Comparing the Effects of Spironolactone With Chlortalidone on LV Mass in Patients With CKD

NCT02502981 | Unknown Phase 4 DMC

• 1 other identifier: SP/12/8/29620
• Study Type: interventional
• Target: 154
• Locations: 1 country
• Sites: 4

Brief Summary

In stage 3 chronic kidney disease (CKD) the risk of death due to cardiovascular causes is high and greatly exceeds the risk of progression to end stage renal failure. This high cardiovascular risk is predominantly due to sudden cardiac death and heart failure, manifestations of left ventricular hypertrophy and fibrosis. Aldosterone appears to play an important role in the causation of this myocardial disease both by direct inflammatory and fibrotic myocardial effects and via increased arterial stiffness due to hypertrophy, inflammation, and fibrosis within the media of large arteries. Levels of aldosterone are high in CKD despite sodium overload and treatment with angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) drugs due to the twin phenomena of aldosterone escape and breakthrough. In a previous British Heart Foundation funded study, Birmingham investigators showed that the addition of the mineralocorticoid receptor blocker (MRB) spironolactone to background therapy with ACE inhibitors or ARBs caused reductions in the prognostically important parameters of arterial stiffness and LV mass. Because spironolactone therapy was also associated with significant falls in arterial pressure it remains possible that these effects were mediated simply by blood pressure reduction. In this multi-centre, randomised controlled study, the effects of treatment with spironolactone on LV mass and arterial stiffness in patients with stage 3 CKD on established ACE or ARB therapy will be compared to those of chlortalidone, a control anti-hypertensive agent. Early stage chronic kidney disease is highly prevalent and new, cost effective treatment strategies are required to reduce cardiovascular risk. This study is designed to provide the rationale for a larger study of morbidity and mortality with MRB therapy in early stage CKD.

Conditions

Renal Insufficiency, Chronic; Cardio-Renal Syndrome

Keywords

CKD; left ventricle; aldosterone; spironolactone

Outcome Measures

Primary Outcomes (1)

• Change in LV mass measured by cardiac MRI

  week 40

Secondary Outcomes (5)

• Change in arterial stiffness measured by carotid-femoral pulse wave velocity

  up to week 40

• Change in serum potassium

  up to week 40

• Change in 24 hour ambulatory blood pressure

  up to week 40

• Change in left ventricular systolic function as measured by Global longitudinal strain using MR tagging

  up to week 40

• Change in renal function

  up to week 40

Study Arms (1)

CKD stage 2 & 3

EXPERIMENTAL

Patients with CKD stage 2 \& 3 (eGFR 30-89ml/min/1.73m2) will be randomly assigned to receive either spironolactone or chlortalidone in a PROBE design. Subjects will undergo cardiac MRI, carotid femoral pulse wave velocity, 24 hour ambulatory blood pressure monitoring, blood tests for renal function and spot urine analysis for proteinuria (albumin:creatinine ratio) at baseline and after 40 weeks of allocated treatment. Additional blood tests for renal function and potassium level will be assessed at week 1,2,4,8 and 20.

Drug: Spironolactone; Drug: Chlortalidone

Interventions

Spironolactone DRUG

25mg orally once a day for 40 weeks

Also known as: Aldactone, Mineralocorticoid receptor antagonist

CKD stage 2 & 3

Chlortalidone DRUG

25mg orally once a day for 40 weeks

Also known as: Hygroton, Thalitone, Thiazide diuretic

CKD stage 2 & 3

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age \>18 years
• Chronic kidney disease stage 2 or 3 (eGFR 30-89 ml/min/1.73m2 by Modification of Diet in Renal Disease equation). eGFR must be within the last 12 months, on at least 2 occasions, at least 90 days apart.
• Well controlled blood pressure
• Established (\>6 weeks) on treatment with ACE inhibitors or ARBs
• Not pregnant or breast feeding
• Males of childbearing age will be required to use medically approved contraception during and for 6 weeks following the last dose of study treatment.

You may not qualify if:

• Diabetes mellitus
• Clinical evidence of hypovolaemia
• Recent (\< 6 months) acute myocardial infarction or other major adverse cardiovascular event (STEMI, NSTEMI, unstable angina, coronary revascularization, stroke, transient ischaemic attack)
• Known left ventricular systolic dysfunction ( ejection fraction \<50%) or severe valvular heart disease
• Active malignant disease with a life expectancy of \<5 years
• Previous hyperkalaemia (K+ \>6.0 mmol/l) without precipitating cause
• Serum K+ \>5.0 mmol/l at entry
• Serum sodium \<130 mmol/l at entry
• Atrial fibrillation on screening ECG
• Use of a thiazide or loop diuretic in the 6 weeks prior to enrolment
• Pregnant or breastfeeding
• Known alcohol or drug abuse
• Active chronic diarrhea
• Recent active gout (within 3 months)
• Acute kidney injury in previous 3 months

Sponsors & Collaborators

• University Hospital Birmingham: lead
• Royal Free Hospital NHS Foundation Trust: collaborator
• University of Edinburgh: collaborator
• University of Cambridge: collaborator

Study Sites (4)

Departments of Cardiology & Nephrology University Hospital Birmingham

Birmingham, West Midlands, B15 2TH, United Kingdom

Location

Cambridge Clinical Trials Unit, University of Cambridge and Addenbrooke's Hospital

Cambridge, CB2 0QQ, United Kingdom

Location

University of Edinburgh: BHF Centre for Cardiovascular Science and Western General Hospital

Edinburgh, EH16 4TJ, United Kingdom

Location

Royal Free Hospital

London, NW3 2QG, United Kingdom

Location

Related Publications (17)

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  PMID: 15385656 BACKGROUND

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  PMID: 18308865 BACKGROUND

• Edwards NC, Steeds RP, Stewart PM, Ferro CJ, Townend JN. Effect of spironolactone on left ventricular mass and aortic stiffness in early-stage chronic kidney disease: a randomized controlled trial. J Am Coll Cardiol. 2009 Aug 4;54(6):505-12. doi: 10.1016/j.jacc.2009.03.066.

  PMID: 19643310 BACKGROUND

• Chue CD, Townend JN, Steeds RP, Ferro CJ. Arterial stiffness in chronic kidney disease: causes and consequences. Heart. 2010 Jun;96(11):817-23. doi: 10.1136/hrt.2009.184879. Epub 2010 Apr 20.

  PMID: 20406771 BACKGROUND

• Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999 Sep 2;341(10):709-17. doi: 10.1056/NEJM199909023411001.

  PMID: 10471456 BACKGROUND

• Brown NJ. Aldosterone and vascular inflammation. Hypertension. 2008 Feb;51(2):161-7. doi: 10.1161/HYPERTENSIONAHA.107.095489. Epub 2008 Jan 2. No abstract available.

  PMID: 18172061 BACKGROUND

• Struthers AD. Aldosterone: cardiovascular assault. Am Heart J. 2002 Nov;144(5 Suppl):S2-7. doi: 10.1067/mhj.2002.129969.

  PMID: 12422134 BACKGROUND

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  PMID: 11014244 BACKGROUND

• Zannad F, Alla F, Dousset B, Perez A, Pitt B. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators. Circulation. 2000 Nov 28;102(22):2700-6. doi: 10.1161/01.cir.102.22.2700.

  PMID: 11094035 BACKGROUND

• Edwards NC, Ferro CJ, Kirkwood H, Chue CD, Young AA, Stewart PM, Steeds RP, Townend JN. Effect of spironolactone on left ventricular systolic and diastolic function in patients with early stage chronic kidney disease. Am J Cardiol. 2010 Nov 15;106(10):1505-11. doi: 10.1016/j.amjcard.2010.07.018.

  PMID: 21059444 BACKGROUND

• Blacher J, Guerin AP, Pannier B, Marchais SJ, Safar ME, London GM. Impact of aortic stiffness on survival in end-stage renal disease. Circulation. 1999 May 11;99(18):2434-9. doi: 10.1161/01.cir.99.18.2434.

  PMID: 10318666 BACKGROUND

• Matsumoto Y, Hamada M, Hiwada K. Aortic distensibility is closely related to the progression of left ventricular hypertrophy in patients receiving hemodialysis. Angiology. 2000 Nov;51(11):933-41. doi: 10.1177/000331970005101106.

  PMID: 11103862 BACKGROUND

• Rahman M, Pressel S, Davis BR, Nwachuku C, Wright JT Jr, Whelton PK, Barzilay J, Batuman V, Eckfeldt JH, Farber M, Henriquez M, Kopyt N, Louis GT, Saklayen M, Stanford C, Walworth C, Ward H, Wiegmann T. Renal outcomes in high-risk hypertensive patients treated with an angiotensin-converting enzyme inhibitor or a calcium channel blocker vs a diuretic: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 2005 Apr 25;165(8):936-46. doi: 10.1001/archinte.165.8.936.

  PMID: 15851647 BACKGROUND

• Smith DH, Neutel JM, Lacourciere Y, Kempthorne-Rawson J. Prospective, randomized, open-label, blinded-endpoint (PROBE) designed trials yield the same results as double-blind, placebo-controlled trials with respect to ABPM measurements. J Hypertens. 2003 Jul;21(7):1291-8. doi: 10.1097/00004872-200307000-00016.

  PMID: 12817175 BACKGROUND

• Mark PB, Johnston N, Groenning BA, Foster JE, Blyth KG, Martin TN, Steedman T, Dargie HJ, Jardine AG. Redefinition of uremic cardiomyopathy by contrast-enhanced cardiac magnetic resonance imaging. Kidney Int. 2006 May;69(10):1839-45. doi: 10.1038/sj.ki.5000249.

  PMID: 16508657 BACKGROUND

• National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002 Feb;39(2 Suppl 1):S1-266. No abstract available.

  PMID: 11904577 RESULT

MeSH Terms

Conditions

Renal Insufficiency, Chronic; Cardio-Renal Syndrome

Interventions

Spironolactone; Mineralocorticoid Receptor Antagonists; Chlorthalidone; Sodium Chloride Symporter Inhibitors

Condition Hierarchy (Ancestors)

Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Heart Failure; Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Lactones; Organic Chemicals; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses; Diuretics, Potassium Sparing; Diuretics; Natriuretic Agents; Benzenesulfonamides; Sulfonamides; Amides; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Benzophenones; Phthalimides; Imides; Ketones; Sulfones; Sulfur Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action

Study Officials

• Gemma Slinn

  University of Birmingham

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Cardiology

Study Record Dates

• First Submitted: July 14, 2015
• First Posted: July 20, 2015
• Study Start: June 1, 2014
• Primary Completion: February 1, 2018
• Study Completion: May 1, 2018
• Last Updated: January 19, 2018

Record last verified: 2018-01

Data Sharing

• IPD Sharing: Will not share

Locations

GB (4)