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NCT Number: NCT07687160

SPIRO-First: A Pragmatic Primary Care-Embedded Pilot Trial of Renin-Guided First-Line Antihypertensive Therapy

The goal of this clinical trial is to determine whether a renin-guided antihypertensive treatment strategy is feasible to implement in community primary care clinics and to explore whether spironolactone improves blood pressure control in adults with low-renin hypertension.

The main questions it aims to answer are:

Is it feasible to identify, recruit, randomize, and follow adults with low-renin hypertension in a pragmatic primary care-based clinical trial?

Does first-line treatment with spironolactone result in greater reductions in ambulatory blood pressure compared with standard first-line antihypertensive therapy among adults with low-renin hypertension?

Researchers will compare spironolactone 25 mg daily with standard first-line antihypertensive therapy (candesartan, hydrochlorothiazide, or amlodipine) to determine whether spironolactone provides better blood pressure control in adults with low-renin hypertension.

Participants will:

Undergo blood pressure assessments, blood tests, and ambulatory blood pressure monitoring (ABPM) to determine eligibility.

Be randomly assigned to receive either spironolactone or a standard first-line antihypertensive medication for 12 weeks.

Complete follow-up visits and laboratory testing to monitor blood pressure response, kidney function, electrolyte levels, medication adherence, and side effects.

Undergo repeat blood pressure measurements and ABPM at the end of the study.

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Key information

Conditions

Hypertension Adrenal Gland Diseases Adrenocortical Hyperfunction Cardiovascular Diseases Endocrine System Diseases Hyperaldosteronism Vascular Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Ottawa Nurse Practitioner-Led Clinic, Ottawa, Ontario, Canada

Loading trial locations.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Age ≥18 years.
  • Under the care of a primary care clinician in Ontario.
  • Standardized office systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHg.
  • Mean daytime baseline ABPM systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHg.
  • Treating primary care clinician has independently determined that initiation of antihypertensive pharmacotherapy is clinically indicated.
  • Either:
  • Not currently receiving antihypertensive therapy, OR
  • Receiving a single antihypertensive medication (ACE inhibitor, ARB, thiazide/thiazide-like diuretic, or calcium channel blocker) which the treating primary care clinician considers safe to discontinue for a 2-week washout period.
  • Suppressed renin defined as direct renin concentration <6 ng/L (<10 mU/L) measured under routine outpatient conditions. Suppressed renin was selected as the primary biologic enrichment criterion because it is the physiologic hallmark of sodium-retaining, aldosterone-mediated hypertension and is more pragmatically scalable in primary care than complex biochemical primary aldosteronism (PA) definitions.
  • In the opinion of the treating primary care clinician, outpatient participation in the study is appropriate.

Exclusion criteria

  • Standardized office systolic blood pressure >170 mmHg if untreated OR >150 mmHg if receiving one antihypertensive medication.
  • Known diagnosis of PA requiring specialist-directed management.
  • Known secondary hypertension requiring disease-specific therapy.
  • Current use of MR antagonists.
  • Known intolerance or contraindication to spironolactone, candesartan, hydrochlorothiazide, or amlodipine.
  • eGFR <30 mL/min/1.73 m2.
  • Serum potassium ≥5.0 mmol/L.
  • Serum sodium <135 mmol/L.
  • Pregnancy, breastfeeding, or intention to become pregnant during the study period. Women of childbearing potential must have a negative pregnancy test prior to randomization.
  • Participation in another interventional study likely to affect blood pressure.
  • Inability to provide consent

Treatment and study plan

Spironolactone (drug)

Drug

Spironolactone 25 mg daily: Spironolactone is a widely available and inexpensive MR antagonist medication which blocks the action of aldosterone. Spironolactone is the most commonly recommended drug for the treatment of primary aldosteronism given its efficacy in improving blood pressure and reducing cardiovascular and kidney disease risk for this patient population, with 25 mg being the standard starting dose.

Candesartan 8mg

Drug

Comparator medications were selected because they represent common guideline-recommended first-line antihypertensive therapies from mechanistically distinct drug classes routinely used in contemporary primary care practice and hypertension guidelines. Doses were selected based on equivalent defined daily doses (DDD). The purpose of including multiple comparator therapies is to emulate real-world first-line prescribing practices in primary care rather than compare spironolactone against a single mechanistic alternative.

Hydrochlorothiazide (HCTZ) 25 milligrams.

Drug

Comparator medications were selected because they represent common guideline-recommended first-line antihypertensive therapies from mechanistically distinct drug classes routinely used in contemporary primary care practice and hypertension guidelines. Doses were selected based on equivalent defined daily doses (DDD). The purpose of including multiple comparator therapies is to emulate real-world first-line prescribing practices in primary care rather than compare spironolactone against a single mechanistic alternative.

Amlodipine (5mg)

Drug

Comparator medications were selected because they represent common guideline-recommended first-line antihypertensive therapies from mechanistically distinct drug classes routinely used in contemporary primary care practice and hypertension guidelines. Doses were selected based on equivalent defined daily doses (DDD). The purpose of including multiple comparator therapies is to emulate real-world first-line prescribing practices in primary care rather than compare spironolactone against a single mechanistic alternative.

Primary outcomes

  1. PRIMARY OUTCOME: Recruitment Rate of Randomized Participants per Month

    Time frame: 12 months following activation of all participating study sites

    Recruitment rate, defined as the average number of participants randomized per month during the recruitment period following activation of all participating study sites. Recruitment feasibility will be assessed by calculating the number of participants randomized each month over the 12-month recruitment period.

Secondary outcomes

  1. SECONDARY OUTCOME #1: Number of Potentially Eligible Participants Identified

    Time frame: 12 months

    Number of potentially eligible participants identified by participating primary care clinicians and referred for study screening.

  2. SECONDARY OUTCOME #2: Eligibility Rate

    Time frame: 12 months

    Eligibility rate, defined as the proportion of screened participants who meet all study eligibility criteria. Calculated as the number of eligible participants divided by the number of screened participants.

  3. SECONDARY OUTCOME #3: Recruitment Acceptance Rate

    Time frame: 12 months

    Recruitment acceptance rate, defined as the proportion of eligible participants who provide informed consent and undergo randomization. Calculated as the number of randomized participants divided by the number of eligible participants.

  4. SECONDARY OUTCOME #4: Prevalence of Suppressed Renin Physiology

    Time frame: 12 months

    Proportion of screened participants with suppressed renin physiology, defined as a direct renin concentration <6 ng/L (<10 mU/L).

  5. SECONDARY OUTCOME #5: Antihypertensive Washout Completion Rate

    Time frame: 12 months

    Proportion of participants for whom the protocol-specified antihypertensive washout procedures are successfully completed when applicable

  6. SECONDARY OUTCOME #6: Ambulatory Blood Pressure Monitoring Completion Rate

    Time frame: 12 weeks

    Proportion of randomized participants who successfully complete ambulatory blood pressure monitoring (ABPM) according to the study protocol.

  7. SECONDARY OUTCOME #7: Protocol Adherence Rate

    Time frame: 12 weeks

    Proportion of randomized participants completing assigned study treatment and the Week 12 outcome assessment procedures according to the study protocol.

  8. SECONDARY OUTCOME #8: Study Completion Rate

    Time frame: 12 weeks

    Proportion of randomized participants completing the Week 12 end-of-study assessment.

  9. SECONDARY OUTCOME #9: Reasons for Non-participation, Treatment Discontinuation, and Study Withdrawal

    Time frame: 12 months

    Frequency and categorized reasons for declining participation, treatment discontinuation, and withdrawal from the study.

  10. SECONDARY OUTCOME #10: Data Completeness

    Time frame: 12 weeks

    Proportion of required study data fields completed without missing or invalid values.

  11. SECONDARY OUTCOME #11: Primary Care Clinician Satisfaction With Patient Participation

    Time frame: end of study (at 12 months)

    Primary care clinician satisfaction with their patients' participation in the study, assessed using a post-study questionnaire.

  12. SECONDARY OUTCOME #12: Primary Care Clinician Satisfaction With Study Communication

    Time frame: end of study (at 12 months)

    Primary care clinician satisfaction regarding communication on participant progress and handover of care following study completion, assessed using a post-study questionnaire.

  13. SECONDARY OUTCOME #13: Primary Care Clinician Engagement

    Time frame: 12 months

    Proportion of participating primary care clinicians who continue referring potentially eligible participants throughout the study period.

Other outcomes

  1. Exploratory Outcome #1 (Blood pressure outcomes): Change in Mean Daytime Systolic Blood Pressure

    Time frame: Baseline to Week 12

    Change in mean daytime systolic blood pressure measured by ambulatory blood pressure monitoring (ABPM) from baseline to Week 12.

  2. Exploratory Outcome #2 (Blood pressure outcomes): Change in Mean Daytime Diastolic Blood Pressure

    Time frame: Baseline to Week 12

    Change in mean daytime diastolic blood pressure measured by ambulatory blood pressure monitoring (ABPM) from baseline to Week 12.

  3. Exploratory Outcome 3 (Blood pressure outcomes): Change in Mean 24-Hour Systolic Blood Pressure

    Time frame: Baseline to Week 12

    Change in mean 24-hour systolic blood pressure measured by ambulatory blood pressure monitoring (ABPM) from baseline to Week 12.

  4. Exploratory Outcome 4 (Blood pressure outcomes): Change in Mean 24-Hour Diastolic Blood Pressure

    Time frame: Baseline to Week 12

    Change in mean 24-hour diastolic blood pressure measured by ambulatory blood pressure monitoring (ABPM) from baseline to Week 12.

  5. Exploratory Outcome 5 (Blood pressure outcomes): Change in Standardized Office Systolic Blood Pressure

    Time frame: Baseline to Week 12

    Change in standardized office systolic blood pressure from baseline to Week 12.

  6. Exploratory Outcome 6 (Blood pressure outcomes): Change in Standardized Office Diastolic Blood Pressure

    Time frame: Baseline to Week 12

    Change in standardized office diastolic blood pressure from baseline to Week 12

  7. Exploratory Outcome 7 (Hypertension Control): Participants Achieving Daytime Ambulatory Blood Pressure Control

    Time frame: Week 12

    Proportion of participants achieving a mean daytime ambulatory systolic blood pressure <130 mmHg at Week 12

  8. Exploratory Outcome 8 (Hypertension Control): Participants Achieving Standardized Office Blood Pressure Control

    Time frame: Week 12

    Proportion of participants achieving a standardized office systolic blood pressure <130 mmHg at Week 12

  9. Exploratory Mechanistic Outcome #1: Change in Direct Renin Concentration

    Time frame: Baseline to Week 12

    Change in direct renin concentration (ng/L) from baseline to Week 12

  10. Exploratory Mechanistic Outcome #2: Renin Unsuppression

    Time frame: week 12

    Proportion of participants achieving renin unsuppression, defined as a direct renin concentration ≥6 ng/L (≥10 ng?L), at Week 12.

  11. Exploratory Mechanistic Outcome #3: Increase in Direct Renin Concentration

    Time frame: Baseline to week 12

    Proportion of participants demonstrating any increase in direct renin concentration from baseline to Week 12.

  12. Exploratory Mechanistic Outcome #4: Association Between Renin Response and Blood Pressure Response

    Time frame: Baseline to Week 12

    Association between the change in direct renin concentration and the change in mean daytime systolic blood pressure measured by ambulatory blood pressure monitoring from baseline to Week 12

  13. Safety Outcome #1: Symptomatic Hypotension

    Time frame: Baseline to Week 12

    Proportion of participants experiencing symptomatic hypotension, including orthostatic symptoms, lightheadedness, injurious falls, or syncope.

  14. Safety Outcome #2: Hyperkalemia

    Time frame: Baseline to Week 12

    Proportion of participants with serum potassium >5.5 mmol/L

  15. Safety Outcome #3: Hypokalemia

    Time frame: Baseline to Week 12

    Proportion of participants with serum potassium <3.5 mmol/L.

  16. Safety Outcome #4: Change in Serum Potassium Concentration

    Time frame: Baseline to Week 12

    Change in serum potassium concentration from baseline to Week 12

  17. Safety Outcome #5: ≥40% Decline in Estimated Glomerular Filtration Rate

    Time frame: Baseline to Week 12

    Proportion of participants experiencing a ≥40% decline in estimated glomerular filtration rate (eGFR) from baseline.

  18. Safety Outcome #6: Dialysis Initiation

    Time frame: Baseline to Week 12

    Proportion of participants initiating dialysis during the study period

  19. Safety Outcome #7: Hyponatremia

    Time frame: Baseline to Week 12

    Proportion of participants with serum sodium <135 mmol/L.

  20. Safety Outcome #8: Gynecomastia

    Time frame: Baseline to Week 12

    Proportion of participants developing gynecomastia during the study period

  21. Safety Outcome #9: Medication Discontinuation Due to Adverse Events

    Time frame: Baseline to Week 12

    Proportion of participants requiring medication discontinuation, dose reduction, or switching because of adverse events

  22. Safety Outcome #10: Major Adverse Cardiovascular Events

    Time frame: Baseline to Week 12

    Proportion of participants experiencing myocardial infarction, stroke, heart failure hospitalization, peripheral arterial revascularization, or cardiovascular death

  23. Safety Outcome #11: All-Cause Hospitalization

    Time frame: Baseline to week 12

    Proportion of participants hospitalized for any cause.

  24. Safety Outcome #12: All-Cause Mortality

    Time frame: Baseline to Week 12

    Proportion of participants who die from any cause during the study period

Study contacts

Contact information is provided by the study sponsor or research team.

Deena Fremont, MSc

CONTACT

[email protected]

Gregory L Hundemer, MD

CONTACT

[email protected]

(613) 738-8400 ext. 81885

Sponsors and collaborators

Lead sponsor

Ottawa Hospital Research Institute

Other

Collaborators

  • The Ottawa Hospital

Registry information

Acronym: SPIRO-First

Important dates

Study start
2026
Primary completion
2028
Study completion
2028
First posted
Jul 7, 2026
Registry last updated
Jul 13, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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