A Phase 2 interventional study of Eplerenone and Amlodipine in Hypertension, sponsored by University of Texas Southwestern Medical Center. Completed at 1 site in United States. Open to participants aged 18 Years and older, including healthy volunteers. Per ClinicalTrials.gov, last updated 2022-03-18.
Sponsored by University of Texas Southwestern Medical Center · Phase 2, Interventional, and Basic science
Hypertensive patients often show an exaggerated rise in blood pressure during exercise through overactivity of the exercise pressor reflex. An increasing body of evidence suggests a role for aldosterone in augmenting the exercise pressor reflex in hypertensive humans. We hypothesize that this effect of aldosterone is mediated by its direct action on the central nervous system and that administration of mineralocorticoid receptor antagonists constitute an effective treatment for EPR overactivity in hypertension, independent of reductions in resting BP.
Hypertensive patients are known to display exaggerated rise in blood pressure (BP) during exercise but the underlying mechanisms are poorly understood.
Traditionally, muscle afferents were dichotomized as metaboreceptors, which are activated slowly and only during intense or ischemic muscle contraction, or mechanoreceptors, which respond quickly to even mild deformation of their receptive fields. The increase in sympathetic nerve activity and BP caused by activation of these receptors, known as exercise pressor reflex, is normally buffered by activation arterial baroreceptors, which are reset to operate at higher BP range but at the same level of sensitivity. Mechanisms responsible for overactive exercise pressor reflex in hypertension remain unknown, but an increasing body of evidence suggested a role for aldosterone in regulating resting central sympathetic outflow in both hypertensive rats and humans.
Experiments will be performed on 3 groups of subjects 1) stage I (140-159/90-99 mmHg) subjects with essential hypertension, 2) stage I hypertensive subjects with Primary Aldosteronism (PA), and 3) normotensive controls. All participants will attend a baseline study visit, which will include a physical examination, a medical history review, vital sign measurements, and blood and urine collection. Small electrodes will be used to measure muscle nerve activity while the subjects perform a series of exercises that include passive arm cycling, active arm cycling, rhythmic hand grip, sustained hand grip and cold pressor test. Muscle blood flow will be measured before and after hand grip exercises.
A subgroup of subjects with essential hypertension and PA will be assigned to receive Eplerenone or Amlodipine on a randomized, double-blinded design. Participants will attend two weeks visits over a period of 16 weeks. Study visits include measurement of vital signs and blood samples collection. After completing 8 weeks on each medication, muscle nerve activity will be measured while performing the same exercises described in the baseline study visit.
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This study's enrollment of 14 is below the median of 90 across 4,995 interventional studies indexed under Hypertension.
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Of its 135 completed or terminated interventional studies of FDA-regulated products, 100 (74%) have results posted.
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Exclusion Criteria:
The subject will be started on Amlodipine 2.5-10 mg daily, which he or she will continue for a period of 12 weeks. Following the 12-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued. The subject will be started on Eplerenone 50 - 200 mg daily, which he or she will continue for a period of 8 weeks. Following the 8 week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued.
Drug: Eplerenone · Drug: Amlodipine · Procedure: Microneurography · Procedure: Rhythmic handgrip exercise · Procedure: Sustained hand grip · Procedure: Forearm blood flow · Procedure: Arm cycling exercise · Procedure: Cold Pressor test
The subject will be started on Eplerenone 50 - 200 mg daily, which he or she will continue for a period of 12 weeks. Following the 12-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued. The subject will be started on Amlodipine 2.5-10 mg daily, which he or she will continue for a period of 8 weeks. Following the 8 week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued.
Drug: Eplerenone · Drug: Amlodipine · Procedure: Microneurography · Procedure: Rhythmic handgrip exercise · Procedure: Sustained hand grip · Procedure: Forearm blood flow · Procedure: Arm cycling exercise · Procedure: Cold Pressor test
The subject will be started on Eplerenone (Inspra) 50-200mg daily, which he or she will continue for a period of 8 weeks. Following the 8-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued
Also known as: Inspra
The subject will be started on Amlodipine (Norvasc) 2.5 -10mg daily, which he or she will continue for a period of 8 weeks. Following the 8-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued.
Also known as: Norvasc
Investigators will measure sympathetic nerve activity from the peroneal nerve by inserting a tiny needle directly into the nerve in the leg. Investigators will localize the nerve by electrical stimulation over the skin using a blunt probe. With this stimulation, subject will notice either involuntary twitching or a tingling sensation, which may be annoying but not painful. Investigators will then introduce a tiny, sterile wire needle (an electrode) through the skin at the same location. When the tip of the needle enters the nerve, subjects may again notice involuntary muscle twitches or tingling in the leg. Investigators will then turn the electrical stimulator off and make minor adjustments in the position of the needle until investigators begin to record the nerve signals. The recording needle will remain in position throughout the study.
Also known as: Assessment of sympathetic nerve activity (SNA)
Subjects will perform a rhythmic handgrip exercise at 30% or 45% of maximal voluntary contraction for 3 minutes. Investigators will measure cardiac output (non-invasive impedance plethysmography), blood pressure, and sympathetic nerve activity (SNA) at baseline and following this handgrip exercise
Subjects will perform a sustained handgrip exercise at 30% of maximal voluntary contraction for 3 minutes. Investigators will measure cardiac output (non-invasive impedance plethysmography), blood pressure, and sympathetic nerve activity (SNA) at baseline and following this handgrip exercise.
Using high-resolution ultrasound, investigators will measure skeletal muscle blood flow in the forearm at rest, following sustained handgrip exercise
Subjects will perform a cycling arm exercise with a stationary cycling device. Investigators will measure cardiac output (non-invasive impedance plethysmography), blood pressure, and sympathetic nerve activity (SNA) at baseline and following this exercise.
Subjects will place hand in cold water with ice for 3 minutes. Investigators will measure cardiac output (non-invasive impedance plethysmography), blood pressure, and sympathetic nerve activity (SNA) at baseline, during and 2 minutes after the test.
Muscle Sympathetic Nerve Activity at Rest
measurement of sympathetic nerve activity by microneurography (intraneural microelectrodes)
Time frame: 8 weeks post treatment initiation
Muscle Sympathetic Nerve Activity During Exercise
measurement of sympathetic nerve activity by microneurography (intraneural microelectrodes) during arm cycling exercise
Time frame: 8 weeks post treatment initiation
| Milestone | Amlodipine Then Eplerenone | Eplerenone Then Amlodipine |
|---|---|---|
| Started | 6 | 8 |
| Completed | 6 | 8 |
| Not completed | 0 | 0 |
| Milestone | Amlodipine Then Eplerenone | Eplerenone Then Amlodipine |
|---|---|---|
| Started | 6 | 8 |
| Completed | 6 | 8 |
| Not completed | 0 | 0 |
measurement of sympathetic nerve activity by microneurography (intraneural microelectrodes)
| bursts/minute | Amlodipine | Eplerenone |
|---|---|---|
| Muscle Sympathetic Nerve Activity at Rest | 41 ± 11.7 | 43.8 ± 13 |
measurement of sympathetic nerve activity by microneurography (intraneural microelectrodes) during arm cycling exercise
| bursts/minute | Amlodipine | Eplerenone |
|---|---|---|
| Muscle Sympathetic Nerve Activity During Exercise | 47 ± 16 | 51 ± 18 |
Collected over 8 weeks. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Amlodipine | 0/14 (0%) | 0/14 (0%) | 0/14 (0%) |
| Eplerenone | 0/14 (0%) | 0/14 (0%) | 0/14 (0%) |
| Age, Continuous(years) | Amlodipine Then Eplerenone | Eplerenone Then Amlodipine | Total |
|---|---|---|---|
| Mean | 53 ± 9 | 50 ± 8 | 51 ± 9 |
| Sex: Female, Male(Participants) | Amlodipine Then Eplerenone | Eplerenone Then Amlodipine | Total |
|---|---|---|---|
| Female | 0 | 3 | 3 |
| Male | 6 | 5 | 11 |
| Race (NIH/OMB)(Participants) | Amlodipine Then Eplerenone | Eplerenone Then Amlodipine | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 1 | 4 | 5 |
| White | 5 | 4 | 9 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Region of Enrollment(participants) | Amlodipine Then Eplerenone | Eplerenone Then Amlodipine | Total |
|---|---|---|---|
| United States | 6 | 8 | 14 |
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University of Texas Southwestern Medical Center