MR Antagonist and LSD1

Mass General Brigham

Status and phase: Enrolling; Phase 4

Conditions: Hypertension; Mineralocorticoid Excess

Treatments: Drug: Amlodipine; Drug: Eplerenone

Study type: Interventional

Funder types: Other

Identifiers

NCT04840342

2021p000990

Details and patient eligibility

About

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).

Full 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.

Enrollment: 300 estimated patients

Sex: All

Ages: 17+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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300 participants in 2 patient groups

Eplerenone Arm

Experimental group

Description:

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.

Treatment:

Drug: Eplerenone

Amlodipine Arm

Experimental group

Description:

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.

Treatment:

Drug: Amlodipine