Mechanism of Masked Hypertension - Intervention

Study Overview
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Brief Summary
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To test the hypothesis that sympatholytic antihypertensive antihypertensive therapy (αβ-blocker - carvedilol) will reduce out-of-clinic ambulatory BP to a greater extent by blocking sympathetic activity than non-sympatholytic antihypertensive medication (dihydropyridine calcium channel blocker - amlodipine) in individuals with masked hypertension.

Detailed Description
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A. Participants. Study participants with masked hypertension (MH) with controlled clinic BP (< 130/80 mmHg) and uncontrolled out-of-clinic awake ambulatory BP (ABP ≥ 130/80 mmHg) untreated with antihypertensive medications will be recruited. B. Study design. This is a double-blinded, randomized, 2-period, 2-treatment crossover clinical trial comparing sympatholytic antihypertensive agent (αβ-blocker - carvedilol 40mg extended release once daily) with non-sympatholytic control agent (dihydropyridine calcium channel blocker - amlodipine 10mg once daily) in individuals with MH. All study participants will undergo out-of-clinic 24hr ABP with actigraphy monitoring for 24-hr, awake and asleep ABP; sympathetic activity assessment by BP and HR variability, 24-hour urinary catecholamines and metanephrines at baseline and after intervention. In order to avoid selection bias, patients will be randomized to their initial therapy. Patients and study personnel will be blinded to the treatment group in order to minimize information bias. An investigator without direct study involvement will be assigned the task of ensuring correct dispensing of the study medication, which will be prepared as matching capsules by the UAB Pharmacy - Investigational Drug Service. After 4 weeks of initial treatment, both treatment groups will undergo a 1-month washout where no study medication is given in order to prevent a carryover effect. The study medication will be taken in the morning between 6 and 9 am except for study visit days. A crossover design is chosen to minimize differences between study groups, as participants will act as their own controls. Electrolytes, kidney function and ECG will be monitored at each visit. Medication adherence will be determined at visit 2 (week 4) and visit 4 (week 12) by measuring 24-hr urinary specimens for medications and their metabolites by LC-MS/MS and by pill count and medication log. C. Outcomes. The primary outcome is the difference in percent change in out-of-clinic mean 24-hr ABP, awake ABP and asleep ABP with carvedilol compared to amlodipine. Secondary outcomes include change in out-of-clinic sympathetic activity by BP and HR variability; and 24-hour urinary catecholamines and metanephrines. D. Preliminary / anticipated results. We anticipate a greater reduction in out-of-clinic 24-hr, awake and asleep ABP due to blocking of sympathetic activity with carvedilol when compared to amlodipine use in individuals with MH. A statistically significant effect estimate will support our hypothesis that higher sympathetic activity contributes to MH, which can be managed by use of sympatholytic agents like carvedilol.

Official Title
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Mechanism of Masked Hypertension - Intervention

Conditions
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Masked Hypertension

Intervention / Treatment
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* Drug: Carvedilol
* Drug: Amlodipine


Participation Criteria
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Eligibility Criteria
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Study participants with masked hypertension i.e. controlled clinic blood pressure (BP) and uncontrolled out-of-clinic awake ambulatory BP will be enrolled. A. Inclusion criteria. Adults (18-75 years of age) Controlled clinic BP (< 130/80 mmHg) untreated with antihypertensive medications Uncontrolled awake ambulatory BP (≥ 130/80 mmHg) untreated with antihypertensive medications B. Exclusion criteria. Hypertensive (Clinic BP ≥ 130/80 mmHg) Hypotensive (Clinic BP < 90/70 mmHg) Bradycardic (Heart rate < 60 beats/minute) Heart block Use of an antihypertensive medication within the last 3 months Use of an steroid containing medications within the last 3 months Body mass index ≥ 30 Kg/m2 Chronic kidney disease (Estimated GFR < 60 mL/min/1.73m2) Primary aldosteronism Renal artery stenosis Pheochromocytoma Diabetes mellitus Pregnant women Breast feeding women Dementia and/or cognitive impairment prohibiting consent History of stroke within the past 6 months History of unstable angina within the past 6 months History of myocardial infarction within the past 6 months Allergy or intolerance to β-blockers Allergy or intolerance to calcium channel blockers

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carvedilol 40mg Extended Release Once Daily<br>participants will be randomized to carvedilol 40 mg extended release once daily for the 1st or 2nd 4 week treatment period | Drug: Carvedilol<br>* Carvedilol 40mg Extended Release Once Daily<br>|
| Active Comparator: Amlodipine 10mg Once Daily<br>participants will be randomized to amlodipine 10 mg once daily for the 1st or 2nd 4 week treatment period | Drug: Amlodipine<br>* Amlodipine 10mg Once Daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Out of clinic 24 hour ambulatory blood pressure | Difference in percent change in out-of-clinic mean 24-hr ambulatory BP in mmHg with carvedilol compared to amlodipine. | 4 weeks | 
| Out of clinic awake blood pressure | Difference in percent change in out-of-clinic mean awake ambulatory BP in mmHg with carvedilol compared to amlodipine. | 4 weeks | 
| Out of clinic asleep blood pressure | Difference in percent change in out-of-clinic mean asleep ambulatory BP in mmHg with carvedilol compared to amlodipine. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Out of clinic blood pressure variability | Change in out-of-clinic sympathetic activity by BP variability in mmHg with carvedilol compared to amlodipine. | 4 weeks | 
| Out of clinic heart rate variability | Change in out-of-clinic sympathetic activity by HR variability in beats/minute with carvedilol compared to amlodipine. | 4 weeks | 
| Out of clinic 24-hour urinary catecholamines | Change in out-of-clinic sympathetic activity by 24-hour urinary catecholamines levels with carvedilol compared to amlodipine. | 4 weeks | 
| Out of clinic 24-hour urinary metanephrines | Change in out-of-clinic sympathetic activity by 24-hour urinary metanephrines levels with carvedilol compared to amlodipine. | 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Masked Hypertension, Sympathetic Activity, Sympatholytic Therapy