Effect of Ertugliflozin on Cardiac Function in Diabetes

Heart Failure Clinical Trial

— ERTU-GLS  

Official title:

A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, to Evaluate the Effect of Ertugliflozin on Cardiac Function in Patients With Type 2 Diabetes Who Have Inadequate Glycemic Control and Stage B Heart Failure

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03717194
• Other study ID #: B-2018-498-002
• Status: Completed
• Phase: Phase 3
• Start date: June 1, 2019
• Est. completion date: April 30, 2023

Study information

• Verified date: August 2023
• Source: Seoul National University Bundang Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The aim of this study is to investigate the beneficial role of ertugliflozin, a new SGLT2 inhibitor, in cardiac function via measuring GLS as well as other hemodynamic factors using echocardiogram in patients with T2D and HF, who are not controlled with oral antidiabetic medications including DPP4 inhibitors.

Description:

This study is a phase 3, randomized, double-blind, active-competitor, parallel-group study that is anticipated to enroll 120 patients. Patients taking metformin and/or DPP4 inhibitors as per local label for ≥12 weeks without a dose adjustment before enrollment will be eligible for screening. All patients will have a screening period comprised of an up to 2-week screening phase prior to randomization. In order to qualify for randomization, patients must demonstrate compliance based upon pill count (80%) and discretion of the investigators during the Run-in phase.

Glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG) will be masked to patients after randomization. To prevent partial unblinding, urinary glucose excretion (UGE) results will be masked to patients. Urine glucose, albumin, calcium, and creatinine will be measured separately on-site visits.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 102
• Est. completion date: April 30, 2023
• Est. primary completion date: December 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years to 75 Years

Eligibility

Inclusion Criteria:

• Patients with T2D taking oral antidiabetic medications (metformin and/or DPP4 inhibitors) except SGLT2 inhibitors for at least 12 weeks without a dose adjustment before enrollment.

• eGFR = 45 mL/min/1.73 m2.

• Stage B HF identified on the basis of either structural or functional markers.

Exclusion Criteria:

• Type 1 diabetes mellitus

• At the time of screening age <20 years

• HbA1c <7% or HbA1c >9.5% at Screening

• FPG >15 mmol/L (270 mg/dL) measured by the laboratory at Screening (Visit 1), and confirmed (>15 mmol/L [>270 mg/dL]) by a repeat test before randomization

• Treated with insulin and/or GLP-1R agonist within 12 weeks preceding the Screening Visit.

• Women of childbearing potential with no effective contraceptive method

• History of gastric surgery including history of gastric banding within 3 years before the Screening Visit

• History of diabetic ketoacidosis or nonketotic hyperosmolar coma prior to the Screening Visit

• Mean blood pressure after 3 separate measurements >180 mmHg in systolic blood pressure (SBP) or >95 mmHg in diastolic blood pressure (DBP)

• Patients with current or prior symptoms of HF.

• Patients with severe anemia, severe respiratory, hepatic, neurological, psychiatric disorders or active malignant tumor or other major systemic disease or patients with short life expectancy making implementation of the protocol or interpretation of the study results difficult

• Aspartate aminotransferase and/or alanine aminotransferase: >3 times the upper limit of the normal laboratory range (ULN)

• Total bilirubin: >1.5 times ULN (except in case of Gilbert's syndrome)

• Use of systemic glucocorticoids (excluding topical or ophthalmic, application or inhaled forms) for more than 10 consecutive days within 90 days prior to the Screening Visit

• Patient who has taken other investigational drugs or prohibited therapy for this study within 3 months

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Heart Failure
• Type2 Diabetes

Intervention

Drug:
• Ertugliflozin
Ertugliflozin as add-on to Metformin and/or DPP4 inhibitors in patients with inadequately controlled type 2 diabetes
• Placebo
Placebo as add-on to Metformin and/or DPP4 inhibitors in patients with inadequately controlled type 2 diabetes

Locations

Country	Name	City	State
Korea, Republic of	Seoul National University Bundang Hospita;	Seongnam-si	Gyeonggi-do

Sponsors (2)

Lead Sponsor	Collaborator
Soo Lim	MSD Korea Ltd.

Country where clinical trial is conducted

Korea, Republic of, 

References & Publications (12)

Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, Reichek N. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol. 1986 Feb 15;57(6):450-8. doi: 10.1016/0002-9149(86)90771-x. — View Citation

Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman AM, Francis GS, Ganiats TG, Goldstein S, Gregoratos G, Jessup ML, Noble RJ, Packer M, Silver MA, Stevenson LW, Gibbons RJ, Antman EM, Alpert JS, Faxon DP, Fuster V, Gregoratos G, Jacobs AK, Hiratzka LF, Russell RO, Smith SC; American College of Cardiology; American Heart Association. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. J Heart Lung Transplant. 2002 Feb;21(2):189-203. doi: 10.1016/s1053-2498(01)00776-8. No abstract available. — View Citation

Kosmala W, Jellis CL, Marwick TH. Exercise limitation associated with asymptomatic left ventricular impairment: analogy with stage B heart failure. J Am Coll Cardiol. 2015 Jan 27;65(3):257-66. doi: 10.1016/j.jacc.2014.10.044. Epub 2014 Dec 19. — View Citation

Kramer DG, Trikalinos TA, Kent DM, Antonopoulos GV, Konstam MA, Udelson JE. Quantitative evaluation of drug or device effects on ventricular remodeling as predictors of therapeutic effects on mortality in patients with heart failure and reduced ejection fraction: a meta-analytic approach. J Am Coll Cardiol. 2010 Jul 27;56(5):392-406. doi: 10.1016/j.jacc.2010.05.011. — View Citation

Krishnasamy R, Isbel NM, Hawley CM, Pascoe EM, Burrage M, Leano R, Haluska BA, Marwick TH, Stanton T. Left Ventricular Global Longitudinal Strain (GLS) Is a Superior Predictor of All-Cause and Cardiovascular Mortality When Compared to Ejection Fraction in Advanced Chronic Kidney Disease. PLoS One. 2015 May 15;10(5):e0127044. doi: 10.1371/journal.pone.0127044. eCollection 2015. — View Citation

Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ; Chamber Quantification Writing Group; American Society of Echocardiography's Guidelines and Standards Committee; European Association of Echocardiography. Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005 Dec;18(12):1440-63. doi: 10.1016/j.echo.2005.10.005. No abstract available. — View Citation

Lima MSM, Villarraga HR, Abduch MCD, Lima MF, Cruz CBBV, Sbano JCN, Voos MC, Mathias W Junior, Tsutsui JM. Global Longitudinal Strain or Left Ventricular Twist and Torsion? Which Correlates Best with Ejection Fraction? Arq Bras Cardiol. 2017 Jul;109(1):23-29. doi: 10.5935/abc.20170085. Epub 2017 Jun 29. — View Citation

Medvedofsky D, Kebed K, Laffin L, Stone J, Addetia K, Lang RM, Mor-Avi V. Reproducibility and experience dependence of echocardiographic indices of left ventricular function: Side-by-side comparison of global longitudinal strain and ejection fraction. Echocardiography. 2017 Mar;34(3):365-370. doi: 10.1111/echo.13446. Epub 2017 Feb 9. — View Citation

Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, Waggoner AD, Flachskampf FA, Pellikka PA, Evangelista A. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr. 2009 Feb;22(2):107-33. doi: 10.1016/j.echo.2008.11.023. No abstract available. — View Citation

Neal B, Perkovic V, Matthews DR. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017 Nov 23;377(21):2099. doi: 10.1056/NEJMc1712572. No abstract available. — View Citation

Reisner SA, Lysyansky P, Agmon Y, Mutlak D, Lessick J, Friedman Z. Global longitudinal strain: a novel index of left ventricular systolic function. J Am Soc Echocardiogr. 2004 Jun;17(6):630-3. doi: 10.1016/j.echo.2004.02.011. — View Citation

Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 10.1056/NEJMoa1504720. Epub 2015 Sep 17. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Global Longitudinal Strain (GLS)	Change of GLS after 24 weeks' treatment	Baseline, week 12, week 24
Secondary	E/e' ratio	Change of E/e' after 24 weeks' treatment	Baseline, week 12, week 24
Secondary	Ejection fraction (EF)	Change of EF after 24 weeks' treatment	Baseline, week 12, week 24
Secondary	Left ventricle mass	Change of LV mass after 24 weeks' treatment	Baseline, week 12, week 24
Secondary	Glycated hemoglobin	Change of HbA1c mass after 24 weeks' treatment	Baseline, week 12, week 24
Secondary	Body weight	Change of body weight mass after 24 weeks' treatment	Baseline, week 12, week 24
Secondary	Body Fat Mass	Change of body fat mass after 24 weeks' treatment	Baseline, week 12, week 24