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Study in Diabetes Mellitus Patients Without Prior Myocardial Infarction or Stroke Undergoing Elective Percutaneous Coronary Intervention. (AUGEAS)

Primary Purpose

Diabetes Mellitus, Microvascular Coronary Artery Disease

Status
Withdrawn
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Ticagrelor
Clopidogrel
Sponsored by
Region Skane
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diabetes Mellitus focused on measuring myocardial infarction, percutaneous coronary invervention, coronary flow velocity reserve (CFR)

Eligibility Criteria

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

Inclusion Criteria:

  1. Provision of informed consent prior to any study specific procedures
  2. Men or women ≥18 years of age
  3. Diagnosed with T2DM defined as treatment with ongoing glucose lowering drug (oral medications and/or insulin) for at least 1 month
  4. Presence of CAD undergoing elective PCI
  5. Impaired coronary microvascular function post PCI as defined by a CFR ≤2.5 (as per local reading)
  6. TIMI 3 flow post PCI

Exclusion Criteria:

  1. Previous MI defined as a documented hospitalization with a final diagnosis of spontaneous MI (with the exception of definite secondary MI [e.g., due to coronary revascularization procedure, profound hypotension, hypertensive emergency, tachycardia, or profound anemia]).
  2. Previous stroke (transient ischemic attack [TIA] is not included in the stroke definition)
  3. Use of an intravenous antiplatelet therapy (i.e., cangrelor or GPI) during PCI
  4. On treatment with clopidogrel, prasugrel, or ticagrelor due to a prior acute major CV event (MI or stroke) (on treatment with clopidogrel due to prior vascular intervention not secondary to a major CV event is allowed)
  5. Planned use of aspirin treatment at doses >150 mg od

  6. Anticipated concomitant oral or intravenous therapy with strong cytochrome P450 3A4 (CYP3A4) inhibitors or CYP3A4 substrates with narrow therapeutic indices that cannot be stopped for the course of the study:

    1. Strong CYP3A4 inhibitors: ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin (but not erythromycin or azithromycin), nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir
    2. CYP3A4 substrates with narrow therapeutic index: quinidine, simvastatin at doses >40 mg daily or lovastatin at doses >40 mg daily
  7. Hypersensitivity to ticagrelor or any of its excipients
  8. Need for chronic oral anticoagulant therapy or chronic low-molecular-weight heparin
  9. Patients with known bleeding diathesis or coagulation disorder
  10. History of intracerebral bleed at any time, gastrointestinal (GI) bleed within the past 6 months prior to randomization, or major surgery within 30 days prior to randomization
  11. Increased risk of bradycardic events (e.g., known sick sinus syndrome, second or third-degree AV block or previous documented syncope suspected to be due to bradycardia) unless treated with a pacemaker
  12. Known severe liver disease (e.g., ascites and/or clinical signs of coagulopathy)
  13. Renal failure requiring dialysis
  14. Known platelet count <145 x109 platelets/L
  15. Known hemoglobin <9 g/dL
  16. Women of child-bearing potential (WOCBP)*, who are not willing to use a method of contraception that is considered highly reliable** per CTFG (Clinical Trial Facilitation Group), OR who have a positive pregnancy test at enrolment or randomization OR women who are breast-feeding
  17. Inability of the patient to understand and/or comply with study procedures and/or follow up, in the opinion of the investigator, OR any conditions that, in the opinion of the investigator, may render the patient unable to complete the study
  18. Life expectancy of less than 6 month based on investigator's judgement
  19. Participation in another clinical study with an investigational (defined as non-approved) product, if taken within five half-lives or 28 days prior to the first administration of the trial medication, whichever is longer
  20. Previous randomization in the present study
  21. Severe asthma
  22. Hypersensitivity to adenosine or mannitol
  23. Long QT syndrome
  24. Chronic obstructive lung disease, with evidence of bronchospasm
  25. Severe low blood pressure
  26. Unstable angina pectoris
  27. Severe heart failure
  28. Hypovolemia
  29. Treatment with dipyradimol
  30. Increased intracranial pressure * fertile, following menarche until becoming post-menopausal, unless permanently sterile (permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy) ** estrogen/progestogen or progestogen (oral, intravaginal or transdermal administration); intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomised partner; sexual abstinence

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Active Comparator

    Arm Label

    Ticagrelor

    Clopidogrel

    Arm Description

    ticagrelor 60mg BID for 30 Days and ASA 75 - 150 mg once daily

    clopidogrel 75mg OD for 30 Days and ASA 75 - 150 mg once daily

    Outcomes

    Primary Outcome Measures

    Coronary Flow Velocity Reserve (CFR)
    Difference in mean of individual absolute change from baseline to 30 days in Coronary Flow Velocity Reserve (CFR) in the mid-distal segment of the left anterior descending (LAD) coronary artery under adenosine infusion measured by Transthoracic Doppler Echocardiography (TDE) between the two arms

    Secondary Outcome Measures

    Coronary flow parameter-LAD hyperemic mean diastolic flow velocity
    Difference in mean of individual absolute change from baseline at 30 days in: - LAD hyperemic mean diastolic flow velocity
    Coronary flow parameter-LAD resting mean diastolic flow velocity
    Difference in mean of individual absolute change from baseline at 30 days - LAD resting mean diastolic flow velocity

    Full Information

    First Posted
    August 20, 2019
    Last Updated
    April 6, 2020
    Sponsor
    Region Skane
    Collaborators
    IHF GmbH - Institut für Herzinfarktforschung, Hippocrates Research, IRW consulting AB, AstraZeneca
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    1. Study Identification

    Unique Protocol Identification Number
    NCT04069234
    Brief Title
    Study in Diabetes Mellitus Patients Without Prior Myocardial Infarction or Stroke Undergoing Elective Percutaneous Coronary Intervention.
    Acronym
    AUGEAS
    Official Title
    30-d Rand, Eval-blind, Controlled, Multi-centre, Parallel, ph III Study to Evaluate Effect of a Low Maint Dose Ticagrelor Regimen vs Standard Dose Clopidogrel on Coronary Flow Reserve in DM Patients With Impaired Microvascular Function Without Prior MI or Stroke Undergoing ePCI.
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    April 2020
    Overall Recruitment Status
    Withdrawn
    Why Stopped
    Sponsor decided to stop the study due to commercial reasons.
    Study Start Date
    September 15, 2019 (Anticipated)
    Primary Completion Date
    October 15, 2021 (Anticipated)
    Study Completion Date
    March 31, 2022 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Region Skane
    Collaborators
    IHF GmbH - Institut für Herzinfarktforschung, Hippocrates Research, IRW consulting AB, AstraZeneca

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Product Manufactured in and Exported from the U.S.
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    This study is designed to test the hypothesis that ticagrelor is superior to clopidogrel, in improving coronary microvascular function, as measured by coronary flow reserve (CFR) in patients with T2DM at high risk of cardiovascular (CV) events undergoing elective PCI.
    Detailed Description
    Coronary artery disease (CAD) can be divided into macrovascular and microvascular disease, both different manifestations of atherosclerosis. Macrovascular CAD, i.e. obstructive CAD of epicardial coronary arteries have traditionally been the focus of CAD treatment. Microvascular circulation, on the other hand, consists of arterioles (diameter <100 μm) within myocardium and abnormalities in this arterial bed may also impair myocardial perfusion and result in ischaemia. An indication of microvascular disease can be achieved with coronary flow reserve (CFR) which is an integrated measure of flow through both large epicardial arteries and coronary microcirculation. CFR measurement is the ratio of resting coronary artery mean diastolic flow velocity in comparison to hyperaemic coronary artery mean diastolic flow velocity, where hyperaemia is often induced with pharmacologic agent such as adenosine infusion. CFR of the left anterior descending (LAD) coronary artery during pharmacologic stress echocardiography has been found to provide effective prognostic information in patients with known or suspected CAD. This seems evident across patient populations, such as those with diabetes or chronic kidney disease, or older age. Particularly, a CFR <2.0 has been associated with markedly increased cardiovascular (CV) risk in an unselected patient population. Ticagrelor primary mode of action is as a direct acting reversibly binding P2Y12 antagonist inhibiting ADP-induced platelet activation. However, ticagrelor has also been shown to increase extracellular adenosine concentration by inhibition of the equilibrative nucleoside transporter 1 (ENT1). Adenosine has been described to have a number of physiological effects including vasodilation, anti-inflammation, anti-platelet and cardioprotective effects and ticagrelor has been shown to enhance many of these adenosine-induced effects in animal models and in man. These adenosine-mediated effects may be beneficial to CAD patients and potentially impact coronary microvascular function and contribute to the clinical profile of ticagrelor. So far only one study has explored ticagrelor effect on coronary microvascular function. They showed, by using rubidium 82 positron emission tomography/computed tomography, that ticagrelor could improve local CFR compared to clopidogrel in CAD patients specifically in those regions that before treatment had impaired CFR (<2.5). CFR has been shown to be a strong independent predictor in diabetic patients with suspected coronary disease for future coronary events and survival. The ongoing THEMIS study is designed to test the hypothesis that ticagrelor is superior to placebo, in prevention of major CV events, as measured by time to first event of the composite of CV death, MI, or stroke in patients with T2DM at high risk of CV events. Patients undergoing elective PCI are excluded from the THEMIS study as these patients are treated with clopidogrel plus aspirin. The current study is designed to fill this data gap by generating clinically meaningful data with ticagrelor in THEMIS-like patients undergoing elective PCI.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Diabetes Mellitus, Microvascular Coronary Artery Disease
    Keywords
    myocardial infarction, percutaneous coronary invervention, coronary flow velocity reserve (CFR)

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 3
    Interventional Study Model
    Parallel Assignment
    Masking
    Outcomes Assessor
    Allocation
    Randomized
    Enrollment
    0 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Ticagrelor
    Arm Type
    Experimental
    Arm Description
    ticagrelor 60mg BID for 30 Days and ASA 75 - 150 mg once daily
    Arm Title
    Clopidogrel
    Arm Type
    Active Comparator
    Arm Description
    clopidogrel 75mg OD for 30 Days and ASA 75 - 150 mg once daily
    Intervention Type
    Drug
    Intervention Name(s)
    Ticagrelor
    Intervention Description
    ticagrelor 60 mg BID for 30 days
    Intervention Type
    Drug
    Intervention Name(s)
    Clopidogrel
    Intervention Description
    clopidogrel 75mg OD for 30 Days
    Primary Outcome Measure Information:
    Title
    Coronary Flow Velocity Reserve (CFR)
    Description
    Difference in mean of individual absolute change from baseline to 30 days in Coronary Flow Velocity Reserve (CFR) in the mid-distal segment of the left anterior descending (LAD) coronary artery under adenosine infusion measured by Transthoracic Doppler Echocardiography (TDE) between the two arms
    Time Frame
    30+/- 3 days after randomization
    Secondary Outcome Measure Information:
    Title
    Coronary flow parameter-LAD hyperemic mean diastolic flow velocity
    Description
    Difference in mean of individual absolute change from baseline at 30 days in: - LAD hyperemic mean diastolic flow velocity
    Time Frame
    30+/- 3 days after randomization
    Title
    Coronary flow parameter-LAD resting mean diastolic flow velocity
    Description
    Difference in mean of individual absolute change from baseline at 30 days - LAD resting mean diastolic flow velocity
    Time Frame
    30+/- 3 days after randomization

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Provision of informed consent prior to any study specific procedures Men or women ≥18 years of age Diagnosed with T2DM defined as treatment with ongoing glucose lowering drug (oral medications and/or insulin) for at least 1 month Presence of CAD undergoing elective PCI Impaired coronary microvascular function post PCI as defined by a CFR ≤2.5 (as per local reading) TIMI 3 flow post PCI Exclusion Criteria: Previous MI defined as a documented hospitalization with a final diagnosis of spontaneous MI (with the exception of definite secondary MI [e.g., due to coronary revascularization procedure, profound hypotension, hypertensive emergency, tachycardia, or profound anemia]). Previous stroke (transient ischemic attack [TIA] is not included in the stroke definition) Use of an intravenous antiplatelet therapy (i.e., cangrelor or GPI) during PCI On treatment with clopidogrel, prasugrel, or ticagrelor due to a prior acute major CV event (MI or stroke) (on treatment with clopidogrel due to prior vascular intervention not secondary to a major CV event is allowed) Planned use of aspirin treatment at doses >150 mg od Anticipated concomitant oral or intravenous therapy with strong cytochrome P450 3A4 (CYP3A4) inhibitors or CYP3A4 substrates with narrow therapeutic indices that cannot be stopped for the course of the study: Strong CYP3A4 inhibitors: ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin (but not erythromycin or azithromycin), nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir CYP3A4 substrates with narrow therapeutic index: quinidine, simvastatin at doses >40 mg daily or lovastatin at doses >40 mg daily Hypersensitivity to ticagrelor or any of its excipients Need for chronic oral anticoagulant therapy or chronic low-molecular-weight heparin Patients with known bleeding diathesis or coagulation disorder History of intracerebral bleed at any time, gastrointestinal (GI) bleed within the past 6 months prior to randomization, or major surgery within 30 days prior to randomization Increased risk of bradycardic events (e.g., known sick sinus syndrome, second or third-degree AV block or previous documented syncope suspected to be due to bradycardia) unless treated with a pacemaker Known severe liver disease (e.g., ascites and/or clinical signs of coagulopathy) Renal failure requiring dialysis Known platelet count <145 x109 platelets/L Known hemoglobin <9 g/dL Women of child-bearing potential (WOCBP)*, who are not willing to use a method of contraception that is considered highly reliable** per CTFG (Clinical Trial Facilitation Group), OR who have a positive pregnancy test at enrolment or randomization OR women who are breast-feeding Inability of the patient to understand and/or comply with study procedures and/or follow up, in the opinion of the investigator, OR any conditions that, in the opinion of the investigator, may render the patient unable to complete the study Life expectancy of less than 6 month based on investigator's judgement Participation in another clinical study with an investigational (defined as non-approved) product, if taken within five half-lives or 28 days prior to the first administration of the trial medication, whichever is longer Previous randomization in the present study Severe asthma Hypersensitivity to adenosine or mannitol Long QT syndrome Chronic obstructive lung disease, with evidence of bronchospasm Severe low blood pressure Unstable angina pectoris Severe heart failure Hypovolemia Treatment with dipyradimol Increased intracranial pressure * fertile, following menarche until becoming post-menopausal, unless permanently sterile (permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy) ** estrogen/progestogen or progestogen (oral, intravaginal or transdermal administration); intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomised partner; sexual abstinence

    12. IPD Sharing Statement

    Learn more about this trial

    Study in Diabetes Mellitus Patients Without Prior Myocardial Infarction or Stroke Undergoing Elective Percutaneous Coronary Intervention.

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