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

Overview

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.

Interventions

• Drug Spironolactone (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.
• Drug Candesartan 8mg
  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
• Drug Hydrochlorothiazide (HCTZ) 25 milligrams.
  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
• Drug Amlodipine (5mg)
  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

Primary outcome measures

• PRIMARY OUTCOME: Recruitment Rate of Randomized Participants per Month [Time frame: 12 months following activation of all participating study sites]

Secondary outcome measures (12)

• SECONDARY OUTCOME #1: Number of Potentially Eligible Participants Identified [Time frame: 12 months]
• SECONDARY OUTCOME #2: Eligibility Rate [Time frame: 12 months]
• SECONDARY OUTCOME #3: Recruitment Acceptance Rate [Time frame: 12 months]
• SECONDARY OUTCOME #4: Prevalence of Suppressed Renin Physiology [Time frame: 12 months]
• SECONDARY OUTCOME #5: Antihypertensive Washout Completion Rate [Time frame: 12 months]
• SECONDARY OUTCOME #6: Ambulatory Blood Pressure Monitoring Completion Rate [Time frame: 12 weeks]
• SECONDARY OUTCOME #7: Protocol Adherence Rate [Time frame: 12 weeks]
• SECONDARY OUTCOME #8: Study Completion Rate [Time frame: 12 weeks]
• SECONDARY OUTCOME #9: Reasons for Non-participation, Treatment Discontinuation, and Study Withdrawal [Time frame: 12 months]
• SECONDARY OUTCOME #10: Data Completeness [Time frame: 12 weeks]
• SECONDARY OUTCOME #11: Primary Care Clinician Satisfaction With Patient Participation [Time frame: end of study (at 12 months)]
• SECONDARY OUTCOME #12: Primary Care Clinician Satisfaction With Study Communication [Time frame: end of study (at 12 months)]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Canada · 3 centers

• The Ottawa Hospital — Ottawa
• Ottawa Nurse Practitioner-Led Clinic — Ottawa
• St-Isidore Médical — Saint Isidore

Identifiers

NCT: NCT07687160 · 7198

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗