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A Clinical Study to Investigate the Effects of Dapagliflozin on Heart Work, Heart Nutrient Uptake, and Heart Muscle Efficiency in Type 2 Diabetes Patients. (DAPACARD)

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ClinicalTrials.gov Identifier: NCT03387683
Recruitment Status : Recruiting
First Posted : January 2, 2018
Last Update Posted : November 5, 2018
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
This is a randomised, placebo-controlled, double-blind, parallel-group, international, multicentre, Phase IV study to investigate the effects of dapagliflozin on cardiac substrate uptake, myocardial efficiency and myocardial contractile work in T2D patients. Eligible subjects with T2D before randomisation and fulfilling all of the inclusion criteria and none of the exclusion criteria will be randomised in a 1:1 ratio to dapagliflozin 10 mg or placebo once daily and treated for six weeks. The study includes five visits.

Condition or disease Intervention/treatment Phase
Diabetes Mellitus Type 2 Drug: dapagliflozin Drug: placebo Phase 4

Detailed Description:

The following will be assessed at Baseline and at the end of the treatment period;

  1. MRI scanning in order to assess cardiac function and morphology. The MRI scanning will be made after fasting for at least 6 hours in the same time of day at all visits. The cardiac MRI examination will be performed in accordance with a pre-defined MRI protocol, with the total scan time at each visit estimated to 45 minutes. Images from all sites will be analyzed centrally at the core-lab using a dedicated software package and certified analysts.
  2. CT-PET scanning will be made to assess myocardial function and metabolism, as well as fatty acid metabolism in brain, liver and kidney cortex. The CT-PET scanning will be made after a fast as well as abstinence from nicotine, alcohol and caffeine for at least 6 hours at the same time of day at all visits.

    • A cardiac 11C-Acetate PET/CT examination is performed (IV 400 MBq 11C-Acetate).
    • A cardiac 18F-FTHA PET/CT examination is performed (IV 150 MBq 18F-FTHA). The subject is further examined by PET/CT over the liver, kidney cortex and brain (in this order) for uptake of 18F-FTHA. Arterialized venous samples are acquired throughout to assess P-NEFA and 18F-FTHA metabolism by metabolite analysis.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 52 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Double-blind, Randomized, Parallel Group, Phase IV Study to Investigate the Effects of DAPAgliflozin on CARDiac Substrate Uptake, Myocardial Efficiency and Myocardial Contractile Work in Type 2 Diabetes Patients
Actual Study Start Date : February 28, 2018
Estimated Primary Completion Date : April 1, 2019
Estimated Study Completion Date : April 1, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Placebo Comparator: placebo
placebo tablets once daily
Drug: placebo
placebo to match dapagliflozin

Experimental: dapagliflozin 10mg
dapagliflozin 10mg tablets once daily
Drug: dapagliflozin
dapagliflozin 10mg
Other Name: Forxiga 10mg




Primary Outcome Measures :
  1. Global longitudinal strain of the left ventricle (GLSLV) [ Time Frame: Baseline and 6 weeks ]
    Change from baseline in global longitudinal strain of the left ventricle (GLSLV) in %


Secondary Outcome Measures :
  1. Myocardial efficiency [ Time Frame: Baseline and 6 weeks ]
    Change from baseline in myocardial efficiency (%)


Other Outcome Measures:
  1. Myocardial perfusion [ Time Frame: Baseline and 6 weeks ]
    Changes from baseline in myocardial perfusion measured by [11C]-Acetate

  2. Myocardial fatty acid uptake [ Time Frame: Baseline and 6 weeks ]
    Changes from baseline in myocardial fatty acid uptake measured by [18F]-FTHA

  3. Left atrial volumes [ Time Frame: Baseline and 6 weeks ]
    Changes from baseline in Left atrial min volume and max volume,

  4. Left atrial ejection fraction [ Time Frame: Baseline and 6 weeks ]
    Left atrial ejection fraction (%)

  5. Left atrial transmitral flow velocity [ Time Frame: Baseline and 6 weeks ]
    Left atrial transmitral flow velocity indices (E/A, E, A and DT)

  6. Fatty acid uptake in the liver [ Time Frame: Baseline and 6 weeks ]
    Changes from baseline in fatty acid uptake in liver by [18F]-FTHA

  7. Fatty acid uptake in the kidney cortex [ Time Frame: Baseline and 6 weeks ]
    Changes from baseline in fatty acid uptake in kidney cortex by [18F]-FTHA

  8. Fatty acid uptake in the brain [ Time Frame: Baseline and 6 weeks ]
    Changes from baseline in fatty acid uptake in brain measured by [18F]-FTHA



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Ages Eligible for Study:   40 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
  • Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses.
  • Females or males ≥40 years up to 75 years of age.
  • Individuals with type 2 diabetes diagnosed for at least 6 months based on the American Diabetes Association standards (ADA, 2017) and on stable dose of metformin for at least 6 weeks prior to screening and HbA1c at screening visit of ≥42 mmol/mol (6.0%) and ≤75 mmol/mol (9.0%) measured at local hospital laboratory.
  • No significant signs or symptoms of coronary artery disease or, if known coronary artery disease, currently free of symptoms and a) all major epicardial vessels with <50% stenosis within 12 months prior to screening, or b) if revascularized with all major epicardial vessels with <50% remaining stenosis after stenting or bypass surgery procedure determined between 3 and 12 months prior to screening.
  • Normal left ventricular ejection fraction (≥50%) assessed within 1 year prior to informed consent, and if applicable, after most recent acute episode of coronary artery syndrome, or at screening visit.
  • Body mass index (BMI) ≥ 25 kg/m2.

Exclusion Criteria:

  • Blood pressure at screening that would require a change in blood pressure treatment over the study period or any of the following: systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg.
  • History of stroke or other clinically significant cerebrovascular disease.
  • Any of the following cardiovascular diseases known within 3 months prior to signing the consent at enrolment:

    1. Atrial fibrillation, or other unstable or severe arrhythmia affecting heart function
    2. Unstable heart failure or any heart failure with NYHA class III and IV
    3. Significant valvular disease
    4. Significant peripheral artery disease
  • Planned cardiac surgery or angioplasty within 3 months from enrolment.
  • Clinical diagnosis of type 1 diabetes, maturity onset diabetes of the young (MODY), secondary diabetes or diabetes insipidus.
  • Verified body weight variability of >3 kg during the 3 proceeding months before screening.
  • Active malignancy requiring treatment at the time of visit 1 (with the exception of successfully treated basal cell or treated squamous cell carcinoma).
  • Patients with severe hepatic impairment (Child-Pugh class C).
  • Unstable or rapidly progressing renal disease.
  • Clinically significant disease or disorder which, in the opinion of the investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study.
  • Ongoing treatment with other antidiabetic drugs than metformin.
  • Ongoing treatment with loop diuretics.
  • Ongoing weight-loss diet (hypocaloric diet) or use of weight loss agents.
  • Contraindications to dapagliflozin therapy.
  • Ongoing treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent or any other uncontrolled endocrine disorder except for T2D.
  • Previous enrolment in the present study or participation in another clinical study with an investigational product during the last 1 month prior to screening.
  • Estimated Glomerular Filtration Rate (eGFR) <45 mL/min/1.73 m2.
  • Alcohol or drug abuse within the 3 months prior to informed consent that would interfere with trial participation or any ongoing condition leading to a decreased compliance to study procedures or study treatment intake.
  • Any condition when MRI and CT-PET is contraindicated such as, but not limited to, having a metallic implant (such as pacemaker or cochlear implant), permanent make up, claustrophobia or BMI ≥40 kg/m2).
  • Involvement in the planning and/or conduct of the study.
  • Plasma donation within one month of screening or any blood donation/blood loss >450 mL during the 3 months prior to screening.
  • Women who has a positive pregnancy test at enrolment or randomization, or are breastfeeding.

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): NCT03387683


Contacts
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
Finland
Research Site Recruiting
Turku, Finland, 20520
Sweden
Research Site Recruiting
Uppsala, Sweden, SE-751 85
Sponsors and Collaborators
AstraZeneca
Investigators
Principal Investigator: Jonas Oldgren, MD, PhD Uppsala Clinical Research Center, Upppsala Sweden
Principal Investigator: Pirjo Nuutila, MD, PhD University of Turku, Turku, Finland

Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03387683     History of Changes
Other Study ID Numbers: D1690C00063
2017-003820-58 ( EudraCT Number )
First Posted: January 2, 2018    Key Record Dates
Last Update Posted: November 5, 2018
Last Verified: November 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases