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Prognostic Predictors of Response to Hypoglycemic Therapy

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ClinicalTrials.gov Identifier: NCT03804411
Recruitment Status : Recruiting
First Posted : January 15, 2019
Last Update Posted : February 10, 2020
Sponsor:
Information provided by (Responsible Party):
Conrady Alexandra, Federal State Budgetary Institution, V. A. Almazov Federal North-West Medical Research Centre, of the Ministry of Health

Tracking Information
First Submitted Date  ICMJE June 8, 2018
First Posted Date  ICMJE January 15, 2019
Last Update Posted Date February 10, 2020
Actual Study Start Date  ICMJE August 1, 2017
Estimated Primary Completion Date March 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 14, 2019)
  • HbA1c [ Time Frame: baseline and 3, 12, and 24 months after intervention ]
    Change from baseline in HbA1c level (%)
  • Body mass index [ Time Frame: baseline and 3, 12, and 24 months after intervention ]
    Change from baseline in body mass index (kg/m^2)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 16, 2019)
  • Estimated glomerular filtration rate [ Time Frame: baseline, 12 and 24 months after intervention ]
    Change from baseline in level of estimated glomerular filtration rate (ml/min/1.73 m^2)
  • HOMA-IR index [ Time Frame: baseline, 6 and 12 months after intervention ]
    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
  • Urinary creatinine-adjusted excretion of albumin [ Time Frame: baseline, 12 and 24 months after intervention ]
    Change from baseline in level of urinary creatinine-adjusted excretion of albumin in morning spot urine samples (mg/mmol)
  • Cardiovascular parameters of PAT and IMT [ Time Frame: baseline, 6 and 12 months after intervention ]
    Change from baseline in peripheral arterial tone by using EndoPAT 2000, the thickness of intima-media complex of carotid arteries (μm)
  • LDL cholesterol [ Time Frame: baseline, 6 and 12 months after intervention ]
    Change from baseline in level of LDL cholesterol (mmol/L)
  • Triglycerides [ Time Frame: baseline, 6 and 12 months after intervention ]
    Change from baseline in level of triglycerides (mmol/L)
  • NT-proBNP [ Time Frame: baseline, 6 and 12 months after intervention ]
    Change from baseline in serum level of NT-proBNP (pmol/L)
  • hsCRP [ Time Frame: baseline, 6 and 12 months after intervention ]
    Change from baseline in serum level of hsCRP ( mg/L)
  • PAT [ Time Frame: baseline, 6 and 12 months after intervention ]
    Change from baseline in peripheral arterial tone by using EndoPAT 2000 (Ratio is created using the post and pre occlusion values)
  • IMT [ Time Frame: baseline, 6 and 12 months after intervention ]
    Change from baseline in the thickness of intima-media complex of carotid arteries (μm)
  • LV ejection fraction [ Time Frame: baseline, 6 and 12 months after intervention ]
    Change from baseline in ejection fraction (%) by echocardiography
  • LV mass index [ Time Frame: baseline, 6 and 12 months after intervention ]
    Change from baseline in LV mass index (g/m^2) by echocardiography
  • GLS by 2D-STE [ Time Frame: baseline, 6 and 12 months after intervention ]
    Change from baseline in global longitudinal strain by 2D Speckle-tracking echocardiography (%)
  • Molecular-genetic markers of endothelial damage [ Time Frame: baseline, 6 and 12 months after intervention ]
    Change from baseline in serum level of microRNA-126, microRNA-21, microRNA-27, miRNA-125 and miRoRNA-155 (relative units)
Original Secondary Outcome Measures  ICMJE
 (submitted: January 14, 2019)
  • Estimated glomerular filtration rate [ Time Frame: baseline, 12 and 24 months after intervention ]
    Change from baseline in level of estimated glomerular filtration rate (ml/min/1.73 m^2)
  • HOMA-IR index [ Time Frame: baseline, 6 and 12 months after intervention ]
    Change from baseline in level of HOMA-IR index (kg/m^2)
  • Urinary creatinine-adjusted excretion of albumin [ Time Frame: baseline, 12 and 24 months after intervention ]
    Change from baseline in level of urinary creatinine-adjusted excretion of albumin in morning spot urine samples (mg/mmol)
  • Cardiovascular parameters of PAT and IMT [ Time Frame: baseline, 6 and 12 months after intervention ]
    Change from baseline in peripheral arterial tone by using EndoPAT 2000, the thickness of intima-media complex of carotid arteries (μm)
  • LDL cholesterol [ Time Frame: baseline, 6 and 12 months after intervention ]
    Change from baseline in level of LDL cholesterol (mmol/L)
  • Triglycerides [ Time Frame: baseline, 6 and 12 months after intervention ]
    Change from baseline in level of triglycerides (mmol/L)
  • NT-proBNP [ Time Frame: baseline, 6 and 12 months after intervention ]
    Change from baseline in serum level of NT-proBNP (pmol/L)
  • hsCRP [ Time Frame: baseline, 6 and 12 months after intervention ]
    Change from baseline in serum level of hsCRP ( mg/L)
  • PAT [ Time Frame: baseline, 6 and 12 months after intervention ]
    Change from baseline in peripheral arterial tone by using EndoPAT 2000 (Ratio is created using the post and pre occlusion values)
  • IMT [ Time Frame: baseline, 6 and 12 months after intervention ]
    Change from baseline in the thickness of intima-media complex of carotid arteries (μm)
  • LV ejection fraction [ Time Frame: baseline, 6 and 12 months after intervention ]
    Change from baseline in ejection fraction (%) by echocardiography
  • LV mass index [ Time Frame: baseline, 6 and 12 months after intervention ]
    Change from baseline in LV mass index (g/m^2) by echocardiography
  • GLS by 2D-STE [ Time Frame: baseline, 6 and 12 months after intervention ]
    Change from baseline in global longitudinal strain by 2D Speckle-tracking echocardiography (%)
  • Molecular-genetic markers of endothelial damage [ Time Frame: baseline, 6 and 12 months after intervention ]
    Change from baseline in serum level of microRNA-126, microRNA-21, microRNA-27, miRNA-125 and miRoRNA-155 (relative units)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Prognostic Predictors of Response to Hypoglycemic Therapy
Official Title  ICMJE Search for Highly Specific Predictors of Response to Different Hypoglycemic Therapy for Cardiovascular Prognosis
Brief 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.
Detailed 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).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Investigator)
Primary Purpose: Basic Science
Condition  ICMJE Diabetes Mellitus, Type 2
Intervention  ICMJE
  • 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
  • Drug: Standard treatment

    Addition of:

    1. B -vildagliptin 100 mg/day
    2. B - sitagliptin 100 mg/day,
    3. B- dapagliflozin 10 mg/day
    4. B- empagliflozin 10 mg/day
    5. B- liraglutide 1,2-1,8 mg/day
    6. B- exenatide 20 μg/day
    7. B - glimepiride
    8. B - gliclazide
Study Arms  ICMJE
  • Experimental: Treatment chosen by automated decision-making system
    Group A: type 2 diabetic patients randomized to receive antidiabetic drugs according to predictors chosen with developed automated decision-making system: subgroup 1A- addition of vildagliptin 100 mg/day, subgroup 2A - addition of sitagliptin 100 mg/day, subgroup 3A- addition of dapagliflozin 10 mg/day, subgroup 4A- addition of empagliflozin 10 mg/day, subgroup 5A- addition of liraglutide 1,2-1,8 mg/day, subgroup 6A- addition of exenatide 20 μg/day, subgroup 7A - addition of glimepiride, subgroup 8A - addition of gliclazide.
    Interventions:
    • Drug: Automatic system guided treatment
    • Drug: Standard treatment
  • Experimental: Treatment based on standard recommendations
    Group B: type 2 diabetic patients randomized to receive antidiabetic drugs according to standard recommendations : subgroup 1B- addition of vildagliptin 100 mg/day, subgroup 2B - addition of sitagliptin 100 mg/day, subgroup 3B- addition of dapagliflozin 10 mg/day, subgroup 4B- addition of empagliflozin 10 mg/day, subgroup 5B- addition of liraglutide 1,2-1,8 mg/day, subgroup 6B- addition of exenatide 20 μg/day, subgroup 7B - addition of glimepiride, subgroup 8B - addition of gliclazide.
    Interventions:
    • Drug: Automatic system guided treatment
    • Drug: Standard treatment
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 14, 2019)
800
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 2020
Estimated Primary Completion Date March 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Alina Babenko, MD, PhD 0078127025586 alina_babenko@mail.ru
Listed Location Countries  ICMJE Russian Federation
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03804411
Other Study ID Numbers  ICMJE 11/2017
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Conrady Alexandra, Federal State Budgetary Institution, V. A. Almazov Federal North-West Medical Research Centre, of the Ministry of Health
Study Sponsor  ICMJE Federal State Budgetary Institution, V. A. Almazov Federal North-West Medical Research Centre, of the Ministry of Health
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Federal State Budgetary Institution, V. A. Almazov Federal North-West Medical Research Centre, of the Ministry of Health
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP