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| Name | Class |
|---|---|
| The Ottawa Hospital | OTHER |
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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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Spironolactone | Experimental | Spironolactone 25 mg daily |
|
| Standard first-line antihypertensive therapy | Active Comparator | Participants randomized to standard therapy will undergo secondary randomization to candesartan (8 mg daily), hydrochlorothiazide (25 mg daily), or amlodipine (5 mg daily) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| PRIMARY OUTCOME: Recruitment Rate of Randomized Participants per Month | 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. | 12 months following activation of all participating study sites |
| Measure | Description | Time Frame |
|---|---|---|
| SECONDARY OUTCOME #1: Number of Potentially Eligible Participants Identified | Number of potentially eligible participants identified by participating primary care clinicians and referred for study screening. | 12 months |
| SECONDARY OUTCOME #2: Eligibility Rate |
| Measure | Description | Time Frame |
|---|---|---|
| Exploratory Outcome #1 (Blood pressure outcomes): Change in Mean Daytime Systolic Blood Pressure | Change in mean daytime systolic blood pressure measured by ambulatory blood pressure monitoring (ABPM) from baseline to Week 12. | Baseline to Week 12 |
| Exploratory Outcome #2 (Blood pressure outcomes): Change in Mean Daytime Diastolic Blood Pressure |
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:
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:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Gregory L Hundemer, MD | Contact | (613) 738-8400 | 81885 | ghundemer@toh.ca |
| Deena Fremont, MSc | Contact | dfremont@ohri.ca |
| Name | Affiliation | Role |
|---|---|---|
| Sharon Johnston, MD | Institut du Savoir Montfort | Principal Investigator |
| Gregory L Hundemer, MD | The Ottawa Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Ottawa Hospital | Ottawa | Ontario | K1H 7W9 | Canada |
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Pragmatic open-label pilot trial conducted in community primary care clinics
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|
| 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. |
|
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. |
| 12 months |
| SECONDARY OUTCOME #3: Recruitment Acceptance Rate | 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. | 12 months |
| SECONDARY OUTCOME #4: Prevalence of Suppressed Renin Physiology | Proportion of screened participants with suppressed renin physiology, defined as a direct renin concentration <6 ng/L (<10 mU/L). | 12 months |
| SECONDARY OUTCOME #5: Antihypertensive Washout Completion Rate | Proportion of participants for whom the protocol-specified antihypertensive washout procedures are successfully completed when applicable | 12 months |
| SECONDARY OUTCOME #6: Ambulatory Blood Pressure Monitoring Completion Rate | Proportion of randomized participants who successfully complete ambulatory blood pressure monitoring (ABPM) according to the study protocol. | 12 weeks |
| SECONDARY OUTCOME #7: Protocol Adherence Rate | Proportion of randomized participants completing assigned study treatment and the Week 12 outcome assessment procedures according to the study protocol. | 12 weeks |
| SECONDARY OUTCOME #8: Study Completion Rate | Proportion of randomized participants completing the Week 12 end-of-study assessment. | 12 weeks |
| SECONDARY OUTCOME #9: Reasons for Non-participation, Treatment Discontinuation, and Study Withdrawal | Frequency and categorized reasons for declining participation, treatment discontinuation, and withdrawal from the study. | 12 months |
| SECONDARY OUTCOME #10: Data Completeness | Proportion of required study data fields completed without missing or invalid values. | 12 weeks |
| SECONDARY OUTCOME #11: Primary Care Clinician Satisfaction With Patient Participation | Primary care clinician satisfaction with their patients' participation in the study, assessed using a post-study questionnaire. | end of study (at 12 months) |
| SECONDARY OUTCOME #12: Primary Care Clinician Satisfaction With Study Communication | Primary care clinician satisfaction regarding communication on participant progress and handover of care following study completion, assessed using a post-study questionnaire. | end of study (at 12 months) |
| SECONDARY OUTCOME #13: Primary Care Clinician Engagement | Proportion of participating primary care clinicians who continue referring potentially eligible participants throughout the study period. | 12 months |
Change in mean daytime diastolic blood pressure measured by ambulatory blood pressure monitoring (ABPM) from baseline to Week 12. |
| Baseline to Week 12 |
| Exploratory Outcome 3 (Blood pressure outcomes): Change in Mean 24-Hour Systolic Blood Pressure | Change in mean 24-hour systolic blood pressure measured by ambulatory blood pressure monitoring (ABPM) from baseline to Week 12. | Baseline to Week 12 |
| Exploratory Outcome 4 (Blood pressure outcomes): Change in Mean 24-Hour Diastolic Blood Pressure | Change in mean 24-hour diastolic blood pressure measured by ambulatory blood pressure monitoring (ABPM) from baseline to Week 12. | Baseline to Week 12 |
| Exploratory Outcome 5 (Blood pressure outcomes): Change in Standardized Office Systolic Blood Pressure | Change in standardized office systolic blood pressure from baseline to Week 12. | Baseline to Week 12 |
| Exploratory Outcome 6 (Blood pressure outcomes): Change in Standardized Office Diastolic Blood Pressure | Change in standardized office diastolic blood pressure from baseline to Week 12 | Baseline to Week 12 |
| Exploratory Outcome 7 (Hypertension Control): Participants Achieving Daytime Ambulatory Blood Pressure Control | Proportion of participants achieving a mean daytime ambulatory systolic blood pressure <130 mmHg at Week 12 | Week 12 |
| Exploratory Outcome 8 (Hypertension Control): Participants Achieving Standardized Office Blood Pressure Control | Proportion of participants achieving a standardized office systolic blood pressure <130 mmHg at Week 12 | Week 12 |
| Exploratory Mechanistic Outcome #1: Change in Direct Renin Concentration | Change in direct renin concentration (ng/L) from baseline to Week 12 | Baseline to Week 12 |
| Exploratory Mechanistic Outcome #2: Renin Unsuppression | Proportion of participants achieving renin unsuppression, defined as a direct renin concentration ≥6 ng/L (≥10 ng?L), at Week 12. | week 12 |
| Exploratory Mechanistic Outcome #3: Increase in Direct Renin Concentration | Proportion of participants demonstrating any increase in direct renin concentration from baseline to Week 12. | Baseline to week 12 |
| Exploratory Mechanistic Outcome #4: Association Between Renin Response and Blood Pressure Response | 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 | Baseline to Week 12 |
| Safety Outcome #1: Symptomatic Hypotension | Proportion of participants experiencing symptomatic hypotension, including orthostatic symptoms, lightheadedness, injurious falls, or syncope. | Baseline to Week 12 |
| Safety Outcome #2: Hyperkalemia | Proportion of participants with serum potassium >5.5 mmol/L | Baseline to Week 12 |
| Safety Outcome #3: Hypokalemia | Proportion of participants with serum potassium <3.5 mmol/L. | Baseline to Week 12 |
| Safety Outcome #4: Change in Serum Potassium Concentration | Change in serum potassium concentration from baseline to Week 12 | Baseline to Week 12 |
| Safety Outcome #5: ≥40% Decline in Estimated Glomerular Filtration Rate | Proportion of participants experiencing a ≥40% decline in estimated glomerular filtration rate (eGFR) from baseline. | Baseline to Week 12 |
| Safety Outcome #6: Dialysis Initiation | Proportion of participants initiating dialysis during the study period | Baseline to Week 12 |
| Safety Outcome #7: Hyponatremia | Proportion of participants with serum sodium <135 mmol/L. | Baseline to Week 12 |
| Safety Outcome #8: Gynecomastia | Proportion of participants developing gynecomastia during the study period | Baseline to Week 12 |
| Safety Outcome #9: Medication Discontinuation Due to Adverse Events | Proportion of participants requiring medication discontinuation, dose reduction, or switching because of adverse events | Baseline to Week 12 |
| Safety Outcome #10: Major Adverse Cardiovascular Events | Proportion of participants experiencing myocardial infarction, stroke, heart failure hospitalization, peripheral arterial revascularization, or cardiovascular death | Baseline to Week 12 |
| Safety Outcome #11: All-Cause Hospitalization | Proportion of participants hospitalized for any cause. | Baseline to week 12 |
| Safety Outcome #12: All-Cause Mortality | Proportion of participants who die from any cause during the study period | Baseline to Week 12 |
| Ottawa Nurse Practitioner-Led Clinic | Ottawa | Ontario | K1L 8L8 | Canada |
|
| St-Isidore Médical | Saint Isidore | Ontario | K0C 2B0 | Canada |
|
| ID | Term |
|---|---|
| D006973 | Hypertension |
| D006929 | Hyperaldosteronism |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D000308 | Adrenocortical Hyperfunction |
| D000307 | Adrenal Gland Diseases |
| D004700 | Endocrine System Diseases |
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| ID | Term |
|---|---|
| D013148 | Spironolactone |
| D004364 | Pharmaceutical Preparations |
| C081643 | candesartan |
| D006852 | Hydrochlorothiazide |
| D017311 | Amlodipine |
| ID | Term |
|---|---|
| D007783 | Lactones |
| D009930 | Organic Chemicals |
| D011283 | Pregnenes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D002740 | Chlorothiazide |
| D001581 | Benzothiadiazines |
| D013449 | Sulfonamides |
| D013450 | Sulfones |
| D013457 | Sulfur Compounds |
| D049971 | Thiazides |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D004095 | Dihydropyridines |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
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