A Phase 2 Dose Selection Trial of Candesartan Cilexetil and Amlodipine Besylate to Treat Essential Hypertension

Study Overview
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Brief Summary
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The purpose of this study is to explore the optimal dose of fixed-dose combination of candesartan cilexetil and amlodipine besylate by examining the safety and efficacy of the combination therapy compared to each of the monotherapy in patients with essential hypertension.

Official Title
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A Randomized, Double-blind, Multi-center, PhaseⅡ Clinical Trial to Evaluate the Antihypertensive Efficacy and Safety of Candesartan Cilexetil and Amlodipine Besylate for the Dose Selection in Patients With Essential Hypertension

Conditions
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Essential Hypertension

Intervention / Treatment
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* Drug: Amlodipine 5mg
* Drug: Amlodipine 10mg
* Drug: Candesartan Cilexetil 8mg
* Drug: Candesartan cilexetil 16mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged ≥ 19 and ≤ 75 years old Subject with mild-to-moderate uncomplicated essential hypertension Subject who have voluntarily agreed to participate in the trial and signed the written informed consent form, after having listened to the purpose, method, and effect of the clinical trial Exclusion Criteria: Subject with severe hypertension (siDBP ≥ 115 mmHg or siSBP ≥ 185 mmHg) Subject with difference in the mean blood pressure of over 10mmHg for siDBP or 20mmHg for siSBP between both arms at the screening visit Subject with known or suspected secondary hypertension [including but not limited to any of the following: renovascular hypertension, adrenal medullary and cortical hyperfunction, coarctation of the aorta, primary hyperaldosteronism, unilateral or bilateral renal artery stenosis, Cushing's disease, pheochromocytoma, polycystic kidney disease, etc.] Subject with symptomatic orthostatic hypotension (a sudden fall in siDBP of at least 10 mmHg or siSBP of at least 20 mmHg after standing compared with blood pressure from the sitting or supine position) Subject with Type 1 diabetes mellitus OR Type 2 diabetes mellitus with poor glucose control (defined as subject on insulin treatment, with HbA1c > 9.0%, or with a modification in the oral anti-hyperglycemic medication regiment within the past 12 weeks prior to Visit 1) Subject with severe heart disease (Congestive heart failure (NYHA Class III-IV), ischemic heart disease within the past 6 months (unstable angina, myocardial infarction), peripheral vascular disease, history of Percutaneous Transluminal Coronary Angioplasty or Coronary Artery Bypass Grafting) Subject with clinically significant ventricular tachycardia, atrial fibrillation, atrial flutter or other clinically significant arrhythmia Subject with hypertrophic obstructive cardiomyopathy, severe obstructive coronary artery disease, aortic stenosis, haemodynamically relevant stenosis of the aortic or mitral valve Subject with severe cerebrovascular disease (history of stroke, cerebral infarction, or cerebral hemorrhage within the past 6 months) Subject with or with a history of wasting disease, autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus), or connective tissue disease Subject with known moderate or malignant retinopathy (history of retinal signs of hemorrhage, visual impairment, retinal microaneurysm, etc. within the past 6 months) Subject with the following clinically significant laboratory abnormalities: AST or ALT > 3 x Upper Limit Normal (ULN) Serum Creatinine > 1.5 ULN Serum potassium < 3.5 mmol/L or > 5.5 mmol/L Subject with any surgical or medical condition of the gastrointestinal tract that might significantly alter the absorption, distribution, metabolism or excretion of the drug Subject with a history of malignant tumors including leukemia and lymphoma within the past 5 years (except for localized basal cell carcinoma of the skin) Subject with any chronic inflammatory condition needing chronic anti-inflammatory therapy Subject with chronic kidney disease on dialysis Subject with cardiogenic shock Subject requiring concomitant use of other antihypertensive or contraindicated drugs during the entire study period Subject with known or suspected contraindications, including history of allergy or hypersensitivity to ARB or dihydropyridine derivatives Subject who have previously experienced symptoms characteristic of angioedema during treatment with ACE inhibitors or ARB Pregnant women, lactating mothers, women suspected of being pregnant, women who wish to be pregnant during the study, or women of child-bearing potential who are not using medically acceptable methods of contraception (oral contraceptive, intra-uterine device, condom, etc.), except for women with surgical sterilization. Pre-menopausal women who are not surgically sterilized must have a negative pregnancy test result at Visit 1 and maintain acceptable methods of contraception throughout the study. Periodic abstinence (eg, symptothermal, calendar, post-ovulation methods), or hormonal contraceptive are not acceptable methods of contraception History of drug or alcohol abuse within the past 1 year Use of other investigational products within the past 4 weeks Subject who are judged unsuitable to participate in the study in the opinion 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: AML 5mg<br>Amlodipine 5 mg, once a day for 8 weeks | Drug: Amlodipine 5mg<br>* Daily oral administration for 8 weeks<br>* Other names: Norvasc 5mg;|
| Experimental: AML 10mg<br>Amlodipine 10 mg, once a day for 8 weeks | Drug: Amlodipine 10mg<br>* Daily oral administration for 8 weeks<br>* Other names: Norvasc 10mg;|
| Experimental: CC 8mg<br>Candesartan Cilexetil 8 mg, once a day for 8 weeks | Drug: Candesartan Cilexetil 8mg<br>* Daily oral administration for 8 weeks<br>* Other names: Atacand 8mg;|
| Experimental: CC 16mg<br>Candesartan Cilexetil 16 mg, once a day for 8 weeks | Drug: Candesartan cilexetil 16mg<br>* Daily oral administration for 8 weeks<br>* Other names: Atacand 16mg;|
| Experimental: AML 5mg/CC 8mg<br>Amlodipine 5 mg and Candesartan 8 mg, once a day for 8 weeks | Drug: Amlodipine 5mg<br>* Daily oral administration for 8 weeks<br>* Other names: Norvasc 5mg;Drug: Candesartan Cilexetil 8mg<br>* Daily oral administration for 8 weeks<br>* Other names: Atacand 8mg;|
| Experimental: AML 5mg/CC16mg<br>Amlodipine 5 mg and Candesartan Cilexetil 16 mg, once a day for 8 weeks | Drug: Amlodipine 5mg<br>* Daily oral administration for 8 weeks<br>* Other names: Norvasc 5mg;Drug: Candesartan cilexetil 16mg<br>* Daily oral administration for 8 weeks<br>* Other names: Atacand 16mg;|
| Experimental: AML 10mg/CC 8mg<br>Amlodipine 10 mg and Candesartan Cilexetil 8 mg, once a day for 8 weeks | Drug: Amlodipine 10mg<br>* Daily oral administration for 8 weeks<br>* Other names: Norvasc 10mg;Drug: Candesartan Cilexetil 8mg<br>* Daily oral administration for 8 weeks<br>* Other names: Atacand 8mg;|
| Experimental: AML 10mg/CC 16mg<br>Amlodipine 10 mg and Candesartan Cilexetil 16 mg, once a day for 8 weeks | Drug: Amlodipine 10mg<br>* Daily oral administration for 8 weeks<br>* Other names: Norvasc 10mg;Drug: Candesartan cilexetil 16mg<br>* Daily oral administration for 8 weeks<br>* Other names: Atacand 16mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in sitting Diastolic Blood Pressure (siDBP) at week 8 compared to baseline |  | Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in sitting Systolic Blood Pressure (siSBP) at week 4 and 8 |  | Week 4 and 8 | 
| Change in siDBP at week 4 |  | Week 4 | 
| Proportion of patients achieving ΔsiDBP > 10 mmHg and ΔsiSBP < 20 mmHg after 8 weeks |  | Week 8 | 
| Proportion of patients achieving siDBP < 90 mmHg and siSBP < 120 mmHg after 8 weeks |  | Week 8 |