Reporting of the methods follows the SPIRIT guidelines [15].

Trial design and study setting

The trial will be a randomized, single-blinded, active-controlled, titration-to-effect, pragmatic study comparing MRA to standard anti-hypertensive treatment for participants with low-renin hypertension referred to the Endocrine Hypertension Clinic at Monash Health, Victoria’s largest public health service. The clinic receives referrals from both general practitioners and specialists. Before performing any trial-specific procedures, a signed consent form will be obtained from each participant. The investigator will confirm that the participant comprehends the information provided and answer any questions about the trial. When the inclusion/exclusion criteria have been addressed and the eligibility of the participant confirmed, the participant will then be randomized 1:1 to one of the trial arms. All participants will undergo a seated saline suppression test to exclude primary aldosteronism. Renin concentration exists on a continuum. The definition of low-renin hypertension is somewhat arbitrary and has traditionally been defined as a plasma renin activity <1 ng/ml/h which approximately equates to a direct renin concentration of 8–12 mU/L. Furthermore, in an eight-week monotherapy study by Weinberger, participants with direct renin concentration <9.4 mU/L had a better blood pressure response to eplerenone compared to losartan: mean change in systolic blood pressure of –17.2 mmHg versus –5.4 mmHg [16]. We therefore selected a threshold of <10 mU/L to define low-renin hypertension.

Trial populationInclusion criteria

Adult ambulatory participants with hypertension, defined as a mean seated blood pressure >140/90 mmHg, and are treatment-naive or with any blood pressure level on up to two antihypertensive agents, have a low direct renin concentration <10 mU/L (measured on non-interfering medications), but who do not have primary aldosteronism or monogenic forms of low-renin hypertension, and can provide informed consent to participate in the trial.

Exclusion criteria

See Table 1.

Table 1 Eligibility criteria.Trial procedure

Study participants meeting the inclusion and exclusion criteria will be randomized 1:1 via REDCap to either MRA, spironolactone (intervention), or standard care, perindopril+/-amlodipine (control), using a block randomization method. The schedule has been prepared by a biostatistician and uploaded to REDCap and is not available to the clinic staff. Participants on antihypertensive treatment at baseline will undergo a washout period of 2–4 weeks before screening and randomization. If there are clinical concerns, prazosin, a short-acting antihypertensive can be continued until 48 h pre-randomization. The standard care group will receive treatment as per local prescribing patterns and hypertension guidelines [14]. Antihypertensive medications will be titrated as required at 12-weekly intervals until target blood pressure of <140/90 mmHg is achieved in both groups and renin is unsuppressed i.e., >15 mU/L in the MRA group (Fig. 1). The biochemical titration target for the MRA group is based on evidence that treatment adequacy is associated with normalized renin [17]. Participants will be reviewed every 6–12 weeks and treated for a total of 48 weeks. Administration of medication will be standardized to night-time dosing once daily for consistency. Blood pressure measurements will be taken seated in triplicates using an automated blood pressure machine (Omron) and the average of 2nd and 3rd readings will be calculated. Automated office blood pressure measurement has been shown to correlate with out-of-clinic measures [18].

Fig. 1

Titration steps in the treatment algorithm.

Pathology will be collected at Monash Health Pathology laboratories. Both aldosterone and direct renin concentration will be measured using chemiluminescent immunoassays (LIAISON, DiaSorin). For the seated saline suppression test, aldosterone concentration will be measured using mass spectrometry as well due to its greater accuracy [19]. Primary aldosteronism will be excluded if aldosterone concentration post saline infusion is <162 pmol/L [20].

Compliance

Medication compliance will be assessed at each study visit using medication diaries and pill counting when medications are returned to the pharmacy.

Relevant concomitant therapies allowed and excluded

Women of childbearing age will need to be on effective contraception given the potential for teratogenicity of the trial medications during study participation and until 2 months after the last dose of trial medications. Trial participants needing to use medications that can interfere with the measurement of blood pressure, renin, or aldosterone during the treatment and follow-up phase of the trial will be excluded.

Safety considerations

All medications used in the trial have been entered into the Australian Register of Therapeutic Goods. Spironolactone, perindopril, and amlodipine are approved by Therapeutic Guides Australia for the treatment of hypertension. The following adverse effects will be noted at each visit: gynecomastia, breast pain, reduced libido, menstrual irregularity, cough, hyperkalemia, and an increase of >30% in serum creatinine.

Adverse effects will be described in the patient’s medical record as follows: a description of symptoms including duration, severity (mild, moderate, or severe), seriousness (i.e., is it a serious adverse event?), any action taken, the outcome and likelihood of the relationship to the trial treatment (unrelated, possible, probable, definite) [21]. All serious adverse effects that occur from the time the participant signs the consent form, up to and including the last scheduled visit, will be reported within 24 h to an independent Data and Safety Monitoring Board, consisting of four members including a biostatistician and doctors with expertise in clinical trials. A trial progress update will be sent quarterly to the Data and Safety Monitoring Board. Trial conduct, protocol compliance, and safety are under their oversight.

Dose and medication modification

If a participant on spironolactone treatment develops troublesome gynecomastia, breast tenderness, or irregular menses, they will be prescribed eplerenone in place of spironolactone at the same dose but twice a day e.g., participants on spironolactone 25 mg daily will be switched to eplerenone 25 mg twice a day. Eplerenone is a less potent but more selective MRA with minimal effect on the progesterone and androgen receptors. If perindopril 5/10 mg is not tolerated due to side effects such as cough, participants will be prescribed irbesartan 150/300 mg, respectively. Participants requiring a change in medication to eplerenone or irbesartan will be unblinded but will remain in the study and contribute to the final analysis. If a participant develops hyperkalemia, defined as serum potassium > 5.5 mmol/L on a non-hemolyzed blood sample, or has a 30% increase in creatinine due to perindopril/irbesartan or spironolactone/eplerenone, the dose of the trial mediation will be reduced to the highest tolerated dose.

Blinding

Participants will be blinded to the treatment by using encapsulating medications through a third party. The nurse and technician performing clinic blood pressure, and transthoracic echocardiograms will also be blinded to reduce any potential bias in the reporting of outcomes. Clinicians prescribing the antihypertensives will not be blinded to treatment allocation as the titration protocol is treatment-specific. Although a possible limitation, we anticipate that any treatment bias will be minimal given that the prescribed treatment will be driven by the study protocol and up-titration of treatments will be based on clinic blood pressure measurements performed by the nurse (blinded to treatment allocation), and direct renin concentration values measured at the hospital laboratory (for the MRA arm only).

Study objectives

The primary objective will be to assess the change in mean clinic systolic blood pressure from baseline to week 48 and to determine the total defined daily dose of antihypertensives required to achieve the target blood pressure. The ‘defined daily dose’ is described by the World Health Organization as the average maintenance dose per day for a drug used for its main indication in adults and is a measure of drug utilization [22]. The defined daily dose of spironolactone is 75 mg/day, perindopril 5 mg/day, and amlodipine 5 mg/day [22].

The secondary and exploratory objectives of this study are summarized in Table 2.

Table 2 Study objectives.Data collection and management

The medical history, examination findings, medication side effects, compliance, and investigation results will be collected at each study visit (Table 3) and entered via the secure web-based data management system, REDCap. Data entry will be performed by the investigators. Data logic and consistency checks are programmed into the data entry forms so that data entry errors can be caught in real time, and queries are auto-generated. Data generated will be held in strict confidence. No information concerning the trial or the data will be released to any unauthorized third party without the prior written approval of the Hudson Institute of Medical Research.

Table 3 Data collection schedule.Biological specimen collection and storage

Blood and urine biospecimens collected at baseline and the end of the trial will be frozen and stored at Monash Pathology and may be retrieved to measure new markers of low-renin hypertension and any subtypes identified in this trial. All other biospecimens will be discarded.

Sample size calculation and statistical analysis

The sample size estimation will be based on the two primary objectives. In a study of hypertensive patients, Weinberger et al showed that after 16 weeks of treatment, systolic blood pressure among patients with low-renin hypertension (renin <9.4 mU/L) was reduced by 17.2 mmHg in the eplerenone group compared with 5.4 mmHg in the losartan group (no standard deviations were reported) [16]. Assuming a similar drop in systolic blood pressure between treatment groups with an equal standard deviation of 10 mmHg for the change in blood pressure, a minimum sample size of 24 patients per arm would be required. For the second primary endpoint of the defined daily dose required to achieve target blood pressure, a comprehensive systematic review of the literature was conducted, but no previous trials reported the expected defined daily dose for either spironolactone or perindopril in low-renin hypertension. Therefore, in the absence of such information, a large effect size will be assumed (Cohen’s d = 0.8). For this effect size, a minimum sample size of 50 patients per group is needed. The two sample size estimations account for 90% power in the study, with a Bonferroni family-wise error rate of 0.025 (two-sided) and a 20% attrition. Bonferroni multiplicity was considered because the outcomes from this study would be confirmative, and the defined daily dose and blood pressure change are presumed to be closely related outcome measures for blood pressure control. Hence the target sample size for this study is 100 patients (50 randomized to each arm of the study).

Participants will be recruited from the Endocrine Hypertension Clinic at Monash Health. In addition to referrals from other specialists, the Endocrine Hypertension research group has established a relationship with over 40 general practice clinics and 200 practitioners who routinely refer patients to the clinic.

Analysis of the efficacy of each intervention will be performed on an intention-to-treat basis. All randomized patients with a baseline assessment and at least one post-baseline assessment will be included in the statistical analysis. Safety analyses will include all randomized patients who received at least one dose of study medication. An additional per-protocol analysis will be considered in the case of non-compliance and/or medication non-adherence. All data will be analyzed as observed and no data imputation is anticipated unless significant missing data is observed.

A generalized linear model will be used to conduct a between-group comparison for the systolic blood pressure, defined daily dose of antihypertensives, left ventricular mass index, global longitudinal strain, endothelial dysfunction, and 24-h urinary microalbumin excretion. If some participants do not achieve target blood pressure, the data will be treated and analyzed using methods for right censored data and between groups comparison will be done using Kaplan–Meier curves and the log-rank test. The difference in the change in blood pressure between groups will be estimated based on the interaction between the time and group variables using a mixed-effects model. A Cox proportional hazards model will be used to assess and compare the time to achieve target blood pressure in the MRA and standard treatment groups. The chi-squared test will be used for between-group comparison of the proportion of participants who discontinued treatment due to adverse effects or developed hyperkalemia during the treatment period. Data will be analyzed using Stata Statistical Package version 17 or later, R Statistical Package version 3 or later, or SPSS Statistical Package version 28 or later. Adverse effects and serious adverse effects will be tabulated and listed, by the treatment group.

Treatment discontinuation

Participants who discontinue trial treatment will remain in the trial and trial procedures and scheduled visits will be conducted where possible.

Post-trial care

At the end of the trial, participants will be unblinded and offered the option of either continuing their randomized treatment or changing to either standard antihypertensives or MRA treatment.

Ethics, trial registration and status

This trial protocol version 10, 19/12/23 has been approved by the local institution Human Research Ethics Committee, (RES-22-0000-044A) and has been registered with the Australian New Zealand Clinical Trials Registry (ACTRN12622000391774). Recruitment began in August 2022 and will continue until the sample size is reached.

Any further change to the protocol that affects the trial design or scientific intent will be submitted for approval to the Human Research Ethics Committee as an amendment.