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Comparing the Effects of Spironolactone With Chlortalidone on LV Mass in Patients With CKD (SPIRO-CKD)

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ClinicalTrials.gov Identifier: NCT02502981
Recruitment Status : Unknown
Verified January 2018 by Dr JN Townend, University Hospital Birmingham.
Recruitment status was:  Active, not recruiting
First Posted : July 20, 2015
Last Update Posted : January 19, 2018
Sponsor:
Collaborators:
Royal Free Hospital NHS Foundation Trust
University of Edinburgh
University of Cambridge
Information provided by (Responsible Party):
Dr JN Townend, University Hospital Birmingham

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.

Condition or disease Intervention/treatment Phase
Renal Insufficiency, Chronic Cardio-Renal Syndrome Drug: Spironolactone Drug: Chlortalidone Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 154 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomised Open Label, Blinded End Point Trial to Compare the Effects of Spironolactone With Chlortalidone on LV Mass in Stage 3 Chronic Kidney Disease (SPIRO-CKD)
Study Start Date : June 2014
Estimated Primary Completion Date : February 2018
Estimated Study Completion Date : May 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: CKD stage 2 & 3

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
25mg orally once a day for 40 weeks
Other Name: Aldactone, Mineralocorticoid receptor antagonist

Drug: Chlortalidone
25mg orally once a day for 40 weeks
Other Name: Hygroton, Thalitone, Thiazide diuretic




Primary Outcome Measures :
  1. Change in LV mass measured by cardiac MRI [ Time Frame: week 40 ]

Secondary Outcome Measures :
  1. Change in arterial stiffness measured by carotid-femoral pulse wave velocity [ Time Frame: up to week 40 ]
  2. Change in serum potassium [ Time Frame: up to week 40 ]
    Potassium will be assessed at baseline, week 1,2,4,8,20 and week 40

  3. Change in 24 hour ambulatory blood pressure [ Time Frame: up to week 40 ]
    Patients will wear an ambulatory monitor at week 0 and 40

  4. Change in left ventricular systolic function as measured by Global longitudinal strain using MR tagging [ Time Frame: up to week 40 ]
    Global longitudinal strain (%) will be assessed at week 0 and 40

  5. Change in renal function [ Time Frame: up to week 40 ]
    Estimated GFR will calculated using the Modification of Diet in Renal Disease equation at baseline, week 1,2,4,8,20 and week 40



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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
  • Documented Addison's disease
  • On treatment with fludrocortisone, co-trimoxazole and / or lithium therapy
  • Combination treatment with ACE inhibitor and ARB
  • Office blood pressure <115 mmHg systolic or <50 mmHg diastolic
  • Office blood pressure uncontrolled and requiring urgent non trial treatment in the opinion of the investigator
  • Unable to provide informed consent

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02502981


Locations
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United Kingdom
Departments of Cardiology & Nephrology University Hospital Birmingham
Birmingham, West Midlands, United Kingdom, B15 2TH
Cambridge Clinical Trials Unit, University of Cambridge and Addenbrooke's Hospital
Cambridge, United Kingdom, CB2 0QQ
University of Edinburgh: BHF Centre for Cardiovascular Science and Western General Hospital
Edinburgh, United Kingdom, EH16 4TJ
Royal Free Hospital
London, United Kingdom, NW3 2QG
Sponsors and Collaborators
University Hospital Birmingham
Royal Free Hospital NHS Foundation Trust
University of Edinburgh
University of Cambridge
Investigators
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Study Director: Gemma Slinn University of Birmingham
Publications of Results:
Other Publications:

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Responsible Party: Dr JN Townend, Professor of Cardiology, University Hospital Birmingham
ClinicalTrials.gov Identifier: NCT02502981    
Other Study ID Numbers: SP/12/8/29620
First Posted: July 20, 2015    Key Record Dates
Last Update Posted: January 19, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Dr JN Townend, University Hospital Birmingham:
CKD
left ventricle
aldosterone
spironolactone
Additional relevant MeSH terms:
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Renal Insufficiency
Renal Insufficiency, Chronic
Cardio-Renal Syndrome
Kidney Diseases
Urologic Diseases
Heart Failure
Heart Diseases
Cardiovascular Diseases
Chlorthalidone
Spironolactone
Mineralocorticoid Receptor Antagonists
Diuretics
Sodium Chloride Symporter Inhibitors
Mineralocorticoids
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Diuretics, Potassium Sparing
Natriuretic Agents
Antihypertensive Agents
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Hormones