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History of Changes for Study: NCT02383238
Effect of Dapagliflozin on Microvascular and Macrovascular Circulation and Total Body Sodium Content (Dapa)
Latest version (submitted May 9, 2018) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 March 2, 2015 None (earliest Version on record)
2 May 28, 2015 Study Status and Arms and Interventions
3 December 1, 2015 Recruitment Status, Study Status and Contacts/Locations
4 January 11, 2018 Study Status and References
5 May 9, 2018 Study Design and Study Status
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Study NCT02383238
Submitted Date:  March 2, 2015 (v1)

Open or close this module Study Identification
Unique Protocol ID: MB102-210
Brief Title: Effect of Dapagliflozin on Microvascular and Macrovascular Circulation and Total Body Sodium Content (Dapa)
Official Title: Randomized, Placebo Controlled, Crossover Clinical Study to Analyse the Effect of Dapagliflozin on Microvascular and Macrovascular Circulation and Total Body Sodium Content
Secondary IDs:
Open or close this module Study Status
Record Verification: March 2015
Overall Status: Recruiting
Study Start: March 2014
Primary Completion: March 2015 [Anticipated]
Study Completion:
First Submitted: July 24, 2014
First Submitted that
Met QC Criteria:
March 2, 2015
First Posted: March 9, 2015 [Estimate]
Last Update Submitted that
Met QC Criteria:
March 2, 2015
Last Update Posted: March 9, 2015 [Estimate]
Open or close this module Sponsor/Collaborators
Sponsor: University of Erlangen-Nürnberg Medical School
Responsible Party: Principal Investigator
Investigator: Roland E. Schmieder
Official Title: Prof. Dr. Roland E. Schmieder
Affiliation: University of Erlangen-Nürnberg Medical School
Collaborators:
Open or close this module Oversight
U.S. FDA-regulated Drug:
U.S. FDA-regulated Device:
Data Monitoring: Yes
Open or close this module Study Description
Brief Summary: Dapagliflozin leads to improved vascular function in the micro- and macrocirculation by action on various cardiovascular risk factors, in particular by effectively controlling hyperglycemia, arterial hypertension and reducing whole sodium content amongst others.
Detailed Description:

Diabetes mellitus, considered at the beginning as a metabolic disorder, mutates into a predominantly vascular disease, once its duration extends over several years or/and when additional cardiovascular risk factors coexist, in particular arterial hypertension. In accordance, patients with type 2 diabetes die because of microvascular and macrovascular complications, and only rarely because of hypoglycaemic or hyperglycaemic shock syndromes [1]. As a consequence, treatment of type 2 diabetes should focus not only on metabolic control but also on improving the global vascular risk. Analyses that have compared the importance of the various cardiovascular risk factors concluded that reductions of blood pressure and lipid levels are significantly more important than reduction of hyperglycemia [2]. Of course, a multidisciplinary approach is desirable and the STENO-2 study has clearly indicated that in mid-term microvascular complications and in long-term macrovascular complications can be prevented in type 2 diabetes [3].

Vascular changes occurring in the course of type 2 diabetes, arterial hypertension and elevated global cardiovascular risk can now reliably assessed non-invasively, and already at the very early stage of vascular remodeling processes. For example, the guidelines of the European Society of Hypertension recommend several vascular

#0284 CSP 130911 v1.4.docx 8 parameters to be assessed already at the diagnosis of the disease in order to analyze early organ damage of the arteries [4]. The measurement of pulse wave velocity, pulse wave analysis, central (aortic) systolic pressure and pulse pressure are tools to detect early vascular changes in the large arteries related to a faster wave reflection in the arterial tree [5]. Wall to lumen ratio of retinal arteries, retinal capillary flow and flow mediated vasodilation are tools to detect changes in the microvascular circulation [6]. These parameters are only infrequently measured in studies with type 2 diabetes, mainly due to lack of awareness that the vascular changes are the key prognostic factor in type-2 diabetes that ultimately determine the fate of the patient.

Dapagliflozin is a novel selective SLGT-2 inhibitor that has been shown to improve glycaemic control after 2, 12, and 24 weeks as well as after 1 and 2 years. Dapagliflozin produced dose dependent increases in glucosuria and clinically meaningful changes of glycemic parameters in type 2 diabetes in addition to weight loss. Most striking, dapagliflozin was also found to lower systolic blood pressure by 5 mmHg. This reduction in blood pressure might be related to weight loss or/and concomitant loss of total body sodium content. However, the precise mechanism of the blood pressure reduction needs to be elucidated. Loss of sodium would lead to a less reactive contraction of the small arteries in response to increased sympathetic activity, angiotensin II [7] and catecholamines.

In summary, dapagliflozin exert beneficial effects on a variety of cardiovascular risk factors, such as hyperglycaemia, hypertension and obesity. These changes should lead (so the hypothesis) to improved vascular function in the micro- and macrocirculation. Moreover, increased total body content of sodium that now can be measured in humans by a specific MRI technique [8] may also be reduced by dapagliflozin that may lead to less vasoreactive responses since the tubular SGLT-2 mediated glucose uptake is sodium related, i.e. blockade should lead to sodium loss. However, the latter is nothing more than hypothesis and requires clear proof by clinical studies in patients with type 2 diabetes.

Open or close this module Conditions
Conditions: Diabetes Mellitus Type 2
Keywords: Dapagliflozin
diabetes mellitus
vascular
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 3
Interventional Study Model: Crossover Assignment
Number of Arms: 2
Masking: Double (Participant, Investigator)
Allocation: Randomized
Enrollment: 63 [Anticipated]
Open or close this module Arms and Interventions
Arms Assigned Interventions
Active Comparator: Dapagliflozin Drug: Dapagliflozin
10 mg, oral for 6 weeks
Other Names:
  • Forxiga
Placebo Comparator: Placebo
Placebo 6 weeks
Drug: Placebo
Open or close this module Outcome Measures
Primary Outcome Measures:
1. Microcirculation
[ Time Frame: 6 weeks ]

To analyse the effects after 6 weeks of treatment with dapagliflozin on retinal capillary flow (given as AU) as the key measurement of vascular remodeling in the microcirculation compared to placebo.
Secondary Outcome Measures:
1. Macrovascular circulation
[ Time Frame: 6 weeks ]

To analyse the effects after 6 weeks of treatment with dapagliflozin on central (aortic) systolic pressure, central (aortic) pulse pressure and augmentation pressure, on retinal capillary flow after flicker light exposure, parameters that all are determined by pulse wave reflection (i.e. arterial wall properties) in the arterial tree compared to placebo.
Open or close this module Eligibility
Minimum Age: 18 Years
Maximum Age: 75 Years
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
Criteria:

Inclusion Criteria:

  1. Type 2 diabetes
  2. HbA1c > 6.5%
  3. age > 18 years
  4. male and females

Exclusion Criteria:

  1. age > 75 years
  2. HbA1c > 10 %,
  3. reduced renal function (eGFR < 60 ml/min/1.73 m²).
  4. insulin therapy, or any antidiabetic medication other than metformin.
  5. uncontrolled hypertension (> 180/>110 mmHg)
  6. cardiovascular event within the last 3 months
  7. Use of loop diuretics
Open or close this module Contacts/Locations
Central Contact Person: Roland Schmieder, Prof
Telephone: +49 9131 / 8 53 - 62 45
Email: roland.schmieder@uk-erlangen.de
Study Officials: Roland Schmieder, Prof.
Principal Investigator
Department of Medicine 4, University of Erlangen-Nuernberg
Locations: Germany
University Erlangen-Nuernberg
[Recruiting]
Erlangen, Germany, 91054
Contact:Contact: Roland Schmieder, Prof +49 9131 / 8 53 - 62 45 roland.schmieder@uk-erlangen.de
Open or close this module IPDSharing
Plan to Share IPD:
Open or close this module References
Links:
Available IPD/Information:

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