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
| ISRCTN | ISRCTN94696478 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN94696478 |
| EudraCT/CTIS number | 2013-002636-25 |
| Secondary identifying numbers | 15739 |
- Submission date
- 16/01/2014
- Registration date
- 16/01/2014
- Last edited
- 20/05/2022
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Circulatory System
Plain English summary of protocol
Current plain English summary as of 26/03/2019:
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 June 2019
Who is funding the study?
British Heart Foundation (BHF) (UK)
Who is the main contact?
Dr Rebekah Wale
spiro-ckd@trials.bham.ac.uk
Previous 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
Contact information
Scientific
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 |
Study information
| Study design | Randomised; Interventional; Design type: Not specified, Treatment |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use contact details to request a participant information sheet |
| 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 |
| Study acronym | SPIRO - CKD |
| Study objectives | 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(s) | 13/WM/0304; First MREC approval date 09/09/2013 |
| Health condition(s) or problem(s) studied | 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 |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | 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 study start date | 15/01/2014 |
| Completion date | 30/06/2019 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 350; UK Sample Size: 350; |
| Total final enrolment | 154 |
| Key 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 |
| Key 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 Addisons disease 17. Current treatment with fludrocortisone or cotrimoxasole 18. Office blood pressure <115 mmHg systolic or <50 mmHg diastolic |
| Date of first enrolment | 15/01/2014 |
| Date of final enrolment | 15/01/2017 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
B15 2TT
United Kingdom
Sponsor information
University/education
Edgbaston
Birmingham
B15 2TT
England
United Kingdom
"ROR" |
https://ror.org/03angcq70 |
|---|
Funders
Funder type
Charity
Private sector organisation / Trusts, charities, foundations (both public and private)
- Alternative name(s)
- the_bhf, The British Heart Foundation, BHF
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 31/07/2020 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Planned publication in a high-impact peer reviewed journal by 01/01/2019. |
| IPD sharing plan | Participant level data sharing is guided by normal CTU policy. It is avaialble upon request from The CI. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | protocol | 01/09/2017 | 17/12/2020 | Yes | No |
| Basic results | 25/06/2020 | 20/05/2022 | No | No | |
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
20/05/2022: EU Clinical Trials Register results added.
17/12/2020: Publication reference added.
24/04/2020: The intention to publish date has been changed from 31/10/2019 to 31/07/2020.
06/11/2019: Internal review.
26/03/2019: The following changes were made:
1. The overall trial end date was changed from 31/03/2018 to 30/06/2019.
2. The intention to publish date was changed from 01/01/2019 to 31/10/2019.
3. The plain English summary was updated.
4. The total final enrolment was added.
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.
