| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with type 2 diabetes mellitus and heart failure |
|
| E.1.1.1 | Medical condition in easily understood language |
| Type 2 diabetes mellitus and heart failure |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10011078 |
| E.1.2 | Term | Coronary artery disease |
| E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To exclude an increase in left ventricular end diastolic volume (LVEDV) index of greater than 10% (non-inferiority margin of 6.5 mL/m2) in patients with T2DM and HF treated with saxagliptin for 24 weeks, compared to placebo. |
|
| E.2.2 | Secondary objectives of the trial |
- Evaluate 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
- Evaluate the effects of saxagliptin compared to placebo on N-terminal prohormone of brain natriuretic peptide (NT-proBNP) after 24 weeks of treatment |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provision of informed consent prior to any study specific procedure (Pre-screening ICF and Informed Consent collected at screening)
2. Male or female, aged ≥18 years at the time of consent
3. 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 pre-screening 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
4. 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
5. Stable HF, with no evidence of volume overload (no rales, jugular venous distention, peripheral edema) at screening
6. 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 |
|
| E.4 | Principal exclusion criteria |
1. MRI contraindications: all implanted defibrillators; implanted pacemakers and other devices/implants that in the judgment of the investigator preclude an MRI evaluation
2. 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
3. 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
4. Receiving incretin therapy (DPP4 inhibitors, GLP-1 mimetics), or having received incretin therapy within the previous 8 weeks of randomization
5. Receiving therapy with a TZD or having received TZD therapy within the previous 8 weeks of randomization
6. Type 1 diabetes mellitus
7. History of unstable or rapidly progressing renal disease
8. A central lab eGFR value <30 mL/min/1.73 m2 on pre-screening or screening
9. New York Heart Association (NYHA) Class IV HF
10. 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
11. Inoperable aortic or mitral valvular heart disease. Recent (within 3 months) or planned valvular heart procedure
12. Heart failure secondary to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, and hypertrophic obstructive cardiomyopathy
13. Previous cardiac transplantation or transplantation indicated or expected within 6 months of randomization
14. Contraindications to saxagliptin therapy as outlined in the saxagliptin Investigator’s Brochure, or to sitagliptin therapy as outlined in the sitagliptin prescribing information
15. Current treatment with strong cytochrome P450 (CYP) 3A4/5 inhibitors
16. Involvement in the planning and/or conduct of the study (applies to both AZ staff and/or staff at the study site)
17. 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
18. Participation in another clinical study with an investigational product during the last 30 days
19. Patients either employed by or immediate relatives of the Sponsor
20. Known human immunodeficiency virus (HIV) infection
21. 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
22. Active malignancy requiring treatment at the time of Visit 1(with the exception of
successfully treated basal cell or treated squamous cell carcinoma).
23. Pregnant, positive pregnancy test, planning to become pregnant during clinical trial or breast feeding
24. 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
25. Unable or unwilling to provide written informed consent |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in LVEDV index measured by Magnetic Resonance Imaging (MRI) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Change from baseline in LVESV index, LVEF, and LVM measured by MRI
- Change from baseline in NT-proBNP |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Bulgaria |
| Canada |
| Chile |
| Hungary |
| Korea, Republic of |
| Romania |
| Russian Federation |
| Thailand |
| Ukraine |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last Subject Last Visit (LSLV) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 28 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 28 |
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