1)

Lead Sponsor	Collaborator
Federal State Budgetary Institution, V. A. Almazov Federal North-West Medical Research Centre, of the Ministry of Health

Country where clinical trial is conducted

Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	HbA1c	Change from baseline in HbA1c level (%)	baseline and 3, 12, and 24 months after intervention
Primary	Body mass index	Change from baseline in body mass index (kg/m^2)	baseline and 3, 12, and 24 months after intervention
Secondary	Estimated glomerular filtration rate	Change from baseline in level of estimated glomerular filtration rate (ml/min/1.73 m^2)	baseline, 12 and 24 months after intervention
Secondary	HOMA-IR index	Change from baseline in level of HOMA-IR index (Homeostasis Model Assessment of Insulin Resistance) derived from the plasma insulin level (mIU/L) and plasma glucose level (mmol/L) of a participant: [(plasma insulin level) x (plasma glucose level)]/22.5, where the value of HOMA-IR index > 2.0 suggests insulin resistance	baseline, 6 and 12 months after intervention
Secondary	Urinary creatinine-adjusted excretion of albumin	Change from baseline in level of urinary creatinine-adjusted excretion of albumin in morning spot urine samples (mg/mmol)	baseline, 12 and 24 months after intervention
Secondary	Cardiovascular parameters of PAT and IMT	Change from baseline in peripheral arterial tone by using EndoPAT 2000, the thickness of intima-media complex of carotid arteries (µm)	baseline, 6 and 12 months after intervention
Secondary	LDL cholesterol	Change from baseline in level of LDL cholesterol (mmol/L)	baseline, 6 and 12 months after intervention
Secondary	Triglycerides	Change from baseline in level of triglycerides (mmol/L)	baseline, 6 and 12 months after intervention
Secondary	NT-proBNP	Change from baseline in serum level of NT-proBNP (pmol/L)	baseline, 6 and 12 months after intervention
Secondary	hsCRP	Change from baseline in serum level of hsCRP ( mg/L)	baseline, 6 and 12 months after intervention
Secondary	PAT	Change from baseline in peripheral arterial tone by using EndoPAT 2000 (Ratio is created using the post and pre occlusion values)	baseline, 6 and 12 months after intervention
Secondary	IMT	Change from baseline in the thickness of intima-media complex of carotid arteries (µm)	baseline, 6 and 12 months after intervention
Secondary	LV ejection fraction	Change from baseline in ejection fraction (%) by echocardiography	baseline, 6 and 12 months after intervention
Secondary	LV mass index	Change from baseline in LV mass index (g/m^2) by echocardiography	baseline, 6 and 12 months after intervention
Secondary	GLS by 2D-STE	Change from baseline in global longitudinal strain by 2D Speckle-tracking echocardiography (%)	baseline, 6 and 12 months after intervention
Secondary	Molecular-genetic markers of endothelial damage	Change from baseline in serum level of microRNA-126, microRNA-21, microRNA-27, miRNA-125 and miRoRNA-155 (relative units)	baseline, 6 and 12 months after intervention