Optimal Medical Treatment of Difficult-to-treat Hypertension (OPTIMAL-HT)

The purpose of this study is to evaluate best medical management to achieve the BP goals of ESC/ESH (120-129 / 70-79 mmHg) in HT patients who are <65 years old and ineffectively treated (BP ≥ 130/80 mg) with 3 or more antihypertensive drugs

Study Overview

• Status: Recruiting
• Conditions: Hypertension
• Intervention / Treatment: Drug: Phase C: Eplerenone; Drug: Phase B: Triplixam / Elestar HCT; Drug: Phase C: Spironolactone; Drug: Phase C: Torasemide; Diagnostic test: Phase A: Confirmation of uncontrolled hypertension

Detailed Description

Purpose: To evaluate best medical management to achieve the ESC/ESH 2018 BP goals of 120-129 / 70-79 mmHg in HT patients aged < 65 y not controlled on 3 or more antihypertensive drugs.

Study design:

Phase A (Active screening) (n = 2500) 7 days Confirmation of the true ineffectiveness of antihypertensive therapy based on 3 or more antihypertensive drugs (single or dual drug preparations) using ABPM and home BP measurements.

Phase B (Open-label, non-randomized) (n = 1250) 12 weeks Replacement of ineffective antihypertensive treatment based on 3 or more antihypertensive drugs (single or dual drug preparations) with a triple single pill combination (SPC) based on optimally combined antihypertensive drugs: perindopril + indapamide + amlodipine (P+I+A) or olmesartan + hydrocholothiazide + amlodipine (O+H+A).

Phase C (Double blind, randomized, parallel-group) (n = 480) 24 weeks

Comparison of antihypertensive efficacy and tolerability profile:

• spironolactone
• eplerenone
• torasemide attached as an antihypertensive drug of 4th choice.

• Study Type: Interventional
• Enrollment (Estimated): 2500
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Piotr Dobrowolski, Professor; Phone Number: 4850 (+48) 228156556; Email: pdobrowolski@ikard.pl
• Study Contact Backup: Name: Aleksander Prejbisz, Professor; Email: aprejbisz@ikard.pl

Study Locations

• Poland
  • Mazowieckie
    • Warsaw, Mazowieckie, Poland, 04628
      • Recruiting
      • National Institute of Cardiology
      • Contact: Agata Skutnik; Email: askutnik@ikard.pl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• documented history of HT
• HT treated for at least six months,
• office BP ≥ 130 and / or ≥80 mm Hg (average seated BP at Visit 1)
• use of 3 or more antihypertensive drugs, including an ACEi/ARB and a thiazide/thiazide-like diuretic or loop diuretic (single drugs or double SPCs)
• stable antihypertensive treatment regimen - no changes in antihypertensive treatment strategy at least for 4 weeks
• able and willing to comply with all study procedures and able to attend one of the study centers

Exclusion Criteria:

• inability to give informed consent
• SBP ≥180 mm Hg and/or DBP ≥110 mm Hg and/or DBP <60 mm Hg
• BMI ≥40 kg/m2
• eGFR of <45 mL/min/1.73 m2
• potassium serum concentration > 4.8 mmol/L or < 3.5 mmol/L
• persistent hyponatremia or history of hyponatremia related to TD/TLD treatment (sodium concentration <135 mmol/L)
• secondary hypertension (not including sleep apnea)
• chronic oral glucocorticoid therapy
• myocardial infarction or cerebrovascular event (e.g. stroke, transient ischemic event, cerebrovascular accident) in the year prior to study inclusion
• heart failure requiring treatment with diuretic or aldosterone antagonists
• cardiomyopathy exluding LVH related to HT
• severe valvular disease
• ascending aortic aneurysm ≥5 cm
• prescribed to any standard antihypertensive of cardiovascular medication (e.g. beta blockers) for other chronic conditions (e.g. chronic coronary syndromes, arytmia) such that discontinuation might pose serious risk to health
• primary pulmonary hypertension
• decompensated hyperthyroidism or hypothyroidism
• severe liver dysfunction (alanine aminotransferase and/or asparagine aminotransferase activity ≥3 times the upper limit of normal value),
• documented contraindication or allergy to studied drugs
• limited life expectancy of < 1 year at the discretion of the Investigator
• any known, unresolved history of drug use or alcohol dependency, lacks the ability to comprehend or follow instructions, or for any reason in the opinion of the investigator, would be unlikely or unable to comply with study protocol requirements
• all women of child bearing potential; women of child bearing potential can be included in the study ONLY after providing documentation of effective contraception (intrauterine device);
• concurrent enrollment in any other investigational drug or device trial
• anticipated change of medical status during the trial (e.g., surgical intervention requiring >2 weeks convalescence)
• current therapy for cancer

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Eplerenone (+placebo of Spironolactone and placebo of Torasemide); Phase C. Participants randomly assigned to this arm take Eplerenone and placebos of Spironolactone and Torasemide	Drug: Phase C: Eplerenone; Participants randomly assigned to this arm take Eplerenone and placebos of Spironolactone and Torasemide; Other Names: Eplerenone; Drug: Phase B: Triplixam / Elestar HCT; Replacement of ineffective antihypertensive treatment based on 3 or more antihypertensive drugs (single or dual drug preparations) with a triple single pill combination (SPC) based on optimally combined antihypertensive drugs: perindopril + indapamide + amlodipine (P+I+A) or olmesartan + hydrocholothiazide + amlodipine (O+H+A).; Other Names: Triple Single Pill Combination: Triplixam / Elestar HCT
Experimental: Spironolactone (+placebo of Eplerenone and placebo of Torasemide); Phase C. Participants randomly assigned to this arm take Spironolactone and placebos of Eplerenone and Torasemide	Drug: Phase B: Triplixam / Elestar HCT; Replacement of ineffective antihypertensive treatment based on 3 or more antihypertensive drugs (single or dual drug preparations) with a triple single pill combination (SPC) based on optimally combined antihypertensive drugs: perindopril + indapamide + amlodipine (P+I+A) or olmesartan + hydrocholothiazide + amlodipine (O+H+A).; Other Names: Triple Single Pill Combination: Triplixam / Elestar HCT; Drug: Phase C: Spironolactone; Participants randomly assigned to this arm take Spironolactone and placebos of Eplerenone and Torasemide; Other Names: Spironolactone
Experimental: Torasemide (+placebo of Eplerenone and placebo of Spironolactone ); Phase C. Participants randomly assigned to this arm take Torasemide and placebos of Eplerenone and Spironolactone	Drug: Phase B: Triplixam / Elestar HCT; Replacement of ineffective antihypertensive treatment based on 3 or more antihypertensive drugs (single or dual drug preparations) with a triple single pill combination (SPC) based on optimally combined antihypertensive drugs: perindopril + indapamide + amlodipine (P+I+A) or olmesartan + hydrocholothiazide + amlodipine (O+H+A).; Other Names: Triple Single Pill Combination: Triplixam / Elestar HCT; Drug: Phase C: Torasemide; Participants randomly assigned to this arm take Torasemide and placebos of Eplerenone and Spironolactone; Other Names: Torasemide
Active Comparator: Open-label; Phase B Replacement of ineffective antihypertensive treatment based on 3 or more antihypertensive drugs (single or dual drug preparations) with a triple single pill combination (SPC) based on optimally combined antihypertensive drugs: perindopril + indapamide + amlodipine (P+I+A) or olmesartan + hydrocholothiazide + amlodipine (O+H+A).	Drug: Phase B: Triplixam / Elestar HCT; Replacement of ineffective antihypertensive treatment based on 3 or more antihypertensive drugs (single or dual drug preparations) with a triple single pill combination (SPC) based on optimally combined antihypertensive drugs: perindopril + indapamide + amlodipine (P+I+A) or olmesartan + hydrocholothiazide + amlodipine (O+H+A).; Other Names: Triple Single Pill Combination: Triplixam / Elestar HCT
Other: Screening; Phase A. Confirmation of the true ineffectiveness of antihypertensive therapy based on 3 or more antihypertensive drugs (single or dual drug preparations) using ABPM and home BP measurements.	Diagnostic test: Phase A: Confirmation of uncontrolled hypertension; Confirmation of the true ineffectiveness of antihypertensive therapy based on 3 or more antihypertensive drugs (single or dual drug preparations) using ABPM and home BP measurements.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patients with uncontrolled BP on ABPM	Percentage of patients with uncontrolled BP confirmed on ABPM (24h mean, SBP ≥125 mm Hg or DBP ≥80 mm Hg)	First week of the patients' participation in the study
Patients with controlled BP after 12 weeks on triple SPC	Percentage of patients with controlled BP after 12 weeks of treatment with triple SPC, confirmed on ABPM (24h mean, SBP <125 mm Hg and DBP <80 mm Hg) - as the efficacy of the treatment strategy (switching ineffective treatment to triple SPC) - the whole group and P+I+A and E+H+A groups separetly.	Next 12 weeks of the patients' participation in the study
Systolic BP reduction on 4th antihypertensive drug	Magnitude of reduction of SBP on ABPM (24h mean) after 12 weeks of treatment - comparison of eplerenone vs spironolactone and torasemide vs spironolactone.	Last 24 weeks of the patients' participation in the study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patients with BP controlled confirmed by HBPM	Percentage of patients with BP controlled confirmed by HBPM (mean over the period of 6 days, SBP ≥130 mm Hg or DBP ≥80 mm Hg)	First week of the patients' participation in the study
Consistency of the rate of uncontrolled BP	Consistency of the rate of uncontrolled BP between ABPM and HBPM	First week of the patients' participation in the study
Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by OBPM	Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by OBPM (SBP <130 mm Hg and DBP <80 mm Hg).	Next 12 weeks of the patients' participation in the study
Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by HBPM	Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by HBPM (mean over 6 days, SBP <130 mm Hg and DBP <80 mm Hg).	Next 12 weeks of the patients' participation in the study
Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by ABPM	Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by ABPM in daytime (SBP <135 mm Hg and DBP <85 mm Hg) and nighttime (SBP <120 mm Hg and DBP <70 mm Hg) reading.	Next 12 weeks of the patients' participation in the study
Percentage of patients requiring an increase in the dose	Percentage of patients requiring an increase in the dose of drugs used in the whole group and in the patients treated with P+I+A and O+H+A separately.	Next 12 weeks of the patients' participation in the study
Consistency of the rate of uncontrolled BP	Consistency of the rate of uncontrolled BP between ABPM, HBPM and OBPM.	Next 12 weeks of the patients' participation in the study
The magnitude of the decrease in SBP and DBP on OBPM, ABPM and HBPM after 12 weeks	The magnitude of the decrease in SBP and DBP on OBPM, ABPM and HBPM after 12 weeks of treatment in the whole group and in the patients treated with P+I+A and O+H+A separately.	Next 12 weeks of the patients' participation in the study
The magnitude of changes in HBPM and ABPM derived indices after 12 weeks	The magnitude of changes in HBPM and ABPM derived indices after 12 weeks of treatment in the whole group and in the patients treated with P+I+A and O+H+A separately.	Next 12 weeks of the patients' participation in the study
Phase C	Changes of SBP on ABPM (24h mean) after 12 weeks of treatment in patients receiving spironolactone, eplerenone or torasemide as compared against baseline.; Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by OBPM (SBP <130 mm Hg and DBP <80 mm Hg) - comparison of eplerenone / torasemide groups against the spironolactone group.; Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by HBPM (mean over 6 days, SBP <130 mm Hg and DBP <80 mm Hg) - comparison of eplerenone / torasemide groups against the spironolactone group.; Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by ABPM, in 24h mean (SBP <125 mm Hg and DBP <80 mm Hg), daytime (SBP <135 mm Hg and DBP <85 mm Hg) and nighttime (SBP <120 mm Hg and DBP <70 mm Hg) readings - comparison of eplerenone / torasemide groups against the spironolactone group.	Last 24 weeks of the patients' participation in the study
Changes of SBP on ABPM (24h mean) after 12 weeks of treatment	Changes of SBP on ABPM (24h mean) after 12 weeks of treatment in patients receiving spironolactone, eplerenone or torasemide as compared against baseline.	Last 24 weeks of the patients' participation in the study
Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by OBPM	Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by OBPM (SBP <130 mm Hg and DBP <80 mm Hg) - comparison of eplerenone / torasemide groups against the spironolactone group.	Last 24 weeks of the patients' participation in the study
Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by HBPM	Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by HBPM (mean over 6 days, SBP <130 mm Hg and DBP <80 mm Hg) - comparison of eplerenone / torasemide groups against the spironolactone group.	Last 24 weeks of the patients' participation in the study
Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by ABPM	Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by ABPM, in 24h mean (SBP <125 mm Hg and DBP <80 mm Hg), daytime (SBP <135 mm Hg and DBP <85 mm Hg) and nighttime (SBP <120 mm Hg and DBP <70 mm Hg) readings - comparison of eplerenone / torasemide groups against the spironolactone group.	Last 24 weeks of the patients' participation in the study
Phase C continuation	Consistency of the rate of controlled BP between ABPM, HBPM and OBPM (after 12 weeks of treatment).	Last 24 weeks of the patients' participation in the study
Phase C continuation	Changes in SBP and DBP on OBPM, ABPM and HBPM after 12 weeks of treatment - comparison of eplerenone / torasemide groups against the spironolactone group and comparison of each of the studied drug groups against baseline.	Last 24 weeks of the patients' participation in the study
Changes in HBPM and ABPM derived indices after 12 weeks - comparison of treatment groups	Changes in HBPM and ABPM derived indices after 12 weeks of treatment - comparison of eplerenone / torasemide groups against the spironolactone group and comparison of each of the studied drug groups against baseline	Last 24 weeks of the patients' participation in the study
Changes of SBP on ABPM (24h mean) after 24 weeks of treatment compared against spironolactone	Changes of SBP on ABPM (24h mean) after 24 weeks of treatment in patients receiving eplerenone or torasemide as compared against spironolactone.	Last 24 weeks of the patients' participation in the study
Changes of SBP on ABPM (24h mean) after 24 weeks of treatment compared against baseline	Changes of SBP on ABPM (24h mean) after 24 weeks of treatment in patients receiving spironolactone, eplerenone or torasemide as compared against baseline.	Last 24 weeks of the patients' participation in the study
Percentage of patients with controlled BP after 24 weeks of treatment, confirmed by OBPM - comparison between groups	Percentage of patients with controlled BP after 24 weeks of treatment, confirmed by OBPM (SBP <130 mm Hg and DBP <80 mm Hg) - comparison of eplerenone / torasemide groups against the spironolactone group.	Last 24 weeks of the patients' participation in the study
Percentage of patients with controlled BP after 24 weeks of treatment, confirmed by HBPM - comparison between groups	Percentage of patients with controlled BP after 24 weeks of treatment, confirmed by HBPM (mean over 6 days, SBP <130 mm Hg and DBP <80 mm Hg) - comparison of eplerenone / torasemide groups against the spironolactone group.	Last 24 weeks of the patients' participation in the study
Percentage of patients with controlled BP after 24 weeks of treatment, confirmed by ABPM - comparison between groups	Percentage of patients with controlled BP after 24 weeks of treatment, confirmed by ABPM, in 24h mean (SBP <125 mm Hg and DBP <80 mm Hg), daytime (SBP <135 mm Hg and DBP <85 mm Hg) and nighttime (SBP <120 mm Hg and DBP <70 mm Hg) readings - comparison of eplerenone / torasemide groups against the spironolactone group.	Last 24 weeks of the patients' participation in the study
Consistency of the rate of controlled BP between ABPM, HBPM and OBPM after 24 weeks	Consistency of the rate of controlled BP between ABPM, HBPM and OBPM after 24 weeks of treatment	Last 24 weeks of the patients' participation in the study
Changes in SBP and DBP on OBPM, ABPM and HBPM after 24 weeks of treatment - comparison between groups	Changes in SBP and DBP on OBPM, ABPM and HBPM after 24 weeks of treatment - comparison of eplerenone / torasemide groups against the spironolactone group and comparison of each of the studied drug groups against baseline.	Last 24 weeks of the patients' participation in the study
Changes in HBPM and ABPM derived indices after 24 weeks of treatment - - comparison between groups	Changes in HBPM and ABPM derived indices after 24 weeks of treatment - comparison of eplerenone / torasemide groups against the spironolactone group and comparison of each of the studied drug groups against baseline	Last 24 weeks of the patients' participation in the study
Percentage of patients requiring an increase in the dose of drugs used after 6 and 12 weeks - comparison between groups	Percentage of patients requiring an increase in the dose of drugs used after 6 and 12 weeks - comparison of eplerenone / torasemide groups against the spironolactone.	Last 24 weeks of the patients' participation in the study

Collaborators and Investigators

• Sponsor: National Institute of Cardiology, Warsaw, Poland
• Investigators: Principal Investigator: Piotr Dobrowolski, Professor, National Institute of Cardiology

Study record dates

Study Major Dates

• Study Start (Actual): October 20, 2023
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: January 4, 2024
• First Submitted That Met QC Criteria: February 16, 2024
• First Posted (Actual): February 23, 2024

Study Record Updates

• Last Update Posted (Actual): February 23, 2024
• Last Update Submitted That Met QC Criteria: February 16, 2024
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Sodium Potassium Chloride Symporter Inhibitors; Spironolactone; Eplerenone; Torsemide
• Other Study ID Numbers: 2020/ABM/01/00037

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