Study to Evaluate the Effect on Improvement of LVH by the Control of BP in Hypertension Patients With AV Disease

Study Overview
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Brief Summary
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To compare changes in Left Ventricular Mass (LVM) depending on each blood pressure regulation between the intensive care group and the usual care group for patients with hypertension accompanied by aortic valve disease and evaluate an influence of blood pressure regulation on improvement of left ventricular hypertrophy and its safety

Detailed Description
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1.Primary objectives - To evaluate changes from baseline in LVM at V5 (24M) 2.Secondary objectives To evaluate changes from baseline in LV global longitudinal strain at V5 (24M) To evaluate changes from baseline in E/E' (E: early diastolic LV inflow velocity, E': early diastolic mitral annulus velocity) at V5 (24M) To evaluate changes from baseline in LV volumes, a stroke volume index and LV ejection fraction at V5 (24M) To evaluate a rate of disease progression In case of Aortic stenosis (AS), to evaluate changes from baseline in Aortic Valve Area (AVA), Vmax, Mean Pressure Gradient (PG) and Valvulo-arterial impedance (Zva) at V5 (24M) In case of Aortic regurgitation (AR), to evaluate changes from baseline in Vena contracta at V5 (24M) To evaluate changes from baseline in blood pressure at V2(6M), V3(12M), V4(18M) and V5(24M) To evaluate a cumulative incidence rate for each visit time point Death, Cardiovascular(CV) death, Heart Failure(HF), Myocardial Infarction(MI), Hospitalization, Aortic Valve Replacement(AVR) To evaluate outcomes of adverse events, physical examination, vital signs (pulse) and laboratory tests (hematological examination, blood biochemical examination, urine test and pregnancy test)

Official Title
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A Prospective, Multicentre, Randomized, Open Label, Evaluator-Blind, Phase IV Study to Evaluate the Effect on Improvement of Left Ventricular Hypertrophy by the Control of Blood Pressure in Hypertension Patients With Aortic Valve Disease

Conditions
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LVM, Aortic Stenosis, Aortic Regurgitation, Hypertension, Left Ventricular Hypertrophy

Intervention / Treatment
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* Drug: Amlodipine 5mg
* Drug: Losartan
* Drug: Losartan and Amlodipine
* Drug: Amlodipine/Losartan/Chlorthalidone
* Drug: current treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged ≥ 19 years and < 80 years Diagnosis of mild-moderate AS or mild-moderate AR Applicable to 2.0 3.9 m/s of aortic jet velocity for mild-moderate AS or to 0.2 0.6 cm of Vena contracta for mild-moderate AR Diagnosis of hypertension (SBP > 130 mmHg if being treated or SBP > 140 mmHg if being untreated) For females of childbearing potential; negative pregnancy test results during the screening period and prior to administration of the investigational product, and agreement on use of medically allowable contraceptive measures (condom, oral contraceptive pills, injectable or implantable contraceptives, intrauterine devices, birth control patches, etc.) during the study period Voluntary written consent to taking part in the clinical study and willingness to comply with requirements of the study Exclusion Criteria: History of a cardiac valve replacement surgery (replacement surgery of mitral valve, aortic valve or tricuspid valve) Accompanied by severe mitral regurgitation Admitted to needing a surgery by the current treatment guidelines Accompanied by symptoms such as angina pectoris, exertional dyspnea, syncope, etc. < 50% of left ventricular ejection fraction History of hypersensitivity reaction to active ingredients of the investigational product (Amlodipine, Losartan and Chlorthalidone), dihydropyridine derivatives, thiazide drugs and other sulfonamide derivatives or their compositions Pregnant or breastfeeding Symptomatic orthostatic hypotension Severe liver failure or renal failure (< 30 mL/min of creatinine clearance) Hereditary angioedema or history of angioedema at treatment with ACE inhibitors or angiotensin II receptor blockers Primary hyperaldosteronism Genetic problems such as galactose intolerance, Lapp Lapp lactase deficiency or glucose-galactose malabsorption Anuria Refractory hypokalemia Hyponatremia or hypercalcemia Symptomatic hyperuricemia (history of gout or uric acid lithiasis) Untreated Addison's disease Appropriately uncontrolled diabetes Congenital or incurable hypertension Diagnosis of severe cerebrovascular disorders (stroke, cerebral infarction, cerebral hemorrhage, etc.) within six months prior to the date of ICF obtainment Wasting disease, autoimmune disease or connective tissue disease Diagnosis of malignant tumor within five years prior to the date of ICF obtainment Administration of another investigational product within four weeks prior to the date of ICF obtainment For a patient who is taking anticoagulants and thrombolytic agents; considered difficult to keep a stable dosage/regimen by the investigator. Considered unsuitable to be a subject by the investigator

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A prospective, multicentre, randomized, open label, evaluator-blind study
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: The intensive care group<br>The intensive care group is targeted at ≤ 130 mmHg of systolic blood pressure, and treatment is done by changing the current treatment to the investigational product. In case of treatment with the investigational product (IP), the IP titration period is total six months. According to an IP titration scheme(Amlodipine 5 mg or Losartan 50 mg -> Losartan and Amlodipine 5/50 mg -> Losartan and Amlodipine 5/100 mg -> Amlodipine/Losartan/Chlorthalidone 5/100/12.5 mg), IP is successively modified until the target blood pressure is reached, and IP will remain the same after the target blood pressure scope for each group is reached. An IP titration interval is decided by the investigator depending on the subject's condition. | Drug: Amlodipine 5mg<br>* Amlodipine 5 mg<br>* Other names: Amodipin Tab.;Drug: Losartan<br>* Losartan Potassium 50 mg<br>* Other names: Osartan Tab. 50 mg;Drug: Losartan and Amlodipine<br>* Amlodipine 5 mg/Losartan Potassium 50 mg, Amlodipine 5 mg/Losartan Potassium 100 mg<br>* Other names: Amosartan Tab. 5/50 mg, Amosartan Tab. 5/100 mg;Drug: Amlodipine/Losartan/Chlorthalidone<br>* Amlodipine 5 mg/Losartan Potassium 100 mg/Chlorthalidone 12.5 mg<br>* Other names: Amosartan Plus Tab. 5/100/12.5 mg;|
| Experimental: The usual care group<br>The usual care group is targeted at ≤ 140 mmHg of systolic blood pressure, and treatment is done by maintaining the current treatment, adding the investigational product, or changing the current treatment to the investigational product. In case of treatment with the investigational product (IP), the IP titration period is total six months. According to an IP titration scheme(Amlodipine 5 mg or Losartan 50 mg -> Losartan and Amlodipine 5/50 mg -> Losartan and Amlodipine 5/100 mg -> Amlodipine/Losartan/Chlorthalidone 5/100/12.5 mg), IP is successively modified until the target blood pressure is reached, and IP will remain the same after the target blood pressure scope for each group is reached. An IP titration interval is decided by the investigator depending on the subject's condition. | Drug: Amlodipine 5mg<br>* Amlodipine 5 mg<br>* Other names: Amodipin Tab.;Drug: Losartan<br>* Losartan Potassium 50 mg<br>* Other names: Osartan Tab. 50 mg;Drug: Losartan and Amlodipine<br>* Amlodipine 5 mg/Losartan Potassium 50 mg, Amlodipine 5 mg/Losartan Potassium 100 mg<br>* Other names: Amosartan Tab. 5/50 mg, Amosartan Tab. 5/100 mg;Drug: Amlodipine/Losartan/Chlorthalidone<br>* Amlodipine 5 mg/Losartan Potassium 100 mg/Chlorthalidone 12.5 mg<br>* Other names: Amosartan Plus Tab. 5/100/12.5 mg;Drug: current treatment<br>* treatment is done by maintaining the current treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate changes from baseline in Left Ventricular Mass at 24M | To evaluate changes from baseline in Left Ventricular Mass at 24M | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes from baseline in Left Ventricular global longitudinal strain at 24M | Changes from baseline in Left Ventricular global longitudinal strain at 24M | 24 months | 
| Changes from baseline in E/E' (E: early diastolic LV inflow velocity, E': early diastolic mitral annulus velocity) at 24M | Changes from baseline in E/E' (E: early diastolic LV inflow velocity, E': early diastolic mitral annulus velocity) at 24M | 24 months | 
| Changes from baseline in Left Ventricular volumes at 24M | Changes from baseline in Left Ventricular volumes at 24M | 24 months | 
| Rate of disease progression | In case of Aortic Stenosis, to evaluate changes from baseline in Aortic Valve Area, tricuspid regurgitation velocity, Mean Pressure Gradient and Valvulo-arterial impedance at 24M In case of Aortic Regurgitation, to evaluate changes from baseline in Vena contracta at 24M | 24 months | 
| To evaluate changes from baseline in systolic blood pressure at 6M, 12M, 18M, 24M | To evaluate changes from baseline in systolic blood pressure at 6M, 12M, 18M, 24M | 6 months, 12 months, 18 months, 24 months | 
| Cumulative incidence rate for each visit time point | Cumulative incidence rate for each visit time point - Death, Cardiovascular death, Heart Failure, Myocardial Infarction, Hospitalization, Aortic Valve Replacement | 6 months, 12 months, 18 months, 24 months | 
| Changes from baseline in stroke volume index at 24M | Changes from baseline in stroke volume index at 24M | 24 months | 
| Changes from baseline in Left Ventricular ejection fraction at 24M | Changes from baseline in Left Ventricular ejection fraction at 24M | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aortic Stenosis, Aortic Regurgitation, Hypertension, LVM, Left Ventricular Hypertrophy