Empagliflozin in Heart Failure With Reduced Ejection Fraction and End Stage Renal Disease

Heart Failure With Reduced Ejection Fraction Clinical Trial

— EMPA-RRED  

Official title:

The Safety and Efficacy of Empagliflozin in Patients With End-stage Renal Disease and Heart Failure With Reduced Ejection Fraction - a Randomized Controlled Trial

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06249932
• Other study ID #: 202301140MINC
• Status: Not yet recruiting
• Phase: Phase 4
• Start date: February 1, 2024
• Est. completion date: December 31, 2030

Study information

• Verified date: January 2024
• Source: National Taiwan University Hospital
• Contact: Donna Shu-Han Lin, MD
• Phone: +886912902379
• Email: Donna.lin24[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

In patients with ESRD, up to 20% of patients suffer from HFrEF, leading to significant CV morbidity and mortality. Several drug classes that provide survival benefits for patients with HFrEF, including SGLT2i, lack data regarding their efficacy and safety in patients under chronic hemodialysis. As the primary target of SGLT2i is expressed mostly in the kidneys, the efficacy of SGLT2i in patients with ESRD may be limited. On the other hand, patients with ESRD are at higher risks of experiencing cardiovascular events and may still benefit from treatment. Several mechanistic studies have demonstrated direct actions of SGLT2i on the myocardium, thus it is possible that the benefits of SGLT2i on heart failure are independent of their glycosuric actions and may still be present in anuric subjects. Furthermore, pharmacokinetics and pharmacodynamics studies on empagliflozin demonstrated that peak plasma levels of empagliflozin in subjects with renal failure/ESRD were similar to those in subjects with normal renal function. The use of empagliflozin in patients with ESRD seemed safe in terms of pharmacokinetics and pharmacodynamics, yet its efficacy remains to be explored.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 95
• Est. completion date: December 31, 2030
• Est. primary completion date: December 31, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years and older

Eligibility

Inclusion Criteria:

• Age =20 years old
• ESRD under chronic, maintenance hemodialysis with stable dry weight for the past 6 months
• Documented left ventricular ejection fraction <50% by any imaging modality within 1 month of screening

Exclusion Criteria:

• Age <20 years old
• Ongoing pregnancy
• NYHA class IV heart failure
• Any hospitalization for heart failure within the past month
• Ongoing acute urinary tract infection at the time of screening
• Known acute genital infection
• Severe peripheral artery disease (Rutherford category 4-6)
• Acute coronary syndrome, stroke or transient ischemic attack within the past month
• Recent initiation of chronic maintenance hemodialysis within 6 months
• Adjustment of dry weight with changes greater than 5% of body weight within the past month
• Documented left ventricular ejection fraction =50% by any imaging modality within 1 month of screening
• Refused informed consent

Related Conditions & MeSH terms

• End Stage Renal Disease on Dialysis
• Heart Failure
• Heart Failure With Reduced Ejection Fraction
• Kidney Diseases
• Kidney Failure, Chronic

Intervention

Drug:
• Empagliflozin 25 MG
The medication will be packed in a customized sealed jar and labeled on the exterior of the jar.
• Placebo
The placebo tablet is manufactured by Prince Pharmaceutical Co., Ltd, a leading manufacturer of nutritional supplements with certifications including cGMP, GMP, ISO, and HACCP. The Prince Pharmaceutical also provides Original Equipment Manufacturing (OEM)/Original Design Manufacturing (ODM) services for a wide array of tablet shapes, and post-processing techniques such as film coating and sugar coating.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
National Taiwan University Hospital	Shin Kong Wu Ho-Su Memorial Hospital

References & Publications (15)

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Ersboll M, Jurgens M, Hasbak P, Kjaer A, Wolsk E, Zerahn B, Brandt-Jacobsen NH, Gaede P, Rossing P, Faber J, Inzucchi SE, Gustafsson F, Schou M, Kistorp C. Effect of empagliflozin on myocardial structure and function in patients with type 2 diabetes at high cardiovascular risk: the SIMPLE randomized clinical trial. Int J Cardiovasc Imaging. 2022 Mar;38(3):579-587. doi: 10.1007/s10554-021-02443-5. Epub 2021 Oct 20. — View Citation

Ferro CJ, Mark PB, Kanbay M, Sarafidis P, Heine GH, Rossignol P, Massy ZA, Mallamaci F, Valdivielso JM, Malyszko J, Verhaar MC, Ekart R, Vanholder R, London G, Ortiz A, Zoccali C. Lipid management in patients with chronic kidney disease. Nat Rev Nephrol. 2018 Dec;14(12):727-749. doi: 10.1038/s41581-018-0072-9. Erratum In: Nat Rev Nephrol. 2019 Feb;15(2):121. — View Citation

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Jurgens M, Schou M, Hasbak P, Kjaer A, Wolsk E, Zerahn B, Wiberg M, Brandt NH, Gaede PH, Rossing P, Faber J, Inzucchi S, Gustafsson F, Kistorp CM. Design of a randomised controlled trial of the effects of empagliflozin on myocardial perfusion, function and metabolism in type 2 diabetes patients at high cardiovascular risk (the SIMPLE trial). BMJ Open. 2019 Nov 27;9(11):e029098. doi: 10.1136/bmjopen-2019-029098. — View Citation

Kotecha D, Gill SK, Flather MD, Holmes J, Packer M, Rosano G, Bohm M, McMurray JJV, Wikstrand J, Anker SD, van Veldhuisen DJ, Manzano L, von Lueder TG, Rigby AS, Andersson B, Kjekshus J, Wedel H, Ruschitzka F, Cleland JGF, Damman K, Redon J, Coats AJS; Beta-Blockers in Heart Failure Collaborative Group. Impact of Renal Impairment on Beta-Blocker Efficacy in Patients With Heart Failure. J Am Coll Cardiol. 2019 Dec 10;74(23):2893-2904. doi: 10.1016/j.jacc.2019.09.059. Erratum In: J Am Coll Cardiol. 2020 Apr 7;75(13):1615. — View Citation

Li X, Lu Q, Qiu Y, do Carmo JM, Wang Z, da Silva AA, Mouton A, Omoto ACM, Hall ME, Li J, Hall JE. Direct Cardiac Actions of the Sodium Glucose Co-Transporter 2 Inhibitor Empagliflozin Improve Myocardial Oxidative Phosphorylation and Attenuate Pressure-Overload Heart Failure. J Am Heart Assoc. 2021 Mar 16;10(6):e018298. doi: 10.1161/JAHA.120.018298. Epub 2021 Mar 13. — View Citation

Macha S, Mattheus M, Halabi A, Pinnetti S, Woerle HJ, Broedl UC. Pharmacokinetics, pharmacodynamics and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in subjects with renal impairment. Diabetes Obes Metab. 2014 Mar;16(3):215-22. doi: 10.1111/dom.12182. Epub 2013 Aug 19. — View Citation

McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Belohlavek J, Bohm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukat A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O'Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjostrand M, Langkilde AM; DAPA-HF Trial Committees and Investigators. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019 Nov 21;381(21):1995-2008. doi: 10.1056/NEJMoa1911303. Epub 2019 Sep 19. — View Citation

Pabel S, Wagner S, Bollenberg H, Bengel P, Kovacs A, Schach C, Tirilomis P, Mustroph J, Renner A, Gummert J, Fischer T, Van Linthout S, Tschope C, Streckfuss-Bomeke K, Hasenfuss G, Maier LS, Hamdani N, Sossalla S. Empagliflozin directly improves diastolic function in human heart failure. Eur J Heart Fail. 2018 Dec;20(12):1690-1700. doi: 10.1002/ejhf.1328. Epub 2018 Oct 17. — View Citation

Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, Jamal W, Kimura K, Schnee J, Zeller C, Cotton D, Bocchi E, Bohm M, Choi DJ, Chopra V, Chuquiure E, Giannetti N, Janssens S, Zhang J, Gonzalez Juanatey JR, Kaul S, Brunner-La Rocca HP, Merkely B, Nicholls SJ, Perrone S, Pina I, Ponikowski P, Sattar N, Senni M, Seronde MF, Spinar J, Squire I, Taddei S, Wanner C, Zannad F; EMPEROR-Reduced Trial Investigators. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020 Oct 8;383(15):1413-1424. doi: 10.1056/NEJMoa2022190. Epub 2020 Aug 28. — View Citation

Roehm B, Gulati G, Weiner DE. Heart failure management in dialysis patients: Many treatment options with no clear evidence. Semin Dial. 2020 May;33(3):198-208. doi: 10.1111/sdi.12878. Epub 2020 Apr 13. — View Citation

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Soga F, Tanaka H, Tatsumi K, Mochizuki Y, Sano H, Toki H, Matsumoto K, Shite J, Takaoka H, Doi T, Hirata KI. Impact of dapagliflozin on left ventricular diastolic function of patients with type 2 diabetic mellitus with chronic heart failure. Cardiovasc Diabetol. 2018 Oct 8;17(1):132. doi: 10.1186/s12933-018-0775-z. — View Citation

Verma S, Mazer CD, Yan AT, Mason T, Garg V, Teoh H, Zuo F, Quan A, Farkouh ME, Fitchett DH, Goodman SG, Goldenberg RM, Al-Omran M, Gilbert RE, Bhatt DL, Leiter LA, Juni P, Zinman B, Connelly KA. Effect of Empagliflozin on Left Ventricular Mass in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease: The EMPA-HEART CardioLink-6 Randomized Clinical Trial. Circulation. 2019 Nov 19;140(21):1693-1702. doi: 10.1161/CIRCULATIONAHA.119.042375. Epub 2019 Aug 22. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Left ventricular mass	As assessed by cardiac magnetic resonance imaging, performed on non-dialysis day	24 weeks of treatment
Secondary	Left ventricular mass index	As assessed by cardiac magnetic resonance imaging, performed on non-dialysis day	24 weeks of treatment
Secondary	LV end-systolic volume index	As assessed by cardiac magnetic resonance imaging, performed on non-dialysis day	24 weeks of treatment
Secondary	LV end-diastolic volume index	As assessed by cardiac magnetic resonance imaging, performed on non-dialysis day	24 weeks of treatment
Secondary	LA volume index	As assessed by cardiac magnetic resonance imaging, performed on non-dialysis day	24 weeks of treatment
Secondary	LV ejection fraction	As assessed by cardiac magnetic resonance imaging, performed on non-dialysis day	24 weeks of treatment
Secondary	Global longitudinal strain	As assessed by cardiac magnetic resonance imaging, performed on non-dialysis day	24 weeks of treatment
Secondary	LV end-systolic volume index	As assessed by echocardiography, performed on non-dialysis day	12 weeks and 24 weeks of treatment
Secondary	LV end-diastolic volume index	As assessed by echocardiography, performed on non-dialysis day	12 weeks and 24 weeks of treatment
Secondary	LA volume index	As assessed by echocardiography, performed on non-dialysis day	12 weeks and 24 weeks of treatment
Secondary	LV ejection fraction	As assessed by echocardiography, performed on non-dialysis day	12 weeks and 24 weeks of treatment
Secondary	Left ventricular mass index	As assessed by echocardiography, performed on non-dialysis day	12 weeks and 24 weeks of treatment
Secondary	Global longitudinal strain	As assessed by echocardiography, performed on non-dialysis day	12 weeks and 24 weeks of treatment
Secondary	LV relative wall thickness	As assessed by echocardiography, performed on non-dialysis day	12 weeks and 24 weeks of treatment
Secondary	Mitral early (E) and late (A) diastolic filling velocity ratio (E/A)	As assessed by echocardiography, performed on non-dialysis day	12 weeks and 24 weeks of treatment
Secondary	Mitral inflow deceleration time	As assessed by echocardiography, performed on non-dialysis day	12 weeks and 24 weeks of treatment
Secondary	Tricuspid regurgitation peak gradient (TRPG)	As assessed by echocardiography, performed on non-dialysis day	12 weeks and 24 weeks of treatment
Secondary	NT-proBNP	Blood tests obtained pre-dialysis session	4 weeks, 12 weeks and 24 weeks of treatment
Secondary	HbA1c	Blood tests obtained pre-dialysis session	4 weeks, 12 weeks and 24 weeks of treatment
Secondary	Lipid profile	Blood tests obtained pre-dialysis session	4 weeks, 12 weeks and 24 weeks of treatment
Secondary	KCCQ-OS	Performed on non-dialysis day	12 weeks and 24 weeks of treatment
Secondary	6-minute walking distance	Performed on non-dialysis day	12 weeks and 24 weeks of treatment
Secondary	3-minute heart rate variability	During hemodialysis session	12 weeks and 24 weeks of treatment
Secondary	Blood pressure	Obtained pre-dialysis session	12 weeks and 24 weeks of treatment
Secondary	Major adverse cardiovascular events (composite of CV death, myocardial infarction, stroke)	By medical record confirmation and by interview	24 weeks of treatment
Secondary	Lower extremity non-traumatic amputation or revascularization	By medical record confirmation and by interview	24 weeks of treatment
Secondary	All-cause mortality	By medical record confirmation and by interview	24 weeks of treatment
Secondary	Hospitalization for heart failure	By medical record confirmation and by interview	24 weeks of treatment
Secondary	Hypoglycemic events	By medical record confirmation and by interview	24 weeks of treatment
Secondary	Hypokalemia	Blood tests obtained pre-dialysis session	4 weeks, 12 weeks and 24 weeks of treatment
Secondary	Diabetic ketoacidosis	By medical record confirmation and by interview	24 weeks of treatment
Secondary	Urinary tract infection	By medical record confirmation and by interview	24 weeks of treatment
Secondary	Genital tract infection	By medical record confirmation and by interview	24 weeks of treatment