Mechanistic Evaluation of Glucose-lowering Strategies in Patients With Heart Failure

Study Overview
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Brief Summary
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This is a 24 week, multicenter, randomized, double-blind, parallel group, placebo-controlled study to investigate the effects of saxagliptin and sitagliptin on cardiac dimensions and function in patients with type 2 diabetes (T2DM) mellitus and heart failure (HF).

Official Title
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A 24-Week, Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled Study to Investigate the Effects of Saxagliptin and Sitagliptin in Patients With Type 2 Diabetes Mellitus and Heart Failure

Conditions
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Type 2 Diabetes Mellitus, Heart Failure

Intervention / Treatment
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* Drug: Saxagliptin
* Drug: Sitagliptin
* Drug: Placebo to match saxagliptin
* Drug: Placebo to match sitagliptin


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Provision of informed consent prior to any study specific procedure (Pre-screening ICF and Informed Consent collected at screening) Male or female, aged ≥18 years at the time of consent Documented, controlled T2DM, as defined by: Diagnosis of Type 2 DM based on current ADA guidelines (Appendix C) Treatment with stable doses of antidiabetic medications that have not increased or decreased for ≥8 weeks before screening For patients taking insulin, the investigator must query the patient at prescreening or screening regarding his/her usual total daily insulin dose (all types combined) during the previous 8 weeks. Insulin dosages during pre-screening and screening should not vary by more than ±20% on more than two occasions Dosage reductions of insulin and sulfonylurea agents may be considered at randomization to minimize the possibility of hypoglycemia Any reductions in the dosage of insulin and sulfonylurea agents will be at the discretion of the investigator For patients treated with insulin, consider a reduction in dose of 20% at randomization For patients receiving sulfonylurea agents, consider a reduction in dose of 50% or discontinue if on a dosage that is considered low at randomization HFrEF demonstrated by all 3 of the following criteria: History of HF and LVEF ≤45% within the last 6 months (echocardiogram, MRI, left ventriculography, or other accepted methodology). Patients without a recent assessment of LV function will undergo a local echocardiogram at the time of screening to determine ejection fraction Elevated NT-proBNP (>300 pg/mL) during screening Patients should receive background standard of care for HFrEF and be treated according to locally recognized guidelines as appropriate. Guideline-recommended medications should be used at recommended doses unless contraindicated or not tolerated. Therapy should have been individually optimized and stable for >or = 4 weeks (this does not apply to diuretics-see NB below) before screening visit and include (unless contraindicated or not tolerated): an ACE inhibitor, or ARB, or sacubitril/valsartan and a beta-blocker and if considered appropriate by the patient's treating physician; a mineralocorticoid receptor antagonist (MRA) NB: Most patients with heart failure require treatment with a diuretic to control sodium and water retention leading to volume overload. It is recognized that diuretic dosing may be titrated to symptoms, signs, weight, and other information and may thus vary. Each patient should, however, be treated with a diuretic regimen aimed at achieving optimal fluid/volume status for that individual Stable HF, with no evidence of volume overload (no rales, jugular venous distention, peripheral edema) at screening Women of childbearing potential (WOCBP): Must be using appropriate birth control to avoid pregnancy throughout the study and for up to 4 weeks after the last dose of investigational product Must have a negative serum or urine pregnancy test within 72 hours prior to the start of investigational product Must not be breastfeeding. EXCLUSION CRITERIA: MRI contraindications: all implanted defibrillators; implanted pacemakers and other devices/implants that in the judgment of the investigator preclude an MRI evaluation Patients with atrial fibrillation/flutter, or any rhythm that would impact on MRI imaging quality would be excluded. Patients with a prior history of atrial fibrillation or paroxysmal atrial fibrillation may be eligible for entry into the study based on the investigator's judgment related to the frequency of AF events and the patient's overall condition Body mass index >45 kg/m2 or any condition, including, but not limited to known claustrophobia, that may preclude the ability to perform an MRI scan of acceptable quality, or unwillingness to undergo MRI imaging Receiving incretin therapy (DPP4 inhibitors, GLP-1 mimetics), or having received incretin therapy within the previous 8 weeks of randomization Receiving therapy with a TZD or having received TZD therapy within the previous 8 weeks of randomization Type 1 diabetes mellitus History of unstable or rapidly progressing renal disease A central lab eGFR value <30 mL/min/1.73 m2 on pre-screening or screening New York Heart Association (NYHA) Class IV HF Myocardial infarction, stroke, transient ischemic attack, or coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]) within the past 3 months of screening Inoperable aortic or mitral valvular heart disease. Recent (within 3 months) or planned valvular heart procedure Heart failure secondary to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, and hypertrophic obstructive cardiomyopathy Previous cardiac transplantation or transplantation indicated or expected within 6 months of randomization Contraindications to saxagliptin therapy as outlined in the saxagliptin Investigator's Brochure, or to sitagliptin therapy as outlined in the sitagliptin prescribing information Current treatment with strong cytochrome P450 (CYP) 3A4/5 inhibitors Involvement in the planning and/or conduct of the study (applies to both AZ staff and/or staff at the study site) Previous enrollment which disqualifies patient from re-enrollment based on the rules in Section 4.1 of the protocol, or previous randomization in the study Participation in another clinical study with an investigational product during the last 30 days Patients either employed by or immediate relatives of the Sponsor Known human immunodeficiency virus (HIV) infection Severe hepatic disease, including chronic active hepatitis. Positive serologic evidence of current infectious liver disease, including patients who are known to be positive for hepatitis B viral antibody IgM, hepatitis B surface antigen, or hepatitis C virus antibody; or aspartate transaminase (AST) or alanine transaminase (ALT) >3X the upper limit of normal; or total bilirubin (TB) >2 mg/dL Active malignancy requiring treatment at the time of Visit 1(with the exception of successfully treated basal cell or treated squamous cell carcinoma). Pregnant, positive pregnancy test, planning to become pregnant during clinical trial or breast feeding History of any clinically significant disease or disorder which, in the opinion of the investigator, may put the patient at risk because of participation in the study, may influence the results, or may limit the patient's ability to participate in or complete the study Unable or unwilling to provide written informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Saxagliptin<br>one tablet of saxagliptin 5 mg or 2.5 mg + one placebo capsule matching sitagliptin | Drug: Saxagliptin<br>* 5 mg or 2.5 mg, plain, yellow, biconvex, round, film-coated tablet<br>* Other names: Onglyza TM;Drug: Placebo to match sitagliptin<br>* 50 mg or 100 mg, gray capsule<br>|
| Active Comparator: Sitagliptin<br>one capsule of sitagliptin 100 mg or 50 mg + one placebo tablet matching saxagliptin | Drug: Sitagliptin<br>* 50 mg or 100 mg, gray capsule<br>* Other names: Januvia®;Drug: Placebo to match saxagliptin<br>* 2.5 mg or 5 mg, plain, yellow, biconvex, round, film-coated tablet<br>|
| Placebo Comparator: Placebo<br>one placebo tablet matching saxagliptin + one placebo capsule matching sitagliptin | Drug: Placebo to match saxagliptin<br>* 2.5 mg or 5 mg, plain, yellow, biconvex, round, film-coated tablet<br>Drug: Placebo to match sitagliptin<br>* 50 mg or 100 mg, gray capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Left Ventricular End Diastolic Volume (LVEDV) Index Measured by Magnetic Resonance Imaging (MRI) at 24 Weeks | MRI was performed to evaluate LVEDV at baseline and Visit 10 (Week 24). Evaluated to exclude an increase in left ventricular end diastolic volume (LVEDV) index of greater than 10% of the overall baseline value (noninferiority margin) in patients with T2DM and HF treated with saxagliptin for 24 weeks, compared to placebo. Baseline is last assessment on or before the date of first dose. | Baseline to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Left Ventricular End Systolic Volume (LVESV) Index, Measured by MRI at 24 Weeks. | Evaluation of the effects of saxagliptin compared to placebo on left ventricular end systolic volume (LVESV) index, after 24 weeks in patients with T2DM and HF. | Baseline to week 24 | 
| Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Measured by MRI at 24 Weeks. | Evaluation the effects of saxagliptin compared to placebo on left ventricular end systolic volume (LVESV) index, left ventricular ejection fraction (LVEF), and left ventricular mass (LVM) after 24 weeks in patients with T2DM and HF. | Baseline to week 24 | 
| Change From Baseline in Left Ventricular Mass (LVM) Measured by MRI at 24 Weeks. | Evaluation of the effects of saxagliptin compared to placebo on left ventricular mass (LVM) after 24 weeks in patients with T2DM and HF. | At 24 week | 
| Change From Baseline in NT-proBNP After 24 Weeks of Treatment | Evaluation of the effects of saxagliptin compared to placebo on N-terminal prohormone of brain natriuretic peptide (NT-proBNP) after 24 weeks of treatment. | Baseline to Week 28 (End of Study visit [EoS]) | 
| Number of Participants With Adverse Events | Assessment of safety and tolerability of saxagliptin and sitagliptin treatment in patients with T2DM and HF | From screening (Days -28 to -1) until Week 28 (follow-up visit) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 Diabetes Mellitus, Heart Failure, Saxagliptin, Sitagliptin