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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
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:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Eplerenone (+placebo of Spironolactone and placebo of Torasemide) | Experimental | Phase C. Participants randomly assigned to this arm take Eplerenone and placebos of Spironolactone and Torasemide |
|
| Spironolactone (+placebo of Eplerenone and placebo of Torasemide) | Experimental | Phase C. Participants randomly assigned to this arm take Spironolactone and placebos of Eplerenone and Torasemide |
|
| Torasemide (+placebo of Eplerenone and placebo of Spironolactone ) | Experimental | Phase C. Participants randomly assigned to this arm take Torasemide and placebos of Eplerenone and Spironolactone |
|
| Open-label | Active Comparator | 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). |
|
| Screening |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Phase C: Eplerenone | Drug | Participants randomly assigned to this arm take Eplerenone and placebos of Spironolactone and Torasemide |
|
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Piotr Dobrowolski, Professor | Contact | (+48) 228156556 | 4850 | pdobrowolski@ikard.pl |
| Aleksander Prejbisz, Professor | Contact | aprejbisz@ikard.pl |
| Name | Affiliation | Role |
|---|---|---|
| Piotr Dobrowolski, Professor | National Institute of Cardiology | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| National Institute of Cardiology | Recruiting | Warsaw | Masovian Voivodeship | 04628 | Poland |
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| ID | Term |
|---|---|
| D006973 | Hypertension |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D000077545 | Eplerenone |
| D013148 | Spironolactone |
| D000077786 | Torsemide |
| ID | Term |
|---|---|
| D007783 | Lactones |
| D009930 | Organic Chemicals |
| D011283 | Pregnenes |
| D011278 | Pregnanes |
| D013256 |
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| Other |
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. |
|
|
| Phase C: Spironolactone | Drug | Participants randomly assigned to this arm take Spironolactone and placebos of Eplerenone and Torasemide |
|
|
| Phase C: Torasemide | Drug | Participants randomly assigned to this arm take Torasemide and placebos of Eplerenone and Spironolactone |
|
|
| Phase B: Triplixam / Elestar HCT | Drug | 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 A: Confirmation of uncontrolled hypertension | Diagnostic Test | 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. |
|
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 |
| 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 |
| Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D013449 | Sulfonamides |
| D000577 | Amides |
| D013450 | Sulfones |
| D013457 | Sulfur Compounds |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |