Heart Failure, Type 2 Diabetes Mellitus
Conditions
Keywords
Type 2 Diabetes Mellitus, Heart Failure, Saxagliptin, Sitagliptin
Brief summary
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).
Interventions
DRUGSaxagliptin
5 mg or 2.5 mg, plain, yellow, biconvex, round, film-coated tablet
DRUGSitagliptin
50 mg or 100 mg, gray capsule
DRUGPlacebo to match saxagliptin
2.5 mg or 5 mg, plain, yellow, biconvex, round, film-coated tablet
DRUGPlacebo to match sitagliptin
50 mg or 100 mg, gray capsule
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
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 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 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.
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Left Ventricular End Diastolic Volume (LVEDV) Index Measured by Magnetic Resonance Imaging (MRI) at 24 Weeks | Baseline to 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Left Ventricular End Systolic Volume (LVESV) Index, Measured by MRI at 24 Weeks. | Baseline to week 24 | 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. |
| Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Measured by MRI at 24 Weeks. | Baseline to week 24 | 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. |
| Change From Baseline in Left Ventricular Mass (LVM) Measured by MRI at 24 Weeks. | At 24 week | Evaluation of the effects of saxagliptin compared to placebo on left ventricular mass (LVM) after 24 weeks in patients with T2DM and HF. |
| Change From Baseline in NT-proBNP After 24 Weeks of Treatment | Baseline to Week 28 (End of Study visit [EoS]) | Evaluation of the effects of saxagliptin compared to placebo on N-terminal prohormone of brain natriuretic peptide (NT-proBNP) after 24 weeks of treatment. |
| Number of Participants With Adverse Events | From screening (Days -28 to -1) until Week 28 (follow-up visit) | Assessment of safety and tolerability of saxagliptin and sitagliptin treatment in patients with T2DM and HF |
Countries
Bulgaria, Canada, Chile, Hungary, Romania, Russia, South Korea, Thailand, Ukraine, United States
Participant flow
Recruitment details
Participants who met all the inclusion and exclusion criteria were enrolled in 9 countries.
Pre-assignment details
Participants with documented Ejection Fraction ≤ 45% and NTproBNP \> 300 pg/mL had eligibility criteria assessed within 28 days of screening period. Informed consent was obtained prior to any study-related procedures or dosing of IP. 1 subject was excluded from the FAS as incorrectly randomized. This subject was terminated from the study on the day of randomization and no investigational product was dispensed.
Participants by arm
| Arm | Count |
|---|---|
| Saxagliptin Participants with an eGFR ≥50 mL/min/1.73m\^2 received one saxagliptin 5 mg tablet and one sitaglipitin placebo capsule administered orally once daily for a 24-week treatment period. Participants with an eGFR ≥30 to \<50 mL/min/1.73m\^2, the dose of saxagliptin was adjusted to one 2.5 mg tablet. | 112 |
| Sitagliptin Participants with an eGFR ≥50 mL/min/1.73m\^2 received one sitagliptin 100 mg capsule and one saxagliptin placebo tablet administered orally once daily for a 24-week treatment period. Participants with an eGFR ≥30 to \<50 mL/min/1.73m\^2, the dose of sitagliptin was adjusted to one 50 mg capsule. | 115 |
| Placebo Participants recieved one saxagliptin placebo tablet and one sitagliptin placebo capsule administered orally once daily for a 24-week treatment period as a control. | 120 |
| Total | 347 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 1 | 5 |
| Overall Study | Death | 2 | 3 | 4 |
| Overall Study | Development of study-specific withdrawal criteria | 1 | 1 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 0 |
| Overall Study | Reason not specified | 7 | 5 | 6 |
| Overall Study | Withdrawal by Subject | 3 | 3 | 0 |
Baseline characteristics
| Characteristic | Saxagliptin | Sitagliptin | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 64.6 Years STANDARD_DEVIATION 7.96 | 64.9 Years STANDARD_DEVIATION 9.85 | 66.5 Years STANDARD_DEVIATION 7.84 | 65.4 Years STANDARD_DEVIATION 8.61 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 16 Participants | 17 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 102 Participants | 99 Participants | 103 Participants | 304 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 17 Participants | 17 Participants | 15 Participants | 49 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 94 Participants | 98 Participants | 102 Participants | 294 Participants |
| Sex: Female, Male Female | 35 Participants | 36 Participants | 37 Participants | 108 Participants |
| Sex: Female, Male Male | 77 Participants | 79 Participants | 83 Participants | 239 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 112 | 3 / 115 | 4 / 120 |
| other Total, other adverse events | 8 / 112 | 9 / 115 | 8 / 120 |
| serious Total, serious adverse events | 17 / 112 | 19 / 115 | 29 / 120 |
Outcome results
Primary
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.
Time frame: Baseline to 24 weeks
Population: Full analysis set (FAS): All randomised patients who took at least one dose of the study medication. Here, overall number of participants analyzed presents only those participants who were analyzed for this particular outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saxagliptin | Change From Baseline in Left Ventricular End Diastolic Volume (LVEDV) Index Measured by Magnetic Resonance Imaging (MRI) at 24 Weeks | -3.395 mL/m^2 | Standard Deviation 15.3412 |
| Placebo | Change From Baseline in Left Ventricular End Diastolic Volume (LVEDV) Index Measured by Magnetic Resonance Imaging (MRI) at 24 Weeks | -0.716 mL/m^2 | Standard Deviation 18.1178 |
Comparison: Change from baseline, saxagliptin versus placebo.p-value: 0.25295% CI: [-7.04, 1.85]ANCOVA
Secondary
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.
Time frame: Baseline to week 24
Population: Full analysis set (FAS): All randomised patients who took at least one dose of the study medication. Here, overall number of participants analysed presents only those participants who were analyzed for this particular outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saxagliptin | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Measured by MRI at 24 Weeks. | 0.533 Percentage | Standard Deviation 7.1971 |
| Placebo | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Measured by MRI at 24 Weeks. | 0.298 Percentage | Standard Deviation 7.2843 |
Comparison: Saxagliptin vs Placebo:~Change from baselinep-value: 0.92595% CI: [-1.996, 2.197]ANCOVA
Secondary
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.
Time frame: Baseline to week 24
Population: FAS: All randomised patients who took at least one dose of the study medication. Here, overall number of participants analysed presents only those participants who were analyzed for this particular outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saxagliptin | Change From Baseline in Left Ventricular End Systolic Volume (LVESV) Index, Measured by MRI at 24 Weeks. | -2.555 mL/m2 | Standard Deviation 12.4136 |
| Placebo | Change From Baseline in Left Ventricular End Systolic Volume (LVESV) Index, Measured by MRI at 24 Weeks. | -0.839 mL/m2 | Standard Deviation 17.2458 |
Comparison: Saxagliptin: Change from baselinep-value: 0.42595% CI: [-5.635, 2.373]ANCOVA
Secondary
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.
Time frame: At 24 week
Population: FAS: All randomised patients who took at least one dose of the study medication. Here, overall number of participants analysed presents only those participants who were analyzed for this particular outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saxagliptin | Change From Baseline in Left Ventricular Mass (LVM) Measured by MRI at 24 Weeks. | -4.211 Gram | Standard Deviation 16.6003 |
| Placebo | Change From Baseline in Left Ventricular Mass (LVM) Measured by MRI at 24 Weeks. | -0.758 Gram | Standard Deviation 16.1763 |
Comparison: Saxagliptin vs placebo: Change from baselinep-value: 0.10595% CI: [-7.97, 0.76]ANCOVA
Secondary
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.
Time frame: Baseline to Week 28 (End of Study visit [EoS])
Population: FAS: All randomised patients who took at least one dose of the study medication. Here, overall number of participants analysed presents only those participants who were analyzed for this particular outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saxagliptin | Change From Baseline in NT-proBNP After 24 Weeks of Treatment | -277.525 pg/mL | Standard Deviation 1324.7471 |
| Placebo | Change From Baseline in NT-proBNP After 24 Weeks of Treatment | -61.895 pg/mL | Standard Deviation 3415.9525 |
Comparison: Saxagliptin vs placebo: Change from baselinep-value: 0.79695% CI: [0.777, 1.214]ANCOVA
Secondary
Number of Participants With Adverse Events
Assessment of safety and tolerability of saxagliptin and sitagliptin treatment in patients with T2DM and HF
Time frame: From screening (Days -28 to -1) until Week 28 (follow-up visit)
Population: Safety analysis set (SAS): All randomised patients who took at least one dose of the study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Saxagliptin | Number of Participants With Adverse Events | Any AE with outcome Death | 2 Participants |
| Saxagliptin | Number of Participants With Adverse Events | Any AE | 53 Participants |
| Saxagliptin | Number of Participants With Adverse Events | Any SAE leading to discontinuation of study treatment | 1 Participants |
| Saxagliptin | Number of Participants With Adverse Events | Any SAE | 17 Participants |
| Saxagliptin | Number of Participants With Adverse Events | Any treatment related SAE | 0 Participants |
| Saxagliptin | Number of Participants With Adverse Events | Any Adverse event of special interest | 12 Participants |
| Saxagliptin | Number of Participants With Adverse Events | Any treatment related AE | 3 Participants |
| Saxagliptin | Number of Participants With Adverse Events | Any severe AE | 9 Participants |
| Saxagliptin | Number of Participants With Adverse Events | Any AE leading to discontinuation of study treatment | 5 Participants |
| Placebo | Number of Participants With Adverse Events | Any SAE | 19 Participants |
| Placebo | Number of Participants With Adverse Events | Any AE | 51 Participants |
| Placebo | Number of Participants With Adverse Events | Any severe AE | 13 Participants |
| Placebo | Number of Participants With Adverse Events | Any treatment related AE | 4 Participants |
| Placebo | Number of Participants With Adverse Events | Any AE with outcome Death | 3 Participants |
| Placebo | Number of Participants With Adverse Events | Any treatment related SAE | 0 Participants |
| Placebo | Number of Participants With Adverse Events | Any SAE leading to discontinuation of study treatment | 0 Participants |
| Placebo | Number of Participants With Adverse Events | Any AE leading to discontinuation of study treatment | 3 Participants |
| Placebo | Number of Participants With Adverse Events | Any Adverse event of special interest | 15 Participants |
| Placebo | Number of Participants With Adverse Events | Any AE with outcome Death | 4 Participants |
| Placebo | Number of Participants With Adverse Events | Any AE | 58 Participants |
| Placebo | Number of Participants With Adverse Events | Any SAE leading to discontinuation of study treatment | 4 Participants |
| Placebo | Number of Participants With Adverse Events | Any treatment related AE | 0 Participants |
| Placebo | Number of Participants With Adverse Events | Any Adverse event of special interest | 16 Participants |
| Placebo | Number of Participants With Adverse Events | Any SAE | 29 Participants |
| Placebo | Number of Participants With Adverse Events | Any AE leading to discontinuation of study treatment | 7 Participants |
| Placebo | Number of Participants With Adverse Events | Any severe AE | 14 Participants |
| Placebo | Number of Participants With Adverse Events | Any treatment related SAE | 0 Participants |