Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000391774
Ethics application status
Approved
Date submitted
25/02/2022
Date registered
7/03/2022
Date last updated
12/05/2023
Date data sharing statement initially provided
7/03/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
A Randomised trial assessing Efficacy and safety of Mineralocorticoid receptor Antagonist therapy compared to Standard antihypertensive Therapy in hypErtension with low Renin (REMASTER)
Scientific title
A randomised, single-blinded, active-controlled, titration-to-effect trial comparing efficacy and safety of mineralocorticoid receptor antagonist therapy to standard anti-hypertensive treatment for hypertension with low renin.
Secondary ID [1] 306405 0
None
Universal Trial Number (UTN)
None
Trial acronym
REMASTER
Linked study record
None

Health condition
Health condition(s) or problem(s) studied:
Low-renin hypertension 325240 0
Condition category
Condition code
Metabolic and Endocrine 322638 322638 0 0
Other endocrine disorders
Cardiovascular 322647 322647 0 0
Hypertension

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be randomised to receive either mineralocorticoid receptor antagonists (MRA) or standard antihypertensive treatment for 48 weeks. Medications will be up-titrated 12-weekly until target blood pressure is reached (both treatment arms) and renin is un-suppressed (in the MRA treatment arm). Medications will be encapsulated and dispensed by the clinical trials pharmacy. Medication adherence will be monitored using a participant medication diary and pill counting of returned medications.

MRA titration schedule:
1. Commence on spironolactone 25mg tablet oral daily
2. Increase to spironolactone 50mg tablet oral daily
3. Increase to spironolactone 75mg tablet oral daily
4. Increase to spironolactone 100mg tablet oral daily
Intervention code [1] 322848 0
Treatment: Drugs
Comparator / control treatment
Standard anti-hypertensive treatment titration schedule:

1. Commence on perindopril 5mg tablet oral daily
2. Add amlodipine 5mg oral daily i.e. perindopril/amlodipine 5/5mg oral tablet daily
3. Increase perindopril to 10mg oral daily i.e. perindopril/amlodipine 10/5mg oral tablet daily
4. Increase amlodipine to 10mg oral daily i.e. perindopril/amlodipine 10/10mg oral tablet daily
Control group
Active

Outcomes
Primary outcome [1] 330449 0
The total defined daily dose of antihypertensives required to achieve target blood pressure.

Data on medication and doses will be extracted from study records. The total defined daily dose will be calculated as defined by the World Health Organization (WHO) Collaborating Centre for Drug Statistics Methodology.
Timepoint [1] 330449 0
The total defined daily dose of antihypertensives will be calculated at the following time points: week 6, 12, 24, 36 and 48 after treatment commencement.
Primary outcome [2] 333148 0
The change in mean clinic systolic blood pressure measured by an automated blood pressure monitor from baseline to week 48.
Timepoint [2] 333148 0
Mean clinic blood pressure will be measured at the following time points: baseline and week 6, 12, 24, 36 and 48 after treatment commencement.
Secondary outcome [1] 406243 0
The change in mean clinic systolic and diastolic blood pressure measured by an automated blood pressure monitor from baseline to week 24 and change in mean clinic diastolic blood pressure from baseline to week 48.
Timepoint [1] 406243 0
Mean clinic blood pressure will be measured at the following time points: baseline and week 6, 12, 24, 36 and 48 after treatment commencement.
Secondary outcome [2] 406244 0
The change in average 24-hour systolic and diastolic blood pressure measured using an ambulatory blood pressure monitor.
Timepoint [2] 406244 0
24-hour ambulatory blood pressure will be measured at the following time points: baseline and week 48 after treatment commencement.
Secondary outcome [3] 406245 0
Time to achieve the target mean clinic blood pressure measured by an automated blood pressure monitor.
Timepoint [3] 406245 0
Mean clinic blood pressure will be measured at the following time points: baseline and week 6, 12, 24, 36 and 48 after treatment commencement.
Secondary outcome [4] 406247 0
The change in the left ventricular mass index on transthoracic echocardiogram.
Timepoint [4] 406247 0
Left ventricular mass index on transthoracic echocardiogram will be measured at the following time points: baseline and week 48 after treatment commencement.
.
Secondary outcome [5] 406248 0
The change in the global longitudinal strain on transthoracic echocardiogram.
Timepoint [5] 406248 0
Global longitudinal strain on transthoracic echocardiogram will be measured at the following time points: baseline and week 48 after treatment commencement.
.
Secondary outcome [6] 406249 0
The change in endothelial function measured by EndoPAT.
Timepoint [6] 406249 0
Endothelial function will be measured at the following time points: baseline and week 48 after treatment commencement.
Secondary outcome [7] 406250 0
The change in 24-hour urinary microalbumin excretion.
Timepoint [7] 406250 0
24-hour urinary microalbumin excretion will be measured at the following time points: baseline and week 48 after treatment commencement.
Secondary outcome [8] 406251 0
The proportion of participants that discontinued trial medication due to adverse effects reported at study visits e.g. gynaecomastia, irregular menstrual cycles.
Timepoint [8] 406251 0
Adverse effects will be queried at study visits at week 6, 12, 24, 36 and 48 after treatment commencement.
Secondary outcome [9] 406252 0
The proportion of participants that developed hyperkalaemia defined as serum potassium > 5.5 mmol/L on a non-haemolysed blood sample.
Timepoint [9] 406252 0
Serum potassium will be measured at baseline and week 6, 12, 24, 36 and 48 after treatment commencement.
Secondary outcome [10] 406253 0
The proportion of participants that achieved target mean clinic blood pressure measured by an automated blood pressure monitor.
Timepoint [10] 406253 0
The proportion of participants that achieved target mean clinic blood pressure will be assessed at week 48 after treatment commencement.
Secondary outcome [11] 406792 0
Quality of life assessed using the SF-36 quality of life questionnaire.
Timepoint [11] 406792 0
Quality of life will be assessed at the following time points: baseline and week 48 after treatment commencement.

Eligibility
Key inclusion criteria
1. Adults with hypertension, defined as a mean seated blood pressure > 140/90 mmHg, who are treatment naïve or are receiving up to two antihypertensive agents, and
2. Have a low plasma renin concentration defined as < 10 mU/L, and
3. Can provide informed consent.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Blood pressure >180/120 mmHg
2. On medications confounding plasma renin concentration or plasma aldosterone concentration such as glucocorticoids, oestrogen-containing oral contraceptive pill and hormone replacement therapy and sodium-glucose co-transporter 2 inhibitors
3. Pregnant, breastfeeding or women of child-bearing potential
4. Uncontrolled diabetes with a glycosylated haemoglobin (HbA1C) > 7.5%
5. Chronic kidney disease with an estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73m2
6. Heart failure class II-IV, ischaemic heart disease, transient ischaemic attack, stroke or atrial fibrillation
7. Liquorice abuse
8. Known secondary cause of hypertension (primary hyperparathyroidism, PA defined as PAC post-SST>162 pmol/L where PAC was measured by liquid chromatography-tandem mass spectrometry or > 170 pmol/L where PAC was only measured by radioimmunoassay, autonomous cortisol secretion, hyperthyroidism, phaeochromocytoma, renal artery stenosis or known monogenic causes of low-renin hypertension
9. Hypersensitivity to the trial medications.
10. Potassium > 5.0mmol/L

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
A statistician will prepare the randomisation schedule.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Block randomisation.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Parallel
Other design features
N/A
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Generalised linear models will be used to conduct a between-group comparison of the defined daily dose of antihypertensives and examine the relationship between secondary outcomes and treatment group. All analyses will be conducted as intention to treat. Assuming a large effect size (Cohen's d=0.7), a minimum sample size of 50 per group will be required for 90% study power, with a=0.05 and allowing for 30% attrition. A detailed statistical analysis plan will be developed before data analyses.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
10/08/2022
Actual
1/09/2022
Date of last participant enrolment
Anticipated
16/10/2024
Actual
Date of last data collection
Anticipated
16/10/2025
Actual
Sample size
Target
100
Accrual to date
13
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 21714 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment postcode(s) [1] 36764 0
3168 - Clayton

Funding & Sponsors
Funding source category [1] 310757 0
Self funded/Unfunded
Name [1] 310757 0
Dr Jun Yang
Country [1] 310757 0
Australia
Primary sponsor type
Individual
Name
Dr Jun Yang
Address
Hudson Institute of Medical Research
27-31 Wright St
Clayton VIC 3168
Country
Australia
Secondary sponsor category [1] 312136 0
None
Name [1] 312136 0
Address [1] 312136 0
Country [1] 312136 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310335 0
Monash Health Human Research Ethics Committee
Ethics committee address [1] 310335 0
Level 2, i Block,
Monash Medical Centre
246 Clayton Road
CLAYTON VIC 3168
Ethics committee country [1] 310335 0
Australia
Date submitted for ethics approval [1] 310335 0
19/01/2022
Approval date [1] 310335 0
29/03/2022
Ethics approval number [1] 310335 0

Summary
Brief summary
High blood pressure, or hypertension, is a major cause of death worldwide and affects over 6 million Australians. Many people with high blood pressure do not achieve good blood pressure control even with more than one medication.

The purpose of this trial is to find out whether personalising treatment by measuring a hormone called renin with a blood test can select people who will benefit from early treatment with a widely used blood pressure medication called spironolactone, an aldosterone blocker.

We will do this by randomly assigning individuals with high blood pressure and low renin to either spironolactone or standard blood pressure lowering medications. Participants will be assessed every 12 weeks for 48 weeks. Medication doses will be slowly increased until blood pressure is controlled. At the end of the trial, we will compare individuals who received aldosterone blockers to standard blood pressure-lowering medications and see if there is a difference in blood pressure control and markers of heart and kidney health.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 117278 0
Dr Jun Yang
Address 117278 0
Hudson Institute of Medical Research
27-31 Wright Street Clayton VIC 3168
Country 117278 0
Australia
Phone 117278 0
+61 3 8572 2515
Fax 117278 0
+61 3 9594 3558
Email 117278 0
jun.yang@hudson.org.au
Contact person for public queries
Name 117279 0
Dr Sonali Shah
Address 117279 0
Hudson Institute of Medical Research
27-31 Wright Street Clayton VIC 3168
Country 117279 0
Australia
Phone 117279 0
+61 3 8572 2515
Fax 117279 0
+61 3 9594 3558
Email 117279 0
sonali.shah@monashhealth.org
Contact person for scientific queries
Name 117280 0
Dr Jun Yang
Address 117280 0
Hudson Institute of Medical Research
27-31 Wright Street Clayton VIC 3168
Country 117280 0
Australia
Phone 117280 0
+61 3 8572 2515
Fax 117280 0
+61 3 9594 3558
Email 117280 0
jun.yang@hudson.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.