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

Phase 4

Completed

• Conditions: Aortic Stenosis; Aortic Regurgitation; Hypertension; LVM; Left Ventricular Hypertrophy
• Interventions: Drug: Amlodipine 5mg; Drug: Losartan; Drug: Losartan and Amlodipine; Drug: Amlodipine/Losartan/Chlorthalidone; Drug: current treatment

• Registration Number: NCT03666351
• Lead Sponsor: Hanmi Pharmaceutical Company Limited

Brief Summary

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

1.Primary objectives

- To evaluate changes from baseline in LVM at V5 (24M)

2.Secondary objectives

1. To evaluate changes from baseline in LV global longitudinal strain at V5 (24M)

2. To evaluate changes from baseline in E/E' (E: early diastolic LV inflow velocity, E': early diastolic mitral annulus velocity) at V5 (24M)

3. To evaluate changes from baseline in LV volumes, a stroke volume index and LV ejection fraction at V5 (24M)

4. 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)

5. To evaluate changes from baseline in blood pressure at V2(6M), V3(12M), V4(18M) and V5(24M)

6. 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)

7. To evaluate outcomes of adverse events, physical examination, vital signs (pulse) and laboratory tests (hematological examination, blood biochemical examination, urine test and pregnancy test)

Study Timeline

• Study First Submitted: 2018-08-20
• Study First Submitted QC: 2018-09-09
• Study First Posted: 2018-09-11
• Study Start: 2018-10-18
• Primary Completion: 2022-07-25
• Study Completion: 2022-07-25
• Status Verified: 2022-09
• Last Update Submitted: 2022-09-13
• Last Update Posted: 2022-09-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 128

Inclusion Criteria

1. Male or female aged ≥ 19 years and < 80 years
2. Diagnosis of mild-moderate AS or mild-moderate AR
3. 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
4. Diagnosis of hypertension (SBP > 130 mmHg if being treated or SBP > 140 mmHg if being untreated)
5. 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
6. Voluntary written consent to taking part in the clinical study and willingness to comply with requirements of the study

Exclusion Criteria

1. History of a cardiac valve replacement surgery (replacement surgery of mitral valve, aortic valve or tricuspid valve)
2. Accompanied by severe mitral regurgitation
3. Admitted to needing a surgery by the current treatment guidelines
4. Accompanied by symptoms such as angina pectoris, exertional dyspnea, syncope, etc.
5. < 50% of left ventricular ejection fraction
6. 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
7. Pregnant or breastfeeding
8. Symptomatic orthostatic hypotension
9. Severe liver failure or renal failure (< 30 mL/min of creatinine clearance)
10. Hereditary angioedema or history of angioedema at treatment with ACE inhibitors or angiotensin II receptor blockers
11. Primary hyperaldosteronism
12. Genetic problems such as galactose intolerance, Lapp Lapp lactase deficiency or glucose-galactose malabsorption
13. Anuria
14. Refractory hypokalemia
15. Hyponatremia or hypercalcemia
16. Symptomatic hyperuricemia (history of gout or uric acid lithiasis)
17. Untreated Addison's disease
18. Appropriately uncontrolled diabetes
19. Congenital or incurable hypertension
20. Diagnosis of severe cerebrovascular disorders (stroke, cerebral infarction, cerebral hemorrhage, etc.) within six months prior to the date of ICF obtainment
21. Wasting disease, autoimmune disease or connective tissue disease
22. Diagnosis of malignant tumor within five years prior to the date of ICF obtainment
23. Administration of another investigational product within four weeks prior to the date of ICF obtainment
24. For a patient who is taking anticoagulants and thrombolytic agents; considered difficult to keep a stable dosage/regimen by the investigator.
25. Considered unsuitable to be a subject by the investigator

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
The usual care group	Losartan and Amlodipine	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.
The intensive care group	Losartan	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.
The intensive care group	Losartan and Amlodipine	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.
The intensive care group	Amlodipine/Losartan/Chlorthalidone	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.
The usual care group	Amlodipine/Losartan/Chlorthalidone	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.
The usual care group	current treatment	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.
The intensive care group	Amlodipine 5mg	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.
The usual care group	Losartan	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.
The usual care group	Amlodipine 5mg	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.

Primary Outcome Measures

Name	Time	Method
To evaluate changes from baseline in Left Ventricular Mass at 24M	24 months	To evaluate changes from baseline in Left Ventricular Mass at 24M

Secondary Outcome Measures

Name	Time	Method
Changes from baseline in Left Ventricular global longitudinal strain at 24M	24 months	Changes from baseline in Left Ventricular global longitudinal strain 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 E/E' (E: early diastolic LV inflow velocity, E': early diastolic mitral annulus velocity) at 24M
Changes from baseline in Left Ventricular volumes at 24M	24 months	Changes from baseline in Left Ventricular volumes at 24M
Rate of disease progression	24 months	* 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
To evaluate changes from baseline in systolic blood pressure at 6M, 12M, 18M, 24M	6 months, 12 months, 18 months, 24 months	To evaluate changes from baseline in systolic blood pressure at 6M, 12M, 18M, 24M
Cumulative incidence rate for each visit time point	6 months, 12 months, 18 months, 24 months	Cumulative incidence rate for each visit time point; - Death, Cardiovascular death, Heart Failure, Myocardial Infarction, Hospitalization, Aortic Valve Replacement
Changes from baseline in stroke volume index at 24M	24 months	Changes from baseline in stroke volume index at 24M
Changes from baseline in Left Ventricular ejection fraction at 24M	24 months	Changes from baseline in Left Ventricular ejection fraction at 24M

Trial Locations

Locations (1)

10 Institutions Including Asan Medical Center; 🇰🇷 Seoul, Korea, Republic of