Mineralocorticoid Receptor (MR) Antagonist (Eplerenone) vs Amlodipine and STRIATIN

NCT03683069 | Completed Phase 4 Results FDA Drug

• 2 other identifiers: 2018P001888R01HL144779
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

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.

Conditions

Hypertension; Genetics Hypertension

Outcome Measures

Primary Outcomes (2)

• Systolic /Diastolic Supine Morning Liberal Salt Automated Blood Pressure

  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

  Change in blood pressure between visit 2 (baseline), visit 3 (four weeks), visit 4 (8 weeks), visit 5 (12 weeks) of randomized drug therapy

• Systolic/Diastolic Blood Pressure Visit 2, 3, 4, 5 Eplerenone vs Amlodipine

  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.

  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

Secondary Outcomes (1)

• 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

Other Outcomes (1)

• The Percent of Individuals Who Achieved Goal Blood Pressure (e.g., <140/90 mmHg) at Each Time

  Those who achieved goal blood pressure at weeks 0 (visit 2), 4 (Visit 3), 8 Visit 4), 12 (Visit 5), and Number that did not achieve goal BP at Visit 5 (week 12). of randomized drug therapy

Study Arms (2)

Eplerenone Arm

EXPERIMENTAL

antihypertensive eplerenone

Drug: Eplerenone vs Amlodipine

Amlodipine Arm

EXPERIMENTAL

antihypertensive amlodipine

Drug: Eplerenone vs Amlodipine

Interventions

Eplerenone vs Amlodipine DRUG

We posit that decreases in striatin activity/levels increases aldosterone secretion resulting in hypertension and salt sensitive blood pressure. Thus, our mechanistic clinical study will assess whether 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). To test this hypothesis, we will perform a randomized, double-blind, active controlled study in hypertensive carriers of the striatin risk allele using a novel two-limb, proof-of-principle study. Our primary outcome will be a liberal salt diet systolic blood pressure with a secondary outcome of salt sensitive blood pressure. Therefore, this mechanistic trial will provide support for using a genetic marker that identifies individuals who are uniquely responsive to mineralocorticoid receptor blockade--personalized, precision medicine.

Amlodipine Arm; Eplerenone Arm

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• We reported in our studies using the HyperPATH cohort that there was no racial, age or ethnic differences in the salt sensitive blood pressure responses related to Striatin allele variants. Thus, an equal number of females and males and the same proportion of Africans as in the HyperPATH cohort will be studied. Subjects in HyperPATH and those recruited for the new study in this project will have the similar characteristics. The range in age is \>17; however, it is anticipated that the clear majority will be between the ages of 40 and 60 years.
• Hypertensive patients previously treated will be weaned off medications for two-four weeks except agents that interfere with the renin-angiotensin-aldosterone system (RAAS) are stopped for three months and amlodipine and/or hydrochlorothiazide is added if necessary for blood pressure control until one month before study initiation. Thus, these subjects will match the characteristics of subjects recruited in HyperPATH. They must have a diastolic blood pressure between 95 and 105 mm Hg off medication in each of three screening visits. Subjects with diastolic blood pressures greater than 105 mm Hg or systolic blood pressures greater than 180 mm Hg will be excluded. Subjects with only elevated systolic blood pressure (but diastolic less than 95 mm Hg) will be excluded because such subjects were not in the HyperPATH cohort.
• The screened, eligible hypertensives will enter a two-week single blind placebo washout phase. Pill count will be used to determine compliance. Those with BP between 145-170/90-109 mmHg and pill count between 80-100% will enter the randomized phase, counseled regarding salt intake, and randomized double blindly into one of our two treatment arms. We will recruit approximately 105 individuals to have 45 individuals in each drug group for analyses. This assumes that we will have 10-15% non-completers.
• Striatin SNP rs2540923 allele carrier OR both Striatin SNP rs888083 and Striatin SNP rs6744560 risk allele carrier
• ages \>17 years;
• hypertension as defined by primary physician;
• not on more than two anti-hypertensives;
• normal renal, metabolic, electrolyte, complete blood cell count, and lipid profile laboratory tests;
• if on an angiotensin converting enzyme inhibitor, angiotensin receptor blocker or mineralocorticoid receptor antagonist, needs to be washed out for 3 months.

You may not qualify if:

• known cardiac disease other than hypertension
• renal, circulatory or neurologic diseases
• diabetes; smoking
• secondary hypertension as indicated by history, physical examination or screening blood and urine tests; any drug therapy, except for anti-hypertensives and replacement thyroid medication.

Sponsors & Collaborators

• Brigham and Women's Hospital: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Related Publications (17)

• Coutinho P, Vega C, Pojoga LH, Rivera A, Prado GN, Yao TM, Adler G, Torres-Grajales M, Maldonado ER, Ramos-Rivera A, Williams JS, Williams G, Romero JR. Aldosterone's rapid, nongenomic effects are mediated by striatin: a modulator of aldosterone's effect on estrogen action. Endocrinology. 2014 Jun;155(6):2233-43. doi: 10.1210/en.2013-1834. Epub 2014 Mar 21.

  PMID: 24654783 RESULT

• Garza AE, Rariy CM, Sun B, Williams J, Lasky-Su J, Baudrand R, Yao T, Moize B, Hafiz WM, Romero JR, Adler GK, Ferri C, Hopkins PN, Pojoga LH, Williams GH. Variants in striatin gene are associated with salt-sensitive blood pressure in mice and humans. Hypertension. 2015 Jan;65(1):211-217. doi: 10.1161/HYPERTENSIONAHA.114.04233. Epub 2014 Nov 3.

  PMID: 25368024 RESULT

• Pojoga LH, Coutinho P, Rivera A, Yao TM, Maldonado ER, Youte R, Adler GK, Williams J, Turchin A, Williams GH, Romero JR. Activation of the mineralocorticoid receptor increases striatin levels. Am J Hypertens. 2012 Feb;25(2):243-9. doi: 10.1038/ajh.2011.197. Epub 2011 Nov 17.

  PMID: 22089104 RESULT

• Garza AE, Pojoga LH, Moize B, Hafiz WM, Opsasnick LA, Siddiqui WT, Horenstein M, Adler GK, Williams GH, Khalil RA. Critical Role of Striatin in Blood Pressure and Vascular Responses to Dietary Sodium Intake. Hypertension. 2015 Sep;66(3):674-80. doi: 10.1161/HYPERTENSIONAHA.115.05600. Epub 2015 Jul 13.

  PMID: 26169051 RESULT

• Baudrand R, Pojoga LH, Romero JR, Williams GH. Aldosterone's mechanism of action: roles of lysine-specific demethylase 1, caveolin and striatin. Curr Opin Nephrol Hypertens. 2014 Jan;23(1):32-7. doi: 10.1097/01.mnh.0000436543.48391.e0.

  PMID: 24275769 RESULT

• Vaidya A, Underwood PC, Hopkins PN, Jeunemaitre X, Ferri C, Williams GH, Adler GK. Abnormal aldosterone physiology and cardiometabolic risk factors. Hypertension. 2013 Apr;61(4):886-93. doi: 10.1161/HYPERTENSIONAHA.111.00662. Epub 2013 Feb 11.

  PMID: 23399714 RESULT

• Brown JM, Williams JS, Luther JM, Garg R, Garza AE, Pojoga LH, Ruan DT, Williams GH, Adler GK, Vaidya A. Human interventions to characterize novel relationships between the renin-angiotensin-aldosterone system and parathyroid hormone. Hypertension. 2014 Feb;63(2):273-80. doi: 10.1161/HYPERTENSIONAHA.113.01910. Epub 2013 Nov 4.

  PMID: 24191286 RESULT

• Baudrand R, Pojoga LH, Vaidya A, Garza AE, Vohringer PA, Jeunemaitre X, Hopkins PN, Yao TM, Williams J, Adler GK, Williams GH. Statin Use and Adrenal Aldosterone Production in Hypertensive and Diabetic Subjects. Circulation. 2015 Nov 10;132(19):1825-33. doi: 10.1161/CIRCULATIONAHA.115.016759. Epub 2015 Oct 2.

  PMID: 26432671 RESULT

• Bentley-Lewis R, Adler GK, Perlstein T, Seely EW, Hopkins PN, Williams GH, Garg R. Body mass index predicts aldosterone production in normotensive adults on a high-salt diet. J Clin Endocrinol Metab. 2007 Nov;92(11):4472-5. doi: 10.1210/jc.2007-1088. Epub 2007 Aug 28.

  PMID: 17726083 RESULT

• Garg R, Williams GH, Hurwitz S, Brown NJ, Hopkins PN, Adler GK. Low-salt diet increases insulin resistance in healthy subjects. Metabolism. 2011 Jul;60(7):965-8. doi: 10.1016/j.metabol.2010.09.005. Epub 2010 Oct 30.

  PMID: 21036373 RESULT

• Pojoga LH, Underwood PC, Goodarzi MO, Williams JS, Adler GK, Jeunemaitre X, Hopkins PN, Raby BA, Lasky-Su J, Sun B, Cui J, Guo X, Taylor KD, Chen YD, Xiang A, Raffel LJ, Buchanan TA, Rotter JI, Williams GH. Variants of the caveolin-1 gene: a translational investigation linking insulin resistance and hypertension. J Clin Endocrinol Metab. 2011 Aug;96(8):E1288-92. doi: 10.1210/jc.2010-2738. Epub 2011 May 25.

  PMID: 21613355 RESULT

• Underwood PC, Sun B, Williams JS, Pojoga LH, Chamarthi B, Lasky-Su J, Raby BA, Hopkins PN, Jeunemaitre X, Brown NJ, Adler GK, Williams GH. The relationship between peroxisome proliferator-activated receptor-gamma and renin: a human genetics study. J Clin Endocrinol Metab. 2010 Sep;95(9):E75-9. doi: 10.1210/jc.2010-0270. Epub 2010 Jul 14.

  PMID: 20631015 RESULT

• Underwood PC, Sun B, Williams JS, Pojoga LH, Raby B, Lasky-Su J, Hunt S, Hopkins PN, Jeunemaitre X, Adler GK, Williams GH. The association of the angiotensinogen gene with insulin sensitivity in humans: a tagging single nucleotide polymorphism and haplotype approach. Metabolism. 2011 Aug;60(8):1150-7. doi: 10.1016/j.metabol.2010.12.009. Epub 2011 Feb 8.

  PMID: 21306748 RESULT

• Pojoga LH, Romero JR, Yao TM, Loutraris P, Ricchiuti V, Coutinho P, Guo C, Lapointe N, Stone JR, Adler GK, Williams GH. Caveolin-1 ablation reduces the adverse cardiovascular effects of N-omega-nitro-L-arginine methyl ester and angiotensin II. Endocrinology. 2010 Mar;151(3):1236-46. doi: 10.1210/en.2009-0514. Epub 2010 Jan 22.

  PMID: 20097717 RESULT

• Chong C, Hamid A, Yao T, Garza AE, Pojoga LH, Adler GK, Romero JR, Williams GH. Regulation of aldosterone secretion by mineralocorticoid receptor-mediated signaling. J Endocrinol. 2017 Mar;232(3):525-534. doi: 10.1530/JOE-16-0452. Epub 2017 Jan 17.

  PMID: 28096435 RESULT

• Pojoga LH, Yao TM, Sinha S, Ross RL, Lin JC, Raffetto JD, Adler GK, Williams GH, Khalil RA. Effect of dietary sodium on vasoconstriction and eNOS-mediated vascular relaxation in caveolin-1-deficient mice. Am J Physiol Heart Circ Physiol. 2008 Mar;294(3):H1258-65. doi: 10.1152/ajpheart.01014.2007. Epub 2008 Jan 4.

  PMID: 18178722 RESULT

• Stone IB, Green JAEM, Koefoed AW, Hornik ES, Williams JS, Adler GK, Williams GH. Striatin genotype-based, mineralocorticoid receptor antagonist-driven clinical trial: study rationale and design. Pharmacogenet Genomics. 2021 Jun 1;31(4):83-88. doi: 10.1097/FPC.0000000000000425.

  PMID: 33904521 DERIVED

MeSH Terms

Conditions

Hypertension

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Limitations and Caveats

Early termination of the trial was secondary to the adverse effects of the Coronavirus Disease 2019 (COVID-19) pandemic. 1. We were shut down for 8 months in 2020-21. 2. Enrolled, not completed subjects, had to begin the study again. 3. Recruiting new subjects during the pandemic was extremely difficult. 4. NIH funded the trial, but no additional funds were available to cover the short fall. Further studies will be required to determine if the hypothesis being tested is correct.

Results Point of Contact

• Title: Gordon H. Williams, Professor of Medicine
• Organization: Brigham and Women's Hospital

gwilliams@bwh.harvard.edu

617-223-1611

Study Officials

• Gordon H Williams

  Brigham and Women's Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The screened, eligible hypertensives will enter a two-week single blind placebo washout phase.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Model Details: Parallel Design

Study Record Dates

• First Submitted: September 17, 2018
• First Posted: September 25, 2018
• Study Start: January 15, 2019
• Primary Completion: August 28, 2023
• Study Completion: January 31, 2024
• Last Updated: March 19, 2025
• Results First Posted: March 19, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)