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

Heart Failure Clinical Trial

— MEASURE-HF  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02917031
• Other study ID #: D1680C00016
• Status: Completed
• Phase: Phase 4
• Start date: January 10, 2017
• Est. completion date: August 23, 2019

Study information

• Verified date: October 2021
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 348
• Est. completion date: August 23, 2019
• Est. primary completion date: August 23, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 130 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Heart Failure
• Type 2 Diabetes Mellitus

Intervention

Drug:
• Saxagliptin
5 mg or 2.5 mg, plain, yellow, biconvex, round, film-coated tablet
• Sitagliptin
50 mg or 100 mg, gray capsule
• Placebo to match saxagliptin
2.5 mg or 5 mg, plain, yellow, biconvex, round, film-coated tablet
• Placebo to match sitagliptin
50 mg or 100 mg, gray capsule

Locations

Country	Name	City	State
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Canada	Research Site	Chicoutimi	Quebec
Chile	Research Site	Santiago
Chile	Research Site	Santiago
Chile	Research Site	Santiago
Chile	Research Site	Santiago
Chile	Research Site	Talcahuano
Chile	Research Site	Viña del Mar
Hungary	Research Site	Balatonfüred
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Debrecen
Hungary	Research Site	Hajdúszoboszló
Hungary	Research Site	Kecskemét
Hungary	Research Site	Kisvárda
Hungary	Research Site	Nyíregyháza
Hungary	Research Site	Orosháza
Hungary	Research Site	Pécs
Hungary	Research Site	Székesfehérvár
Korea, Republic of	Research Site	Busan
Korea, Republic of	Research Site	Daejeon
Korea, Republic of	Research Site	Gwangju
Korea, Republic of	Research Site	Hwaseong-si
Korea, Republic of	Research Site	Seongnam-si
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Wonju-si
Romania	Research Site	Brasov
Romania	Research Site	Iasi
Romania	Research Site	Iasi
Russian Federation	Research Site	Izhevsk
Russian Federation	Research Site	Kemerovo
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Nizhnii Novgorod
Russian Federation	Research Site	Novosibirsk
Russian Federation	Research Site	Novosibirsk
Russian Federation	Research Site	Novosibirsk
Russian Federation	Research Site	Saint-Petersburg
Russian Federation	Research Site	Saint-Petersburg
Russian Federation	Research Site	St Petersburg
Russian Federation	Research Site	Tomsk
Russian Federation	Research Site	Tomsk
Russian Federation	Research Site	Yaroslavl
Thailand	Research Site	Bangkok
Thailand	Research Site	Bangkok
Thailand	Research Site	Bangkoknoi
Thailand	Research Site	Chiang Mai
Thailand	Research Site	Khon Kaen
Ukraine	Research Site	Ivano-Frankivsk
Ukraine	Research Site	Ivano-Frankivsk
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Lviv
Ukraine	Research Site	Rivne
United States	Research Site	Bronx	New York
United States	Research Site	Bronx	New York
United States	Research Site	Chicago	Illinois
United States	Research Site	Houston	Texas
United States	Research Site	Miami	Florida
United States	Research Site	Milwaukee	Wisconsin
United States	Research Site	Ormond Beach	Florida
United States	Research Site	Sayre	Pennsylvania
United States	Research Site	Spartanburg	South Carolina
United States	Research Site	Torrance	California
United States	Research Site	Upland	California

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Bulgaria,  Canada,  Chile,  Hungary,  Korea, Republic of,  Romania,  Russian Federation,  Thailand,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Baseline to 24 weeks
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.	Baseline to week 24
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.	Baseline to week 24
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.	At 24 week
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.	Baseline to Week 28 (End of Study visit [EoS])
Secondary	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)

External Links

•   redacted Protocol (CSP)
•   Statistical Analysis Plan (SAP)