EMPAgliflozin in Heart Failure With PReserved Ejection Fraction and End Stage Renal Disease

Heart Failure With Preserved Ejection Fraction Clinical Trial

— EMPA-PRED  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06249945
• Other study ID #: 202301126MINC
• 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

The presence of CKD has been linked to the development of HFpEF. Currently, the treatment for HFpEF is limited. SGLT2i are one of the few drug classes that have proven efficacy in HFpEF in randomized controlled trials. The results of mechanistic studies suggest that the benefits of SGLT2i on diastolic heart failure are independent of their glycosuric actions and may still be present in anuric subjects. Despite the significance of HFpEF in patients with CKD, patients with advanced kidney disease have been excluded from studies investigating anti-heart failure drugs. The effects of SGLT2i in patients under maintenance dialysis are largely unknown. Past pharmacokinetics and pharmacodynamics studies on empagliflozin in patients with end-stage renal disease (ESRD) demonstrated that the use of empagliflozin in patients with ESRD seemed safe, yet its efficacy remains to be explored.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 150
• 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 dialysis with stable dry weight for the past 6 months
• Prior diagnosis of HFpEF, as defined by a score of =5 on the HFA-PEFF diagnostic algorithm.

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 =<40% 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 Preserved 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 (21)

Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Bohm M, Brunner-La Rocca HP, Choi DJ, Chopra V, Chuquiure-Valenzuela E, Giannetti N, Gomez-Mesa JE, Janssens S, Januzzi JL, Gonzalez-Juanatey JR, Merkely B, Nicholls SJ, Perrone SV, Pina IL, Ponikowski P, Senni M, Sim D, Spinar J, Squire I, Taddei S, Tsutsui H, Verma S, Vinereanu D, Zhang J, Carson P, Lam CSP, Marx N, Zeller C, Sattar N, Jamal W, Schnaidt S, Schnee JM, Brueckmann M, Pocock SJ, Zannad F, Packer M; EMPEROR-Preserved Trial Investigators. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021 Oct 14;385(16):1451-1461. doi: 10.1056/NEJMoa2107038. Epub 2021 Aug 27. — View Citation

Bansal N, Zelnick L, Bhat Z, Dobre M, He J, Lash J, Jaar B, Mehta R, Raj D, Rincon-Choles H, Saunders M, Schrauben S, Weir M, Wright J, Go AS; CRIC Study Investigators. Burden and Outcomes of Heart Failure Hospitalizations in Adults With Chronic Kidney Disease. J Am Coll Cardiol. 2019 Jun 4;73(21):2691-2700. doi: 10.1016/j.jacc.2019.02.071. — View Citation

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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

GBD Chronic Kidney Disease Collaboration. Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020 Feb 29;395(10225):709-733. doi: 10.1016/S0140-6736(20)30045-3. Epub 2020 Feb 13. — View Citation

Junger C, Prochaska JH, Gori T, Schulz A, Binder H, Daiber A, Koeck T, Rapp S, Lackner KJ, Munzel T, Wild PS. Rationale and design of the effects of EMpagliflozin on left ventricular DIAstolic function in diabetes (EmDia) study. J Cardiovasc Med (Hagerstown). 2022 Mar 1;23(3):191-197. doi: 10.2459/JCM.0000000000001267. — View Citation

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

Kalantar-Zadeh K, Jafar TH, Nitsch D, Neuen BL, Perkovic V. Chronic kidney disease. Lancet. 2021 Aug 28;398(10302):786-802. doi: 10.1016/S0140-6736(21)00519-5. Epub 2021 Jun 24. — 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

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

Pieske B, Tschope C, de Boer RA, Fraser AG, Anker SD, Donal E, Edelmann F, Fu M, Guazzi M, Lam CSP, Lancellotti P, Melenovsky V, Morris DA, Nagel E, Pieske-Kraigher E, Ponikowski P, Solomon SD, Vasan RS, Rutten FH, Voors AA, Ruschitzka F, Paulus WJ, Seferovic P, Filippatos G. How to diagnose heart failure with preserved ejection fraction: the HFA-PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur Heart J. 2019 Oct 21;40(40):3297-3317. doi: 10.1093/eurheartj/ehz641. Erratum In: Eur Heart J. 2021 Mar 31;42(13):1274. — View Citation

Rau M, Thiele K, Hartmann NK, Schuh A, Altiok E, Mollmann J, Keszei AP, Bohm M, Marx N, Lehrke M. Empagliflozin does not change cardiac index nor systemic vascular resistance but rapidly improves left ventricular filling pressure in patients with type 2 diabetes: a randomized controlled study. Cardiovasc Diabetol. 2021 Jan 7;20(1):6. doi: 10.1186/s12933-020-01175-5. — View Citation

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Shim CY, Seo J, Cho I, Lee CJ, Cho IJ, Lhagvasuren P, Kang SM, Ha JW, Han G, Jang Y, Hong GR. Randomized, Controlled Trial to Evaluate the Effect of Dapagliflozin on Left Ventricular Diastolic Function in Patients With Type 2 Diabetes Mellitus: The IDDIA Trial. Circulation. 2021 Feb 2;143(5):510-512. doi: 10.1161/CIRCULATIONAHA.120.051992. Epub 2020 Nov 13. No abstract available. — View Citation

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Ter Maaten JM, Damman K, Verhaar MC, Paulus WJ, Duncker DJ, Cheng C, van Heerebeek L, Hillege HL, Lam CS, Navis G, Voors AA. Connecting heart failure with preserved ejection fraction and renal dysfunction: the role of endothelial dysfunction and inflammation. Eur J Heart Fail. 2016 Jun;18(6):588-98. doi: 10.1002/ejhf.497. Epub 2016 Feb 10. — View Citation

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* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mitral early (E) and late (A) diastolic filling velocity ratio (E/A)	As assessed by echocardiography, 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	LA strain	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	Mitral inflow deceleration time LV relative wall thickness	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	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
Secondary	Hypokalemia	Blood tests obtained pre-dialysis session	4 weeks, 12 weeks and 24 weeks of treatment