Effects of Dapagliflozin on Central Hemodynamics and Urine Albumin Excretion in Patients With Type 2 Diabetes.

Study Overview
=================
Brief Summary
-----------------
This study is designed to test the hypothesis that the treatment-induced reductions in the ambulatory aortic pressure are more pronounced in the group of dapagliflozin than in the group of placebo. It is a 12 week, double-blind, randomized, placebo-controlled clinical trial of dapagliflozin versus placebo in 160 adult patients with type 2 diabetes mellitus (DM). It will be conducted in three centers. Potentially eligible patients will be asked to provide written informed consent (Screening Visit). Patients, who fulfill the inclusion and exclusion criteria, will be asked to visit the sites one week (Visit 1 - V1) after the screening visit. On Visit 2 (V2) all eligible patients will be randomized to one of the two treatment arms and will continue with the next visits as appropriate (Visit 3, Telephone Visit 1, Visit 4-end of study). Aortic blood pressure (BP) and arterial stiffness parameters will be measured as indicated by the protocol in V1 and V3 with the Mobil-O-Graph monitor. Blood samples will be collected as indicated by the protocol in Screening Visit for the measurement of glycated hemoglobin (HbA1c), creatinine and liver function parameters. In addition, blood samples will be collected in V1 and V3 for routine hematological and biochemical tests including creatinine, fasting glucose, HbA1c, lipid profile and liver function parameters. Urine samples will be collected as indicated by the protocol in V1 and V3 for the measurement of albumin to creatinine ratio.

Detailed Description
-----------------
Study design Screening visit: Potentially eligible patients will be asked to provide written informed consent. The investigators will record full medical history, clinical examination, demographic characteristics, electrocardiogram (ECG), body weight, height, body mass index (BMI) and waist perimeter. Office blood pressure (BP) will be measured by the physicians three times using a mercury sphygmomanometer [cuffs will be placed at the level of brachial artery and a three minute interval will intercept each measurement, following 10 minutes of rest in the seated position (the cuff will cover at least 80% of the brachial circumference and 2/3 of the brachial length.)]. The investigators will also collect blood samples to determine glycated hemoglobin (HbA1C), creatinine, glomerular filtration rate (GFR) and liver function. Visit 1 (V1): Patients, who fulfill the inclusion and exclusion criteria, will be asked to visit the sites 1 week after the screening visit (+/-2 days), following a 12-hour fast. Three measurements of office BP at the level of brachial artery, with a three minutes interval between each measurement, will be performed with the use of a mercury sphygmomanometer, after 10 minutes-rest in the sitting posture (cuff with bladder size encircling at least 80% of arm circumference and covering two thirds of arm length). After that, venous blood specimens and a spot urine specimen will be collected for relevant blood tests and albumin/creatinine ratio (ACR) respectively. Subsequently, the Mobil-O-Graph monitor with a cuff of appropriate size will be fitted and the BP recording will be initiated for 24 hours. The device will be programmed to collect data every 20 minutes, except for 23:00 to 07:00 (data collection every 30 minutes). Visit 2 (V2): An appointment will be scheduled the following day for the patient to drop-off the Mobil-O-Graph device. Patients will be randomized in a 1:1 ratio to the dapagliflozin or placebo group and will start receiving the drug regimen the same day. Moreover, all patients will receive dietary and lifestyle advice commencing from this visit. Telephone Visit 1 (ΤV1): A telephone visit (TV1) will be scheduled 6 weeks after V2 (+/-2 days). Patient history will be obtained, emphasizing on possible adverse events during the previous 6 weeks. Home blood glucose levels, if available, would be also discussed. Visit 3 (V3): Visit 3 will be scheduled 6 weeks after telephone visit 1 (TV1) (+/-2 days). The following parameters will be determined: medical history of the last weeks, clinical examination (including three brachial BP measurements with a mercury sphygmomanometer as mentioned before), venous blood specimen collection (under 12-hour fast) and the initiation of 24-hour ambulatory blood pressure monitoring (ABPM) (Mobil-O-Graph device). The patients will also provide a spot urine specimen for ACR evaluation. Visit 4 (V4): Visit 4 will be scheduled 1 day after visit 3. Patients will drop-off the Mobil-O-Graph device.

Official Title
-----------------
A Study of the Effects of Dapagliflozin on Ambulatory Aortic Pressure, Arterial Stiffness and Urine Albumin Excretion in Patients With Type 2 Diabetes

Conditions
-----------------
Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: Dapagliflozin
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age >18 and ≤75 years old Type 2 diabetes mellitus Glycated hemoglobin ≥7% and ≤ 9% Patients on monotherapy or combination of two of the following type of antidiabetic agents :metformin, sulphonylurea,DPP-4 inhibitor,or insulin for the past 3 months. Patient to provide informed consent Exclusion Criteria: Hypovolemic patients. Patients on loop diuretics. Patients with low BP (office SBP <110 mmHg) or orthostatic hypotension (BP drop >20 mmHg and SBP <110 mmHg in standing position at 1 min). Patients on GLP-1 receptor agonist or pioglitazone. Secondary hypertension. Stage 2 hypertension or higher (office SBP ≥160 mmHg or DBP ≥100 mmHg). Chronic kidney disease stage 3 or higher (GFR<60 mL/min/1.73 m2). Myocardial infarction or unstable angina episode within the past 3 months, or congestive heart failure class III-IV according to New York Heart Association criteria. Pregnancy or childbearing potential [defined as women which have entered menses and are not post-menopausal (menopause is defined as the absence of menses for at least 12 months without any other medical cause in women of typical age) or women that have been subjected to permanent sterilization (ie. tubal ligation, hysterectomy, bilateral oophorectomy or bilateral salpingectomy)]. History of liver disease or significant abnormal liver function defined as aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and/or alanine aminotransferase (ALT) >3x ULN or total bilirubin >2.0 mg/dL. History of malignancy of any organ system (resected basal cell carcinoma considered cured is exempted) within the past 5 years prior to Visit 1 (V1). History of drug or alcohol abuse within the last one year. Any contraindication or history of hypersensitivity to the study drug or to drugs with similar chemical structures. Any other surgical or medical condition that, in the opinion of the investigator, place the patient at higher risk from his/her participation in the study, or are likely to prevent the patient from complying with the requirements of the study or completing the trial period. Intake of an investigational drug in another trial within 30 days prior to Visit 1 (V1).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dapagliflozin<br>Dapagliflozin for oral administration. Patients will be randomized in a 1:1 ratio to the dapagliflozin or placebo group. | Drug: Dapagliflozin<br>* Administration of dapagliflozin (film-coated tablet of 10mg, per os, q24h, 12 weeks)<br>* Other names: Forxiga;|
| Placebo Comparator: Placebo<br>Placebo for oral administration. Patients will be randomized in a 1:1 ratio to the dapagliflozin or placebo group. | Drug: Placebo<br>* Administration of placebo (film-coated tablet of same color and texture with dapagliflozin, 10mg, per os, q24h, 12 weeks).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ambulatory systolic aortic pressure |  | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ambulatory aortic (central) diastolic blood pressure (DBP) |  | 12 weeks | 
| Ambulatory brachial systolic blood pressure (SBP) and DBP |  | 12 weeks | 
| Ambulatory augmentation index (AIx) |  | 12 weeks | 
| Ambulatory pulse wave velocity (PWV) |  | 12 weeks | 
| Office brachial SBP and DBP |  | 12 weeks | 
| Albumin/creatinine ratio (ACR) |  | 12 weeks | 
| Lipid profile (Total-Cholesterol, LDL-Cholesterol, HDL-Cholesterol, triglycerides) |  | 12 weeks | 
| HbA1c |  | 12 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Dapagliflozin, Arterial Stiffness, Aortic Pressure