Condition category
Circulatory System
Date applied
16/01/2014
Date assigned
16/01/2014
Last edited
26/04/2018
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
Chronic kidney disease (CKD) is a major risk factor for heart and blood vessel disease. Mild CKD is surprisingly common, affecting almost 1 in 7 of the population. The adverse cardiovascular (heart) effects of CKD are caused mainly by damage and thickening of the heart muscle and an increase in artery stiffness, which together cause stroke, heart failure and sudden cardiac death. We have previously shown that an old and inexpensive drug called spironolactone reduces the heart thickening and arterial stiffening in CKD compared to an inactive (placebo) tablet. During treatment with spironolactone however, blood pressure fell and it is not clear whether the beneficial effects of this drug on the heart and arteries were caused by this fall in blood pressure or were specific to the effects of spironolactone. The aim of this study is to compare the effects of spironolactone to a different blood pressure lowering drug called chlortalidone on patients with early CKD.

Who can participate?
Patients aged over 18 with early CKD

What does the study involve?
Participants are randomly allocated to take either spironolactone or chlortalidone for 40 weeks. Changes in heart muscle weight and arterial stiffness are measured.

What are the possible benefits and risks of participating?
The results should show whether or not the effects of spironolactone on the arteries and heart in patients with CKD are due to blood pressure lowering alone or are due to the special effects of spironolactone. If the effects are specific to spironolactone and occur over and above the blood pressure lowering effects, the drug may be a very effective and inexpensive way to prevent death and disability due to heart and artery disease in patients with CKD.

Where is the study run from?
Birmingham Clinical Trials Unit (UK)

When is the study starting and how long is it expected to run for?
January 2014 to March 2018

Who is funding the study?
British Heart Foundation (BHF) (UK)

Who is the main contact?
Dr Rebekah Wale
spiro-ckd@trials.bham.ac.uk

Trial website

https://www.birmingham.ac.uk/spiro-ckd

Contact information

Type

Scientific

Primary contact

Dr Rebekah Wale

ORCID ID

Contact details

Institute of Applied Health Research
College of Medical and Dental Sciences
Public Health Building
University of Birmingham
Birmingham
B15 2TT
United Kingdom
-
spiro-ckd@trials.bham.ac.uk

Additional identifiers

EudraCT number

2013-002636-25

ClinicalTrials.gov number

Protocol/serial number

15739

Study information

Scientific title

A randomised multicentre open label blinded end point trial to compare the effects of spironolactone to chlortalidone on left ventricular mass in stage 2 and stage 3 chronic kidney disease

Acronym

SPIRO - CKD

Study hypothesis

Chronic kidney disease (CKD) is a major but poorly recognised risk factor for heart and blood vessel disease. Mild CKD is surprisngly common affecting almost 1 in 7 of the population. The adverse cardiovascular effects of CKD are caused mainly by damage and thickening of heart muscle and an increase in artery stiffness which together cause stroke, heart failure and sudden cardiac death. We have previously shown that an old and inexpensive drug called spironolactone reduces the heart thickening and arterial stiffening in CKD compared to an inactive placebo tablet. During treatment with spironolactone however, blood pressure fell and it is not clear whether the beneficial effects of this drug on the heart and arteries were caused by this fall in blood pressure or were specific to the effects of spironolactone.

Ethics approval

13/WM/0304; First MREC approval date 09/09/2013

Study design

Randomised; Interventional; Design type: Not specified, Treatment

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use contact details to request a participant information sheet

Condition

Topic: Cardiovascular, Renal and Urogenital; Subtopic: Cardiovascular (all Subtopics), Renal and Urogenital (all Subtopics); Disease: Cardiovascular, Renal

Intervention

Participants are randomly allocated to treatment with either spironolactone (25 mg od.) or chlortalidone (half a 50 mg tablet od.) for 40 weeks.

12-lead ECG: 12-lead ECG to be performed at the screening visit according to standard clinical practice. The primary function of the ECG is to detect any evidence of Q-wave myocardial infarction or atrial fibrillation (which would exclude the participant from the study).

Ambulatory BP: A mobilograph will be used to record 24 hour brachial and central blood pressure, cardiac output and other indices derived from pulse wave analysis; Arterial haemodynamics, SphygmoCor system to be used to record central blood pressure and arterial stiffness.

Cardiac MRI scan: CMR scans will be performed at the randomisation/baseline visit and visit 6

Laboratory assessments: Standard clinical lab investigations done at: screening visit; visit 3; visit 6.

Additional clinical lab investigations for renal function and safety to be done at: randomisation visit; visit 1; visit 2; visit 4 and visit 5.

Blood and urine for cardiovascular biomarkers to be taken at: randomisation visit; visit 3; visit 5; visit 6 and visit 7

Intervention type

Drug

Phase

Not Applicable

Drug names

Spironolactone, chlortalidone

Primary outcome measure

Current primary outcome measure as of 26/04/2018:
Change between baseline and 40 weeks in left ventricular mass measured by cardiac magnetic resonance imaging at 40 weeks.
This change is per protocol v4.0, 28/11/2016

Previous primary outcome measure as of 13/02/2018:
Change between baseline and 40 weeks in left ventricular mass measured by cardiac magnetic resonance imaging at 40 weeks

Previous primary outcome measure:
Change between baseline and 40 weeks in arterial stiffness measured by carotid-femoral PWV; Timepoint(s): 40 weeks

Secondary outcome measures

Current secondary outcome measures as of 13/02/2018:
1. Change between baseline and 40 weeks in arterial stiffness measured by carotid-femoral PWV (following change to single primary end point); Timepoint(s): 40 weeks
2. Incidence of hyperkalaemia; Timepoint(s): 46 weeks
3. Change between baseline and 40 weeks in blood pressure; Timepoint(s): 40 weeks
4. Change between baseline and 40 weeks in urinary albumin:creatinine ratio; Timepoint(s): 40 weeks
5. Decline in renal function (requiring discontinuation from the trial therapy); Timepoint(s): 40 weeks
6. Symptomatic hypotension (requiring discontinuation from trial therapy); Timepoint(s): 40 weeks
7. Incidence of side-effects (requiring discontinuation from trial therapy); Timepoint(s): 40 weeks
8. Changes between baseline and 40 weeks in left ventricular volumes and systolic function; Timepoint(s): 40 weeks
9. Changes between baseline and 40 weeks in plasma NT-pro-BNP therapy; Timepoint(s): 40 weeks
10. Changes in plasma NT-pro-BNP and arterial stiffness measures including PWV, augmentation index and central blood pressure measured at 24 weeks; Timepoint(s): 24 weeks

Previous secondary outcome measures:
1. Change between baseline and 40 weeks in blood pressure; Timepoint(s): 40 weeks
2. Change between baseline and 40 weeks in LV mass measured by cardiac MRI (co-primary outcome); Timepoint(s): 40 weeks
3. Change between baseline and 40 weeks in urinary albumin:creatinine ratio; Timepoint(s): 40 weeks
4. Changes between baseline and 40 weeks in plasma NT-pro-BNP therapy; Timepoint(s): 40 weeks
5. Changes in plasma NT-pro-BNP and arterial stiffness measures; Timepoint(s): 24 weeks
6. Decline in renal function (requiring discontinuation from trial therapy); Timepoint(s): 40 weeks
7. Incidence of hyperkalaemia; Timepoint(s): 46 weeks
8. Incidence of side-effects (requiring discontinuation from trial therapy); Timepoint(s): 40 weeks
9. Symptomatic hypotension (requiring discontinuation from trial therapy); Timepoint(s): 40 weeks

Overall trial start date

15/01/2014

Overall trial end date

31/03/2018

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

Current inclusion criteria as of 13/02/2018:
1. Aged over 18 years
2. Willingness to undertake all procedural investigations
3. Patients with either stage 2 or stage 3 CKD (eGFR by 4 MDRD equation of 30-89 ml/min/1.732, from blood tests performed within the last 12 months, on 2 occasions, at least 90 days apart)
4. Controlled blood pressure. The local PI must be satisfied that BP control will be clinically satisfactory during the 46 week study period
5. On established (>6 weeks) treatment with ACE inhibitors or ARBs
6. Clinically stable (no hospital admission or significant acute illness within 3 months and no recent (<6 months) acute myocardial infarction or symptoms, or other evidence, of heart failure and/or left ventricular dysfunction)
7. Written informed consent

Previous inclusion criteria:
1. Aged over 18 years
2. Diagnosis of stage 3 CKD [estimated glomerular filtration rate (eGFR) by 4 variable Modification of Diet in Renal Disease (MDRD) of 3059ml/min/1.73m2 on 2 occasions, at least 3 months apart]
3. Well controlled blood pressure (office reading of <150/90 mmHg, i.e. within 10 mmHg of the systolic level recommended in the Renal Association Clinical Practice Guideline, Fifth edition)
4. On established (>6 weeks) treatment with angiotensin-converting-enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs)
5. Written informed consent

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 350; UK Sample Size: 350;

Participant exclusion criteria

Current exclusion criteria as of 13/02/2018:
1. Diabetes mellitus
2. Clinical evidence of hypovolaemia
3. On current regular treatment with non-steroidal anti-inflammatory drugs, or other agents (except ACEi, ARB or low-dose aspirin) that might cause a reduction in GFR.
4. Recent (<6 months) acute myocardial infarction or other major adverse cardiovascular event
5. Known left ventricular systolic dysfunction or severe valvular disease
6. Active malignant disease with a life expectancy of <5 years
7. Previous hyperkalaemia (K+ =6.0 mmol/l without precipitating cause)
8. Serum K+ =5.0 mmol/l at entry
9. Serum sodium <130 mmol/l at entry
10. Current treatment with spironolactone or other MRB
11. Atrial fibrillation on screening ECG
12. Use of a thiazide or loop diuretic in the 6 weeks prior to enrolment
13. Pregnant or breast feeding
14. Known alcohol or drug abuse
15. Active chronic diarrhoea
16. Recent active gout (within 3 months)
17. Episode of acute kidney injury within 3 months
18. Documented Addisons disease
19. Current treatment with fludrocortisone, lithium, or cotrimoxasole
20. Combination treatment with ACE inhibitor and ARB
21. Office blood pressure <115 mmHg systolic or <50 mmHg diastolic
22. Office blood pressure uncontrolled and requiring urgent non trial treatment in the opinion of the clinical investigator

Previous exclusion criteria:
1. Diabetes mellitus
2. Clinical evidence of hypovolaemia
3. Recent (<6 months) acute myocardial infarction or other major adverse cardiovascular event
4. Established diagnosis of left ventricular dysfunction or heart failure
5. Active malignant disease with a life expectancy of <5 years
6. Previous hyperkalaemia (K+ =6.0 mmol/l without precipitating cause)
7. Serum K+ =5.0 mmol/l at entry
8. Serum sodium <132 mmol/l at entry
9. Atrial fibrillation on screening ECG
10. Use of a thiazide or loop diuretic in the 6 weeks prior to enrolment
11. Pregnancy
12. Known alcohol or drug abuse
13. Active chronic diarrhoeal illness
14. Recent active gout (within 3 months)
15. Episode of acute kidney injury within 3 months
16. Documented Addison’s disease
17. Current treatment with fludrocortisone or cotrimoxasole
18. Office blood pressure <115 mmHg systolic or <50 mmHg diastolic

Recruitment start date

15/01/2014

Recruitment end date

15/01/2017

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Birmingham Clinical Trials Unit
Birmingham
B15 2TT
United Kingdom

Sponsor information

Organisation

University of Birmingham (UK)

Sponsor details

Edgbaston
Birmingham
B15 2TT
United Kingdom

Sponsor type

University/education

Website

Funders

Funder type

Charity

Funder name

British Heart Foundation (BHF) (UK); Grant Codes: SP/12/8/29620

Alternative name(s)

BHF

Funding Body Type

private sector organisation

Funding Body Subtype

foundation

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer reviewed journal by 01/01/2019.

IPD sharing statement:
Participant level data sharing is guided by normal CTU policy. It is avaialble upon request from The CI.

Intention to publish date

01/01/2019

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

26/04/2018: The primary outcome measure has been updated to include the date of the protocol change. 15/02/2018: The publication and dissemination plans have been added and the participant level data sharing plans have been added. 13/02/2018: The public title has been updated from "A randomised multicentre open-label blinded end point trial to compare the effects of spironolactone to chlortalidone on left ventricular mass and arterial stiffness in stage 3 chronic kidney disease" to "A randomised multicentre open label blinded end point trial to compare the effects of spironolactone to chlortalidone on left ventricular mass in stage 2 and stage 3 chronic kidney disease". The scientific title has been updated from "A randomised multicentre open-label blinded end point trial to compare the effects of spironolactone to chlortalidone on left ventricular mass and arterial stiffness in stage 3 chronic kidney disease" to "A randomised multicentre open label blinded end point trial to compare the effects of spironolactone to chlortalidone on left ventricular mass in stage 2 and stage 3 chronic kidney disease". The overall trial end date has been updated from 15/01/2017 to 31/03/2018. Ms Gemma Slinn (g.slinn@bham.ac.uk) has been removed as the main study contact and Dr Rebekah Wale (spiro-ckd@trials.bham.ac.uk) has been added. 09/06/2016: Plain English summary added.