search
Back to results

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

Primary Purpose

Type 2 Diabetes Mellitus, Myocardial Fibrosis, Myocardial Inflammation

Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
dapagliflozin
Placebo
Sponsored by
University of Washington
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional screening trial for Type 2 Diabetes Mellitus

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 glucagon-like peptide (GLP)-1 receptor antagonist
  4. Glomerular filtration rate (GFR) <60 mL/min/1.73 m2
  5. Unstable or rapidly progressive renal disease
  6. Hypotension with systolic blood pressure (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. Heart Failure - New York Heart Association (NYHA) Class IV
    5. Transient ischemic attack (TIA) or significant cerebrovascular disease
    6. Unstable or previously undiagnosed arrhythmia
    7. Established peripheral artery disease (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 study drug, OR women who are breast-feeding.

Sites / Locations

  • University of Washington

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Active Comparator

Arm Label

Placebo

Active

Arm Description

10mg tabs placebo matching dapagliflozin.

10mg tabs of dapagliflozin

Outcomes

Primary Outcome Measures

Extracellular volume fraction (ECV)
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.
Global myocardial longitudinal strain (GLS)
Global myocardial longitudinal strain (GLS) measured from cardiac MRI with T1-mapping at two timepoints. MRI at Randomization and MRI at approximately 12 Months. Myocardial strain measurements with feature tracking will be performed to measure myocardial strain and strain rate from the bSSFP short-axis and long-axis cine images. Long-axis cine images will be further used to compute GLS. Ancova test with adjusted for baseline GLS will be used to compare change in GLS over 12 months between 2 treatment groups.

Secondary Outcome Measures

T2 relaxation time
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

Full Information

First Posted
October 24, 2018
Last Updated
January 9, 2023
Sponsor
University of Washington
Collaborators
AstraZeneca
search

1. Study Identification

Unique Protocol Identification Number
NCT03782259
Brief Title
Effects of SGLT-2 Inhibition on Myocardial Fibrosis and Inflammation as Assessed by Cardiac MRI in Patients With DM2
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
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Completed
Study Start Date
February 26, 2019 (Actual)
Primary Completion Date
November 16, 2022 (Actual)
Study Completion Date
November 16, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Washington
Collaborators
AstraZeneca

4. Oversight

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
Data Monitoring Committee
No

5. Study Description

Brief Summary
There is an unmet need for Cardiovascular Disease (CVD) 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 strain, 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 University of Washington research imaging centers will take place. One at randomization and the second scan will occur approximately 12 months after the first scan.
Detailed Description
Given the unmet needs for CVD risk reduction in patients with Type 2 Diabetes Mellitus (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 (CMRI) 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 strain, 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 strain endpoint includes global myocardial longitudinal strain (GLS). 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 2 Diabetes Mellitus, Myocardial Fibrosis, Myocardial Inflammation

7. Study Design

Primary Purpose
Screening
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
Randomized, double-blind and placebo controlled cardiac MRI study
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
60 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
10mg tabs placebo matching dapagliflozin.
Arm Title
Active
Arm Type
Active Comparator
Arm Description
10mg tabs of dapagliflozin
Intervention Type
Drug
Intervention Name(s)
dapagliflozin
Other Intervention Name(s)
Forxiga
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Placebo
Primary Outcome Measure Information:
Title
Extracellular volume fraction (ECV)
Description
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.
Time Frame
Approximately 12 Months
Title
Global myocardial longitudinal strain (GLS)
Description
Global myocardial longitudinal strain (GLS) measured from cardiac MRI with T1-mapping at two timepoints. MRI at Randomization and MRI at approximately 12 Months. Myocardial strain measurements with feature tracking will be performed to measure myocardial strain and strain rate from the bSSFP short-axis and long-axis cine images. Long-axis cine images will be further used to compute GLS. Ancova test with adjusted for baseline GLS will be used to compare change in GLS over 12 months between 2 treatment groups.
Time Frame
Approximately 12 Months
Secondary Outcome Measure Information:
Title
T2 relaxation time
Description
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
Time Frame
Approximately 12 Months
Other Pre-specified Outcome Measures:
Title
Epicardial fat
Description
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.
Time Frame
Approximately 12 Months
Title
Fasting glucose
Description
Fasting glucose will be measured every 3 months for approximately 12 months.
Time Frame
Approximately 12 Months
Title
HbA1C
Description
Hemoglobin A1c (HbA1c) will be measured every 3 months for approximately 12 months.
Time Frame
Approximately 12 Months
Title
LDL particle size
Description
LDL particle size measured from plasma samples at Randomization and at approximately 12 Months
Time Frame
Approximately 12 Months
Title
hsCRP
Description
Inflammatory marker hsCRP at Screening, 6 months and at approximately 12 Months.
Time Frame
Approximately 12 Months
Title
Tumor necrosis factor (TNF)-α
Description
Inflammatory marker TNF-α measured from plasma samples at Randomization and at approximately 12 Months
Time Frame
Approximately 12 Months
Title
Iinterleukin (IL)-6
Description
Inflammatory marker IL-6 measured from plasma samples at Randomization and at approximately 12 Months
Time Frame
Approximately 12 Months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Men and women at least 18 years of age Subjects with type-2 diabetes history >=5 years HbA1C 7-10% with glucose control medications including insulin, metformin or sulfonylurea Medically stable Willing to participate and sign informed consent. Exclusion Criteria: Contraindication to MRI Currently or within last three months treatment with a SGLT2 inhibitor Currently taking glucagon-like peptide (GLP)-1 receptor antagonist Glomerular filtration rate (GFR) <60 mL/min/1.73 m2 Unstable or rapidly progressive renal disease Hypotension with systolic blood pressure (SBP) <100 mmHg Hypersensitivity to dapagliflozin or any excipients Patients with severe hepatic impairment (Child-Pugh class C) Patients with active hepatitis B or C infection Any of the following CV/Vascular Diseases within 3 months prior to signing the consent at enrollment, as assessed by the investigator: Myocardial infarction Cardiac surgery or revascularization (CABG/PTCA) Unstable angina Heart Failure - New York Heart Association (NYHA) Class IV Transient ischemic attack (TIA) or significant cerebrovascular disease Unstable or previously undiagnosed arrhythmia Established peripheral artery disease (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 study drug, OR women who are breast-feeding.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Xue-Qiao Zhao, MD
Organizational Affiliation
University of Washington
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Washington
City
Seattle
State/Province
Washington
ZIP/Postal Code
98104
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

We'll reach out to this number within 24 hrs