Mineralocorticoid Receptor (MR) Antagonist (Eplerenone) vs Amlodipine and STRIATIN
- Conditions
- HypertensionGenetics Hypertension
- Interventions
- Registration Number
- NCT03683069
- Lead Sponsor
- Brigham and Women's Hospital
- Brief Summary
Salt sensitivity of blood pressure is a substantial risk factor for cardiovascular morbidity and mortality. Inappropriate increases in renal sodium reabsorption lead to volume expansion, hypertension and salt sensitive blood pressure. Key homeostatic mechanisms that regulate renal sodium reabsorption are: first, hormonal, e.g., renin-angiotensin-aldosterone system and second, vascular, e.g., renal vasculature. Dysfunction in one or both mechanisms leads to hypertension and salt sensitive blood pressure. The investigators recently documented that striatin plays a novel role in the development of salt sensitive blood pressure. However, the mechanisms that lead to striatin-mediated salt sensitive blood pressure are not clear; defining these mechanisms is the overall goal of this proposal.
Striatin is a calmodulin- and caveolin-binding protein that can function as either a scaffolding and/or signaling protein, specifically in relation to the mechanism of action of steroids. In a large study of well characterized subjects from the International Hypertensive Pathotype (HyperPATH) cohort, the investigators documented that hypertensive and normotensive humans who are striatin risk allele carriers have salt sensitive blood pressure.
The investigators then developed a striatin heterozygous knockout mouse as a tool to identify potential mechanisms for the salt sensitive blood pressure. The investigators documented that these mice also have salt sensitive blood pressure with higher blood pressure levels and inappropriately increased aldosterone levels on a liberal salt diet.
- Detailed Description
HYPOTHESIS:
Hypertensive striatin risk allele carriers will show significantly greater reductions in blood pressure with a specific aldosterone mediated treatment approach (mineralocorticoid receptor blockade) than with a non-specific approach (amlodipine).
PROTOCOL:
1. The screened, eligible hypertensives will enter a two to three-week single blind placebo washout phase. Pill count will be used to determine compliance. Those with blood pressure between 145-170/90-109 mmHg and pill count between 80-100% after two to three-weeks will enter the randomized phase and counseled regarding salt intake.
2. The first step: subjects will be fed a 10 mEq Na+, 100 mEq K+ calculated diet for 6 days. The meals will be provided by the CCI Dietary Core. On the 7th day, the subjects will come to the CCI Ambulatory Clinical Center. After remaining supine for 60-90 minutes, the subjects will have blood samples obtained for future analyses and their blood pressure measured using an automatic recording sphygmomanometer (Space Labs, Snoqualmie, WA). Readings will be obtained every 2 minutes for 20 minutes with the highest and lowest values discarded and the rest averaged. From the morning of the 6th to the morning of the 7th day, a 24-hr. urine will be collected for creatinine and sodium as a check on balance and stored for future analyses.
3. The second step: Subjects will be counseled regarding liberal salt dietary intake. Subjects will be given high salt broth packets, calcium tablets (as calcium bicarbonate), and potassium tablets (as potassium bicarbonate) to supplement their diet to ensure similar intakes in all subjects \[Na+ (200 mEq), potassium (K+, 100 mEq) and calcium (800 mg)\]. This or a greater level of Na+ intake was consumed by 60-70% of subjects before entering the HyperPATH protocol. On the morning of the 6th day the subject will begin a 24-hour blood pressure recording, using a blood pressure machine provided by study staff. After completion of this diet for 6 days, the subject will come to the Center for Clinical Investigation (CCI) Ambulatory Clinical Center and after remaining supine for 60-90 mins will have blood samples obtained for future analyses, and their BP measured using an automatic recording sphygmomanometer (Space Labs, Snoqualmie, WA). Readings will be obtained every 2 mins for 20 mins with the highest and lowest values discarded and the rest averaged. From the morning of the 6th to the morning of the 7th day, a 24-hr. urine will be collected for creatinine and Na+ as a check on balance and stored for future analyses. The BP data from 2) and 3) will allow us to calculate Salt Sensitivity of Blood Pressure (SSBP), an approach performed successfully more than 500 times in the HyperPATH cohort.
4. The hypertensive striatin risk carrier subjects will be randomized, double blinded to one of two primary treatment groups and titrated to effect every four weeks, as was previously reported (1, 2), eplerenone 50, 100 and 200 mg daily or amlodipine 2.5, 5 and 10 mg daily. Study duration will be sixteen weeks.
5. Participants will be randomized in blocks of four to 1 of 2 study drugs (amlodipine and eplerenone). The drug class assignment will remain the same throughout the study for each subject. The PI or Co-PI will notify The Brigham and Womens Hospital Investigational Drug Pharmacy Service to escalate or maintain current dose on each of the two visits. The Brigham and Womens Hospital Investigational Drug Pharmacy Service will be responsible for the randomization schema, recording of study drug assignment, and dispensing of prescriptions. All others (PI, Co-PI, research staff, subject) will be blinded as to drug assignment.
6. Home seated, morning cuff blood pressure and pulse will be obtained daily and monitored by study staff weekly as a safety check with the information provided to the study staff by email or phone. The blood pressure results from the 7 days prior to the next visit will be averaged, with the highest and lowest values discarded. This average blood pressure value will be used to determine if the drug dose will be titrated after the next visit If the subject has reached goal blood pressure (less than or equal to140/90 mmHg), then the subject is maintained on his/her current dose. If not, the subject's dose is up titrated as per protocol. A member of the research team will contact the subject if the blood pressure data are not received within 24-hr of the designated time. If the cuff blood pressure is greater than 170/109 mmHg on two consecutive occasions 24 hours apart, or the subject develops cardiovascular symptoms, the subject will be terminated from the study and re-started on medications used before the washout period. The subject's physician will be contacted.
7. Because eplerenone may increase Serum K+ levels, we will monitor its level monthly during the study. This will be obtained at the time of their monthly visit unless a dose increase is made at the time of the visit. Then, the Serum K+ will be obtain one week later. If Serum K+ is greater than 5.5 milliMolar (mM) on two consecutive occasions 24 hours apart, the subject will be terminated from the study. If unexpected adverse event is noted The Brigham and Women's Hospital Investigational Drug Pharmacy Service will be notified so as to break code and identify agent.
8. At the end of four weeks since randomization and the subjects have completed the first dose of the agent, the subject will be counseled regarding a 24-hour dietary intake of sodium (200 mEq), potassium (100 mEq) and calcium (800 mg). Subjects will receive supplementary high salt broth packets to ensure that they are reaching the target Na+ intake. After completion of this diet for 6 days, the subject returns to Center for Clinical Investigation - Ambulatory Clinical Center and after remaining supine for 60-90 minutes again will have blood samples obtained for future analyses and their blood pressure measured using an automatic recording sphygmomanometer. Readings will be obtained every 2 minutes for 20 minutes with the highest and lowest values discarded and the rest averaged. This measurement will be used to assess the blood pressure response to a single dose of each agent. From the morning of the 6th to the morning of the 7th day, a 24-hr. urine will be collected for creatinine and sodium as a check on balance and stored for future analyses.
9. Home seated, morning cuff blood pressure and pulse will be obtained daily and monitored by study staff weekly as a safety check with the information provided to the study staff by email or phone. The blood pressure results from the 7 days prior to the next visit will be averaged, with the highest and lowest values discarded. This average blood pressure value will be used to determine if the drug dose will be titrated after the next visit If the subject has reached goal blood pressure (less than or equal to140/90 mmHg), then the subject is maintained on his/her current dose. If not, the subject's dose is up titrated as per protocol. A member of the research team will contact the subject if the blood pressure data are not received within 24-hr of the designated time. If the cuff blood pressure is greater than 170/109 mmHg on two consecutive occasions 24 hours apart, or the subject develops cardiovascular symptoms, the subject will be terminated from the study and re-started on medications used before the washout period. The subject's physician will be contacted.
10. Because eplerenone may increase Serum K+ levels, we will monitor its level monthly during the study. This will be obtained at the time of their monthly visit unless a dose increase is made at the time of the visit. Then, the Serum K+ will be obtain one week later. If Serum K+ is greater than 5.5 mM on two consecutive occasions 24 hours apart, the subject will be terminated from the study. If unexpected adverse event is noted The Brigham and Women's Hospital Investigational Drug Pharmacy Service will be notified so as to break code and identify agent.
11. At the end of eight weeks since randomization and the subjects have completed the second dose of the agent, the subject will be counseled regarding a 24-hour dietary intake of sodium (200 mEq), potassium (100 mEq) and calcium (800 mg). Subjects will receive supplementary high salt broth packets to ensure that they are reaching the target Na+ intake. After completion of this diet for 6 days, the subject returns to Center for Clinical Investigation - Ambulatory Clinical Center and after remaining supine for 60-90 minutes again will have blood samples obtained for future analyses and will have their blood pressure measured using an automatic recording sphygmomanometer. Readings will be obtained every 2 minutes for 20 minutes with the highest and lowest values discarded and the rest averaged. From the morning of the 6th to the morning of the 7th day, a 24-hr. urine will be collected for creatinine and sodium as a check on balance and stored for future analyses.
12. Home seated, morning cuff blood pressure and pulse will be obtained daily and monitored by study staff weekly as a safety check with the information provided to the study staff by email or phone. A member of the research team will contact the subject if the blood pressure data are not received within 24-hr of the designated time. If the cuff blood pressure is greater than 170/109 mmHg on two consecutive occasions 24 hours apart, or the subject develops cardiovascular symptoms, the subject will be terminated from the study and re-started on medications used before the washout period. The subject's physician will be contacted.
13. Because eplerenone may increase Serum K+ levels, we will monitor its level monthly during the study. This will be obtained at the time of their monthly visit unless a dose increase is made at the time of the visit. Then, the Serum K+ will be obtain one week later. If Serum K+ is greater than 5.5 mM on two consecutive occasions 24 hours apart, the subject will be terminated from the study. If unexpected adverse event is noted The Brigham and Women's Hospital Investigational Drug Pharmacy Service will be notified so as to break code and identify agent.
14. At the end of the study, twelve weeks after randomization, subjects will be counseled regarding liberal salt dietary intake. Subjects will be given high salt broth packets, calcium tablets (as calcium bicarbonate), and potassium tablets (as potassium bicarbonate) to supplement their diet to ensure similar intakes in all subjects \[Na+ (200 mEq), potassium (K+, 100 mEq) and calcium (800 mg)\]. This or a greater level of Na+ intake was consumed by 60-70% of subjects before entering the HyperPATH protocol. On the morning of the 6th day the subject will begin a 24-hour blood pressure recording, using a blood pressure machine provided by study staff. After completion of this diet for 6 days, the subject will come to the Center for Clinical Investigation (CCI) Ambulatory Clinical Center and after remaining supine for 60-90 mins will have blood samples obtained for future analyses, and their BP measured using an automatic recording sphygmomanometer (Space Labs, Snoqualmie, WA). Readings will be obtained every 2 mins for 20 mins with the highest and lowest values discarded and the rest averaged. From the morning of the 6th to the morning of the 7th day, a 24-hr. urine will be collected for creatinine and Na+ as a check on balance and stored for future analyses.
15. The subject then will have completed the study and will be re-started on medications used before the washout period. The subject's physician will be contacted.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 90
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Eplerenone Arm Eplerenone vs Amlodipine antihypertensive eplerenone Amlodipine Arm Eplerenone vs Amlodipine antihypertensive amlodipine
- Primary Outcome Measures
Name Time Method Systolic /Diastolic Supine Morning Liberal Salt Automated Blood Pressure Change in blood pressure between visit 2 (baseline), visit 3 (four weeks), visit 4 (8 weeks), visit 5 (12 weeks) of randomized drug therapy Subjects will be counseled regarding liberal salt dietary intake to ensure similar intakes in all subjects \[Na+ (200 mEq), potassium (K+, 100 mEq) and calcium (800 mg)\]. This or a greater level of Na+ intake was consumed by 60-70% of subjects before entering the International Hypertensive Pathotype (HyperPATH) protocol. After completion of this diet for 7 days, the subject will come to the Center for Clinical Investigation (CCI) Ambulatory Clinical Center between 7-8 morning (AM), fasting, and after remaining supine for 60-90 mins will have blood samples obtained for future analyses, and their BP measured using an automatic recording sphygmomanometer. Readings will be obtained every 2 mins for 20 mins with the highest and lowest values discarded and the rest averaged. From the morning of the 6th to the morning of the 7th day, a 24hr. urine will be collected for creatinine and Na+ as a check on balance and stored for future analyses. Procedure will be performed before randomization and
Systolic/Diastolic Blood Pressure Visit 2, 3, 4, 5 Eplerenone vs Amlodipine Change in blood pressure between eplerenone and amlodipine at visit 2 (baseline), visit 3 (four weeks), visit 4 (8 weeks), visit 5 (12 weeks) of randomized drug therapy First step: subjects will ingest a liberal salt intake \[Na+ (200 mEq/day)\] for 7 days. The subject will come to the study unit between 7-8 AM, fasting. After remaining supine for 60-90 mins, their BP will be measured using an automatic recording sphygmomanometer. Readings will be obtained every 2 mins for 20 mins with the highest and lowest values discarded and the rest averaged. From the morning of the 6th to the morning of the 7th day, a 24-hr. urine will be collected for creatinine and Na+ as a check on balance and stored for future analyses. Second step: subjects will then be fed a restricted salt diet (10 mEq Na+/day) for 7 days. On the morning of the 7th day, the subjects will come fasting to the study unit between 7-8 AM, and the studies performed as detailed above. The BP data from the two diet studies will allow us to calculate SSBP. The procedures will be performed before randomization and at the completion of 12 weeks of therapy.
- Secondary Outcome Measures
Name Time Method 24 hr bp total 24 hour, daytime and night Change in blood pressure between visit 2 (baseline) and visit 5 (12 weeks) of randomized drug therapy For this measurement, we used a separate set of data - continuous monitoring of blood pressure. These blood pressure measurements are different than those reported in the Primary Outcomes section. The Secondary Outcomes are continuous 24-hour blood pressures, measured twice. The 24 hour assessment was divided into 3 sections: total 24-hour, daytime and night; Change in blood pressure between visit 2 (baseline) and visit 5 (12 weeks) of randomized drug therapy
Trial Locations
- Locations (1)
Brigham and Women's Hospital
🇺🇸Boston, Massachusetts, United States