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Effects of SGLT-2 Inhibition on Myocardial Fibrosis and Inflammation as Assessed by Cardiac MRI in Patients With DM2

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ClinicalTrials.gov Identifier: NCT03782259
Recruitment Status : Unknown
Verified February 2019 by Xue-Qiao Zhao, University of Washington.
Recruitment status was:  Recruiting
First Posted : December 20, 2018
Last Update Posted : February 28, 2019
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
Xue-Qiao Zhao, University of Washington

Brief Summary:

There is an unmet need for Cardiovascular Disease risk reduction in patients with Type 2 Diabetes. In recent trials there has been promising findings of more effective glucose management and reductions in overall CVD events and hospitalization for heart failure with SGLT-2 inhibition. Using the capability of cardiac MRI with T1- and T2-mapping in assessments of myocardial fibrosis and inflammation, the investigators propose to conduct a clinical trial to investigate the effects of SGLT-2 inhibition with dapagliflozin on myocardial fibrosis and inflammation as assessed by cardiac MRI with T1- and T2-mapping in patients with type-2 diabetes.

Over approximately 12 months subjects will have 6 clinical visits at the investigators research clinic. During this time subjects will be randomized to receive either active 10mg dapagliflozin or a matching placebo. 2 MRI scans at one of the two UW research imaging centers will take place. One at randomization and the second scan will occur approximately 12 months after the first scan.


Condition or disease Intervention/treatment Phase
Type 2 Diabetes Mellitus Myocardial Fibrosis Myocardial Inflammation Drug: dapagliflozin Other: Placebo Phase 4

Detailed Description:

Given the unmet needs for CVD risk reduction in patients with T2DM, the promising findings of more effective glucose management and reductions in overall CVD events and hospitalization for heart failure with SGLT-2 inhibition demonstrated in recent trials, and the capability of cardiac MRI with T1- and T2-mapping in assessments of myocardial fibrosis and inflammation, the investigators propose to conduct a staged research program using adaptive study design to investigate the effects of SGLT-2 inhibition with dapagliflozin on myocardial fibrosis and inflammation as assessed by cardiac MRI with T1- and T2-mapping in patients with type-2 diabetes.

A total of 60 subjects with >=18 years of age, type-2 diabetes history >=5 years and HbA1C 7-10% will be randomized at 1:1 to Dapagliflozin 10mg or matching placebo once daily for 1 year. All subjects will be followed every 3 months for clinical and laboratory evaluations and assessments. All subjects will undergo CMRI at baseline and 1 year.

The primary myocardial fibrosis endpoint is change in extracellular volume fraction (ECV) as assessed by T1-mapping over 12 months. ECV combines native and contrast-enhanced T1 mapping. The change of the T1 relaxation rate (i.e., 1/T1) in blood between pre- and post-contrast imaging is converted with the blood hematocrit into a reference for plasma T1, which serves as reference for the T1 changes in tissue.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized, double-blind and placebo controlled cardiac MRI study
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Screening
Official Title: Effects of SGLT-2 Inhibition With Dapagliflozin on Myocardial Fibrosis and Inflammation as Assessed by Cardiac MRI With T1- and T2-mapping in Patients With Type-2 Diabetes
Actual Study Start Date : February 26, 2019
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2020


Arm Intervention/treatment
Placebo Comparator: Placebo
10mg tabs placebo matching dapagliflozin.
Other: Placebo
Placebo

Active Comparator: Active
10mg tabs of dapagliflozin
Drug: dapagliflozin
Subjects will either receive 10mg tabs of dapagliflozin or identical looking placebo - inactive medication. Subjects have an equal chance of receiving dapagliflozin or placebo. Which treatment subjects receive is decided at random by a computer (purely by chance, like the tossing of a coin). Neither subjects nor the Study Site personnel will know which treatment subjects are assigned to. The study drug must be taken daily. The subject's other medications will not be changed by the study.
Other Name: Forxiga




Primary Outcome Measures :
  1. Extracellular volume fraction (ECV) [ Time Frame: Approximately 12 Months ]
    Extracellular volume fraction (ECV) measured from cardiac MRI with T1-mapping at two timepoints. MRI at Randomization and MRI at approximately 12 Months. ECV combines native and contrast-enhanced T1 mapping. Ancova test with adjusted for baseline ECV will be used to compare change in ECV over 12 months between 2 treatment groups.


Secondary Outcome Measures :
  1. T2 relaxation time [ Time Frame: Approximately 12 Months ]
    Change from baseline in T2 relaxation time measured from cardiac MRI with T2-mapping at two timepoints. MRI at Randomization and MRI at approximately 12 Months


Other Outcome Measures:
  1. Epicardial fat [ Time Frame: Approximately 12 Months ]

    Change from baseline in Epicardial fat measured from cardiac MRI with T1-mapping at two timepoints. MRI at Randomization and MRI at approximately 12 Months

    Ancova test will be used for comparisons of epicardial fat between 2 different timepoints within each treatment group, at between 2 treatments at the same time point, and changes during the study.


  2. Fasting glucose [ Time Frame: Approximately 12 Months ]
    Fasting glucose will be measured every 3 months for approximately 12 months.

  3. HbA1C [ Time Frame: Approximately 12 Months ]
    Hemoglobin A1c (HbA1c) will be measured every 3 months for approximately 12 months.

  4. LDL particle size [ Time Frame: Approximately 12 Months ]
    LDL particle size measured from plasma samples at Randomization and at approximately 12 Months

  5. hsCRP [ Time Frame: Approximately 12 Months ]
    Inflammatory marker hsCRP at Screening, 6 months and at approximately 12 Months.

  6. TNF-α [ Time Frame: Approximately 12 Months ]
    Inflammatory marker TNF-α measured from plasma samples at Randomization and at approximately 12 Months

  7. IL-6 [ Time Frame: Approximately 12 Months ]
    Inflammatory marker IL-6 measured from plasma samples at Randomization and at approximately 12 Months



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Men and women at least 18 years of age
  2. Subjects with type-2 diabetes history >=5 years
  3. HbA1C 7-10% with glucose control medications including insulin, metformin or sulfonylurea
  4. Medically stable
  5. Willing to participate and sign informed consent.

Exclusion Criteria:

  1. Contraindication to MRI
  2. Currently or within last three months treatment with a SGLT2 inhibitor
  3. Currently taking GLP-1 receptor antagonist
  4. GFR <60 mL/min/1.73 m2
  5. Unstable or rapidly progressive renal disease
  6. Hypotension with SBP <100 mmHg
  7. Hypersensitivity to dapagliflozin or any excipients
  8. Patients with severe hepatic impairment (Child-Pugh class C)
  9. Patients with active hepatitis B or C infection
  10. Any of the following CV/Vascular Diseases within 3 months prior to signing the consent at enrollment, as assessed by the investigator:

    1. Myocardial infarction
    2. Cardiac surgery or revascularization (CABG/PTCA)
    3. Unstable angina
    4. HF New York Heart Association (NYHA) Class IV
    5. Transient ischemic attack (TIA) or significant cerebrovascular disease
    6. Unstable or previously undiagnosed arrhythmia
    7. Established PAD

(18) Active bladder cancer (19) Recent episode of Diabetic ketoacidosis (DKA), frequent episodes of DKA (20) High risk of fractures, amputations and fibrosis (21) Women of child-bearing potential (ie, those who are not chemically or surgically sterilized or who are not post-menopausal) who have a positive pregnancy test at enrollment or randomization, OR women who are not willing to use a medically accepted method of contraception that is considered reliable in the judgment of the investigator, from the time of signing the informed consent until two weeks after the last dose of IP, OR women who are breast-feeding.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03782259


Contacts
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Contact: Xue-Qiao Zhao, MD 206-744-8305 xueqiao@uw.edu

Locations
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United States, Washington
University of Washington Recruiting
Seattle, Washington, United States, 98104
Contact: Xue-Qiao Zhao, MD    206-744-8305    xueqiao@uw.edu   
Sponsors and Collaborators
University of Washington
AstraZeneca
Investigators
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Principal Investigator: Xue-Qiao Zhao, MD University of Washington
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Responsible Party: Xue-Qiao Zhao, Research Professor, Department of Medicine - Cardiology, University of Washington
ClinicalTrials.gov Identifier: NCT03782259    
Other Study ID Numbers: STUDY00004982
ESR 17-13124 ( Other Identifier: AstraZeneca Pharmaceuticals, LP )
First Posted: December 20, 2018    Key Record Dates
Last Update Posted: February 28, 2019
Last Verified: February 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Myocarditis
Diabetes Mellitus, Type 2
Fibrosis
Inflammation
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Pathologic Processes
Cardiomyopathies
Heart Diseases
Cardiovascular Diseases
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs