Mineralocorticoid Receptor Antagonists in End Stage Renal Disease (MiREnDa)

Phase II Trial to Evaluate the Efficacy and Safety of Spironolactone in Hemodialysis Patients

End stage renal disease (ESRD) patients exhibit an extraordinarily high annual mortality. Cardiovascular (CV) causes account for almost half of all-cause mortality. Increased left ventricular mass (LVM) is a common finding in ESRD patients on dialysis and is an independent predictor of survival. Yet, to date there is no established medical treatment to reduce CV morbidity and mortality in ESRD patients on hemodialysis. Blockade of aldosterone action by means of mineralocorticoid receptor antagonists (MRA) provides cardioprotection and improves outcome in heart failure patients. Furthermore, the MRA spironolactone has recently been shown to reduce LVM in patients with mild-to-moderate chronic kidney disease (CKD). The investigators here hypothesize that spironolactone treatment is cardioprotective by reducing LVM in ESRD patients on dialysis.

Study Overview

• Status: Completed
• Conditions: End Stage Renal Disease / Hemodialysis
• Intervention / Treatment: Drug: Placebo; Drug: Spironolactone

• Study Type: Interventional
• Enrollment (Actual): 118
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Erlangen, Germany, 91054
    • University hospital Erlangen-Nurnberg
  • Frankfurt, Germany, 60590
    • University Hospital Frankfurt
  • Wuerzburg, Germany, 97080
    • University Hospital Wuerzburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age >18 years
• Hemodialysis treatment for at least 3 months
• At least 3 dialysis sessions per week
• Written informed consent

Exclusion Criteria:

• Contraindications for cardiac magnet resonance imaging (CMR)
• Mineralocorticoid receptor antagonist treatment within the last 6 months
• Estimated life expectancy < 12 months as judged by the nephrologist
• History of hyperkalemia, defined as pre-dialysis potassium > 6.5 mmol/l occurring ≥ 3 times within the last 3 months prior to enrolment.
• High risk to develop hyperkalemia defined as pre-dialysis potassium > 6.0 mmol/l
• Hypotension (systolic blood pressure < 100 mmHg)
• Planned kidney transplantation (living donor) within the prospected study duration
• Any acute illness within the last 4 weeks precluding a study participation as judged by the nephrologist
• Non-amenorrheic women with child bearing potential without reliable contraception, pregnancy/lactation
• Allergy/hypersensitivity to spironolactone
• Non-compliance suspected or demonstrated

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo
Active Comparator: Spironolactone	Drug: Spironolactone; 50mg once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left Ventricular Mass Index	as assessed by cardiac MRI	9 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiac function parameters	cardiac volumes, systolic and diastolic function, cardiac output as measured by cardiac MRI and echocardiography	9 months
Office and 24h blood pressure		9 months
Clinical measures of heart failure severity	New York Heart Association (NYHA) functional class, 6 minute walk test	9 months
Vascular function	Carotid intima meda thickness, pulse wave analysis, carotid artery distensibility, flow mediated dilatation of the brachial artery	9 months
Biomarkers of heart failure, inflammation and fibrosis		9 months
Quality of Life - Hospital Anxiety and Depression Scale (HADS)	Quality of life will be measured by analyzing HADS	9 months
Cardiac death and/or hospitalization for heart failure		9 months
Safety measures	Pre-dialysis potassium levels, frequency of hyperkalemic episodes (K>6.5mmol/l), measurement of residual kidney function (if applicable)	9 months
Quality of Life - Kidney Disease Quality of Life Instrument (KDQOL-SF36)	Quality of life will be measured by analyzing KDQOL-SF36	9 months

Collaborators and Investigators

• Sponsor: Wuerzburg University Hospital
• Collaborators: German Federal Ministry of Education and Research; Clinical Trial Center Wuerzburg (CTCW)
• Investigators: Principal Investigator: Christoph Wanner, MD, University Hospital Wuerzburg; Principal Investigator: Fabian Hammer, MD, PhD, University Hospital Wuerzburg; Principal Investigator: Vera Krane, MD, University Hospital Wuerzburg

Publications and helpful links

General Publications

• Hasegawa T, Nishiwaki H, Ota E, Levack WM, Noma H. Aldosterone antagonists for people with chronic kidney disease requiring dialysis. Cochrane Database Syst Rev. 2021 Feb 15;2(2):CD013109. doi: 10.1002/14651858.CD013109.pub2.
• Hauser T, Dornberger V, Malzahn U, Grebe SJ, Liu D, Stork S, Nauck M, Friedrich N, Dorr M, Wanner C, Krane V, Hammer F; MiREnDa Study Group; Collaborating investigators (sites). The effect of spironolactone on diastolic function in haemodialysis patients. Int J Cardiovasc Imaging. 2021 Jun;37(6):1927-1936. doi: 10.1007/s10554-021-02176-5. Epub 2021 Feb 5.
• Grebe SJ, Malzahn U, Donhauser J, Liu D, Wanner C, Krane V, Hammer F. Quantification of left ventricular mass by echocardiography compared to cardiac magnet resonance imaging in hemodialysis patients. Cardiovasc Ultrasound. 2020 Sep 16;18(1):39. doi: 10.1186/s12947-020-00217-y.
• Hammer F, Krane V, Stork S, Roser C, Hofmann K, Pollak N, Allolio B, Wanner C. Rationale and design of the Mineralocorticoid Receptor Antagonists in End-Stage Renal Disease Study (MiREnDa). Nephrol Dial Transplant. 2014 Feb;29(2):400-5. doi: 10.1093/ndt/gft409. Epub 2013 Oct 28.

Study record dates

Study Major Dates

• Study Start: December 1, 2012
• Primary Completion (Actual): February 14, 2017
• Study Completion (Actual): March 28, 2018

Study Registration Dates

• First Submitted: September 19, 2012
• First Submitted That Met QC Criteria: September 21, 2012
• First Posted (Estimate): September 24, 2012

Study Record Updates

• Last Update Posted (Actual): August 6, 2019
• Last Update Submitted That Met QC Criteria: August 1, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: End stage renal disease; Hemodialysis; Spironolactone; Left ventricular hypertrophy
• Additional Relevant MeSH Terms: Urologic Diseases; Renal Insufficiency; Renal Insufficiency, Chronic; Kidney Diseases; Kidney Failure, Chronic; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Spironolactone
• Other Study ID Numbers: MN0511_1; 2011-003179-12 (EudraCT Number); 01KG1202 (Other Grant/Funding Number: German Ministry of Education and Research)