MR Antagonist and LSD1

Role of LSD1 in Hypertension in Blacks

Lysine specific demethylase-1 (LSD1) is an epigenetic regulator of gene transcription involved in the pathophysiology of elevated blood pressure and likely renal damage in Blacks. This project investigates whether a genetically driven anti-hypertensive approach proves superior in controlling blood pressure and mitigating renal injury in Blacks who carry the risk allele for LSD1 (rs587168). The findings of these investigations may lead to a new approach in treating a subset (~30%) of the essential hypertension population (Black LSD1 risk allele hypertensives).

Study Overview

• Status: Recruiting
• Conditions: Hypertension; Mineralocorticoid Excess
• Intervention / Treatment: Drug: Eplerenone; Drug: Amlodipine

Detailed Description

This proof-of-principle physiologic study in hypertensive Black LSD1 risk allele carriers testing the hypothesis that reductions in blood pressure will be greater with a genetically-driven anti-hypertensive approach (mineralocorticoid receptor antagonist, eplerenone) compared to a non-specific approach (amlodipine). 56 participants will be enrolled in a 12-week randomized, double-blind, active controlled, outpatient study to assess whether eplerenone (LSD1 specific treatment) proves superior in 24-hr ambulatory systolic blood pressure reduction than amlodipine (non-specific treatment). Participants will be randomized to either eplerenone 50mg or amlodipine 2.5mg with escalations in dose of study drug every 4 weeks if the participant's blood pressure is > 140/90.

• Study Type: Interventional
• Enrollment (Estimated): 300
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Andrea Haas, MD; Phone Number: 6177325666; Email: ahaas2@bwh.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Brigham and Women's
      • Contact: Andrea Haas, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• untreated as well as currently treated hypertensives
• rs587168 allele carriers
• not on more than two anti-hypertensives
• normal renal, metabolic, electrolyte, and CBC laboratory tests
• self-identified Black race
• age >17 yrs.

Exclusion Criteria:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Eplerenone Arm; We posit that individuals who carry the LSD1 risk allele have increased mineralocorticoid receptor activity, which results in hypertension. Thus, our mechanistic clinical study will assess whether hypertensive LSD1 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 LSD1 risk allele using a novel two-limb, proof-of-principle study. Our primary outcome will be a liberal salt diet systolic 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.	Drug: Eplerenone; Dose escalations of eplerenone 50, 100, or 200mg
Experimental: Amlodipine Arm; We posit that individuals who carry the LSD1 risk allele have increased mineralocorticoid receptor activity, which results in hypertension. Thus, our mechanistic clinical study will assess whether hypertensive LSD1 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 LSD1 risk allele using a novel two-limb, proof-of-principle study. Our primary outcome will be a liberal salt diet systolic 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.	Drug: Amlodipine; Dose escalations of amlodipine 2.5, 5, or 10mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
24-hour systolic ambulatory 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)]. After completion of this diet for 6 days, the subject will collect a 24-hour ambulatory blood pressure. Procedure will be performed before randomization and after 4 weeks of therapy.	Change in systolic blood pressure between baseline and 4 weeks on study drug

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Investigators: Principal Investigator: Andrea Haas, MD, Brigham and Women's

Study record dates

Study Major Dates

• Study Start (Actual): February 3, 2022
• Primary Completion (Estimated): February 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: April 7, 2021
• First Submitted That Met QC Criteria: April 7, 2021
• First Posted (Actual): April 12, 2021

Study Record Updates

• Last Update Posted (Actual): August 1, 2023
• Last Update Submitted That Met QC Criteria: July 27, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Endocrine System Diseases; Adrenocortical Hyperfunction; Adrenal Gland Diseases; Hypertension; Hyperaldosteronism; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Hormone Antagonists; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Amlodipine; Eplerenone
• Other Study ID Numbers: 2021p000990

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No