Study to Confirm the Efficacy and Safety of Fixed-dose Combinations of Amlodipine and Candesartan

Study Overview
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Brief Summary
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To evaluate the efficacy and safety of amlodipine besylate and candesartan cilexetil administered in a fixed-dose combination tablet versus co-administered as their separate formulations in patients with essential hypertension who have shown inadequate response on monotherapy of amlodipine or candesartan cilexetil or who are with blood pressure adequately controlled by co-administration of amlodipine besylate and candesartan cilexetil single agents

Official Title
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A Randomized, Double-blind, Multi-center, Phase Ⅳ Clinical Trial to Evaluate the Antihypertensive Efficacy and Safety Between Amlodipine Besylate/Candesartan Cilexetil Combination Tablets and Co-administration of Amlodipine Besylate and Candesartan Cilexetil in Patients With Essential Hypertension

Conditions
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Hypertension

Intervention / Treatment
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* Drug: Group I
* Drug: Group II


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult male and female aged 19 to 75 years Diagnosed with essential hypertension Patients with essential hypertension meeting one of the following two inclusion criteria: 2.1. Patients with essential hypertension who have shown inadequate response (mean siSBP ≥ 140 mmHg or mean siDBP ≥ 90 mmHg) to treatment with amlodipine or candesartan cilexetil. 2.2. Patients with essential hypertension with blood pressure adequately controlled by co-administration of amlodipine besylate and candesartan cilexetil (mean siSBP < 140 mmHg and mean siDBP < 90 mmHg). Voluntarily consented to participate in the study and signed the informed consent form after receiving the explanation of the objectives, methods and effects of the study. Exclusion Criteria: The difference in blood pressure between the selected arm versus non-selected arm is ≥ 20 mmHg for siSBP and ≥ 10 mmHg for siDBP at Visit 1 (screening). Blood pressure taken at screening and randomization is ≥ 180 mmHg for siSBP or ≥ 110 mmHg for siDBP. Diagnosed with secondary hypertension or suspected of secondary hypertension [e.g., renovascular disease, adrenal medullary and cortical hyperfunction, coarctation of the aorta, hyperaldosteronism, unilateral or bilateral renal artery stenosis, Cushing's syndrome, pheochromocytoma, polycystic kidney disease, etc.] Patients with symptomatic orthostatic hypertension (the difference in the blood pressures between measured at supine position and measured at standing position is ≥ 20 mmHg for siSBP and ≥ 10 mmHg for siDBP) Diagnosis of type 1 diabetes mellitus (DM) or uncontrolled DM (patients on insulin therapy or with HbA1c > 9%) Patients with severe cardiac conditions: heart failure (NYHA Class 3 or 4), history of ischemic cardiac disease (unstable angina, myocardial infarction), peripheral vascular diseases, percutaneous transluminal angioplasty or coronary artery bypass graft within recent 6 months. Patients with clinically significant ventricular tachycardia, atrial fibrillation, atrial flutter or other clinically significant arrhythmia at the discretion of the investigator Patients with hypertrophic occlusive myocardiopathy, severe occlusive coronary artery disease, aortic stenosis, hemodynamically significant aortic valve or mitral valve stenosis History of cardiogenic shock Presence of severe cerebrovascular disorders (diagnosis of stroke, cerebral infarction or cerebral hemorrhage within recent 6 months) History or current evidence of wasting, autoimmune (such as rheumatoid arthritis and systemic lupus erythematosus) or connective tissue diseases Known diagnosis of moderate or malignant retinopathy (including retinal hemorrhage, visual disturbance and retinal microaneurysm within 6 months) Patients with surgical or medical intestinal diseases or having received surgeries that could interfere with drug absorption distribution, metabolism and elimination History of malignancy including leukemia and lymphoma within recent 5 years except for localized basal cell carcinoma of the skin) Patients with any inflammatory diseases requiring chronic anti-inflammatory therapy Renal failure on dialysis Laboratory abnormalities as follows: AST or ALT >2 x upper limit of normal (ULN) Serum creatinine > 1.5 x ULN Serum potassium < 3.5 mmol/L or >5.5 mmol/L Needs for co-administration of non-study antihypertensive agents or contraindicated medications during the study History of hypersensitivity to ARBs or dihydropyridines History of angioedema to treatment with ACE inhibitors or ARBs Pregnant or lactating women and female volunteers of childbearing potential (except for women who are surgically sterile) who are not willing to use an adequate method of contraception (oral contraceptives, intrauterine device, condom, etc.) during the study. Women of childbearing potential who are not surgically sterile will be allowed to participate in the study only if they have negative pregnancy test at Visit 1 (screening) and should continue to use medically acceptable method of contraception (basic body temperature method and rhythm method will not be allowed). Women with no menses for ≥ 12 months will be considered as postmenopausal state and method of contraception using hormonal contraception such as oral contraceptive should be initiated from or prior to the screening. History of drug or alcohol abuse within recent 1 year Patients having received any other investigational product within recent 12 weeks Conditions which render a subject ineligible for the study at the discretion of the investigator

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 75 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I<br>Fixed-Dose combination of Candesartan cilexetil 8mg and Amlodipine 5mg(or Fixed-Dose combination of Candesartan cilexetil 16mg and Amlodipine 5mg), once a day for 8 weeks | Drug: Group I<br>* Machkhan Tab. 8/5 mg + Atacan Tab. 8 mg placebo + Norvasc Tab. 5 mg placebo for 8 weeks or Machkhan Tab. 16/5 mg + Atacan Tab. 16 mg placebo + Norvasc Tab. 5 mg placebo for 8 weeks<br>* Other names: Machkhan Tab. 8/5 mg(or Machkhan Tab. 16/5 mg);|
| Active Comparator: Group II<br>Candesartan cilexetil 8mg and Amlodipine 5mg(or Candesartan cilexetil 16mg and Amlodipine 5mg), once a day for 8 weeks | Drug: Group II<br>* Atacan Tab. 8 mg + Norvasc Tab. 5 mg + Machkhan Tab.8/5 mg placebo for 8 weeks or Atacan Tab. 16 mg + Norvasc Tab. 5 mg + Machkhan Tab.16/5 mg placebo for 8 weeks<br>* Other names: Atacan Tab. 8 mg(or Atacan Tab. 16 mg), Norvasc Tab. 5 mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in sitting Systolic Blood Pressure(siSBP) from baseline after 8 weeks of treatment | For change in siSBP from baseline after 8 weeks of treatment, the mean, standard deviation, median, minimum and maximum will be presented by treatment arm. The LS mean change in siSBP from baseline after 8 weeks of treatment adjusted for baseline siSBP and its standard error will be presented by treatment arm. Non-inferiority test will be conducted using ANCOVA including change in siSBP from baseline after 8 weeks of treatment as response variable and baseline siSBP and treatment arm as independent variables. Amlodipine besylate/candesartan cilexetil combination tablet will be considered non-inferior to co-administration of amlodipine besylate and candesartan cilexetil if the lower bound of 2-sided 95% CI for the LS mean of difference in siSBP change between the treatment arms is greater than -5. | Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in siSBP from baseline after 4 weeks of treatment | For change in siSBP from baseline after 4 weeks of treatment, the mean, standard deviation, median, minimum and maximum will be presented by treatment arm. The LS mean change in siSBP from baseline after 4 weeks of treatment adjusted for baseline siSBP and its standard error will be presented by treatment arm. Non-inferiority test will be conducted using ANCOVA including change in siSBP from baseline after 4 weeks of treatment as response variable and baseline siSBP and treatment arm as independent variables. Amlodipine besylate/candesartan cilexetil combination tablet will be considered non-inferior to co-administration of amlodipine besylate and candesartan cilexetil if the lower bound of 2-sided 95% CI for the LS mean of difference in siSBP change between the treatment arms is greater than -5. | Week 4 | 
| Change in siDBP from baseline after 4 and 8 weeks of treatment | For change in siDBP from baseline after 4 and 8 weeks of treatment, the mean, standard deviation, median, minimum and maximum will be presented by treatment arm. The LS mean change in siSBP from baseline after 4 and 8 weeks of treatment adjusted for baseline siDBP and its standard error will be presented by treatment arm. Non-inferiority test will be conducted using ANCOVA including change in siDBP from baseline after 4 and 8 weeks of treatment as response variable and baseline siDBP and treatment arm as independent variables. Amlodipine besylate/candesartan cilexetil combination tablet will be considered non-inferior to co-administration of amlodipine besylate and candesartan cilexetil if the lower bound of 2-sided 95% CI for the LS mean of difference in siSBP change between the treatment arms is greater than -5. | Week 4 and Week 8 | 
| Proportion of subjects with siDBP < 90 mmHg and siSBP <140 mmHg after 8 weeks of treatment | The frequency and percentage of subjects with siDBP < 90 mmHg and the frequency and percentage of subjects with siSBP < 140 mmHg after 8 weeks of treatment will be presented by treatment arm. Additionally, the frequency and percentage of subjects with both siDBP < 90 mmHg and siSBP <140 mmHg after 8 weeks of treatment will be presented by treatment arm. The difference in proportion between treatment arms will be tested using the χ2 test or Fisher's exact test. | Week8 |