Efficacy and Safety Study of Olmesartan Medoxomil, Amlodipine and Hydrochlorothiazide Combination Therapy in Patients With Hypertension Not Controlled With Olmesartan Medoxomil and Hydrochlorothiazide Combination Therapy

Study Overview
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Brief Summary
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CS-8635 combines three widely prescribed antihypertensive medications, olmesartan medoxomil(OM), amlodipine (AML), and hydrochlorothiazide (HCTZ), to lower blood pressure. The purpose of the study is to evaluate the efficacy and safety of triple therapy with CS-8635 compared with dual therapy in Korean patients with hypertension not controlled with dual fixed dose combination therapy (Olmetec® Plus). The treatments that will be used in this study are as follows: Run-in period -OM/HCTZ 20/12.5 mg (Olmetec® Plus 20/12.5 mg) ; Double blind treatment period - OM/AML/HCTZ 20/5/12.5mg (CS8635 20/5/12.5mg) + its matching placebo vs.OM/HCTZ 20/12.5mg (Olmetec® Plus 20/12.5 mg) + its matching placebo; Open label extension period - OM/AML/HCTZ 40/5/12.5mg (CS8635 40/5/12.5mg) or OM/AML/HCTZ 20/5/12.5mg (CS8635 20/5/12.5mg).

Detailed Description
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Please refer to arms, outcome measures and eligibility criteria for details.

Official Title
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A Randomized, Double-blind, Parallel Group Study to Evaluate the Efficacy and Safety of Triple Fixed Dose Combination Therapy With Olmesartan Medoxomil 20mg, Amlodipine 5mg and Hydrochlorothiazide 12.5mg in Patients With Hypertension Not Controlled With Dual Fixed Dose Combination Therapy With Olmesartan Medoxomil 20mg and Hydrochlorothiazide 12.5mg

Conditions
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Essential Hypertension

Intervention / Treatment
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* Drug: CS8635 20/5/12.5mg and placebo
* Drug: Olmetec® Plus 20/12.5mg and placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Screening Male or female at the age of 20 to 75 years Voluntary written informed consent to participation in this study Patients with hypertension either newly diagnosed or without treatment of antihypertensive drugs within 4 weeks of screening, who have mean seated diastolic blood pressure (msDBP) ≥ 100 mmHg at screening, or Patients who have been on a stable dose of antihypertensive drugs for at least 4 weeks before run-in period and meet the following blood pressure criteria at screening: Monotherapy: msDBP ≥ 95 mmHg, or Dual combination therapy: msDBP ≥ 90 mmHg, or Triple combination therapy: 70 mmHg ≤ msDBP < 90 mmHg Inclusion criteria for randomization msSBP/DBP at randomization: msSBP ≥ 140 mmHg (msSBP ≥ 130 mmHg in subjects with diabetes or chronic renal disease), and msDBP ≥ 90 mmHg (msDBP ≥ 80 mmHg in subjects with diabetes or chronic renal disease) Exclusion Criteria: msDBP ≥ 115mmHg or msSBP ≥ 200 mmHg measured at screening and randomization Patients with mini-max blood pressure difference of SeSBP ≥ 20 mmHg or SeDBP ≥ 10 mmHg in the chosen arm at screening Patients with blood pressure difference of SeSBP ≥ 20 mmHg and SeDBP ≥ 10 mmHg in both arms at screening Patients with hypersensitivity to the investigational product or any of its components Patients with medical history or hypersensitivity to sulfonamide, dihydropyridine, or thiazide diuretics History of secondary hypertension or history of any of the diseases suspected of secondary hypertension Symptomatic orthostatic hypotension Uncontrolled diabetes mellitus Severe heart disease, or ischemic heart disease, peripheral vascular disease Clinically significant ventricular tachycardia, atrial fibrillation, atrial flutter, or other arrhythmia considered clinically significant Hypertrophic obstructive cardiomyopathy, severe obstructive coronary artery disease, aortic stenosis, or hemodynamically significant stenosis on aortic valve or mitral valve. Severe cerebrovascular disorder Known moderate or malignant retinopathy Consumption disease , autoimmune disease, or connective tissue disease Patients requiring chronic anti-inflammatory treatment Anuria or severe renal failure Severe hepatic failure, AST or ALT > 3 times the upper limit of normal, biliary obstruction, biliary cirrhosis, or cholestasis Patients who have been treated for hyponatremia, hypokalemia, hyperkalemia, hypercalcemia, or symptomatic hyperuricemia Addison's disease Glucose-galactose malabsorption, galactose intolerance, or Lapp lactase deficiency Gastrointestinal tract disease or surgical operation that may affect absorption, distribution, metabolism, and excretion of drugs, presence of active gastritis or gastrointestinal/rectal bleeding considered clinical significant by the investigator, active inflammatory bowel syndrome within the last 12 months, etc Patients with history of or suspected of drug or alcohol abuse Pregnant or lactating women, or women of childbearing potential who do not agree to use appropriate contraceptive methods such as progestin hormone therapy (Oral, implant), intrauterine device, barrier methods of contraception (condom or occlusive cap (diaphragm or cervical/vault caps) with spermicide), male sterilisation or true abstinence Patients who participated in other clinical study within 1 month prior to screening Patients considered to be incapable of complying with the protocol

Ages Eligible for Study
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Minimum Age: 20 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: CS8635 20/5/12.5mg and placebo<br>Participants receiving Olmetec® Plus 20/12.5mg (OM/HCTZ 20/12.5 mg) for the 4-week, Run-in Period but who do not meet their blood pressure goals(Non-responders) could start receiving this triple fixed dose combination therapy (CS8635 20/5/12.5mg (OM/AML/HCTZ 20/5/12.5mg) + placebo) in randomized, 8-week, double-blind Period. The non-responders finishing double-blind treatment could continue the 8-week Open-label Period with CS8635 40/5/12.5mg (OM/AML/HCTZ 40/5/12.5 mg). | Drug: CS8635 20/5/12.5mg and placebo<br>* Run-in period: Coated, Oral tablet containing Olmesartan medoxomil(OM)-Hydrochlorothiazide(HCTZ) 20-12.5mg, given once a day. Double-blind period: Coated, Oral tablet containing Olmesartan medoxomil(OM)-Amlodipine (AML)-Hydrochlorothiazide(HCTZ) 20-5-12.5mg, oral placebo tablet. All tablets are given once a day. Open-label period: Coated, Oral tablet containing Olmesartan medoxomil(OM)-Amlodipine(AML)-Hydrochlorothiazide(HCTZ) 40-5-12.5mg, given once a day.<br>|
| Active Comparator: Olmetec® Plus 20/12.5mg and placebo<br>Participants receiving Olmetec® Plus 20/12.5mg (OM/HCTZ 20/12.5 mg) for the 4-week, Run-in Period but who do not meet their blood pressure goals(Non-responders) could start receiving this dual fixed dose combination therapy (Olmetec® Plus 20/12.5mg (OM/HCTZ 20/12.5mg) + Placebo) in randomized, 8-week, double-blind Period. The non-responders finishing double-blind treatment could continue the 8-week Open-label Period with CS8635 20/5/12.5mg (OM/AML/HCTZ 20/5/12.5 mg). | Drug: Olmetec® Plus 20/12.5mg and placebo<br>* Run-in period: Coated, Oral tablet containing Olmesartan medoxomil(OM)-Hydrochlorothiazide(HCTZ) 20-12.5mg, given once a day. Double-blind period: Coated, Oral tablet containing Olmesartan medoxomil(OM)-Hydrochlorothiazide(HCTZ) 20-12.5mg, oral placebo tablet. All tablets are given once a day. Open-label period: Coated, Oral tablet containing Olmesartan medoxomil(OM)-Amlodipine(AML)-Hydrochlorothiazide(HCTZ) 20-5-12.5mg, given once a day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The changes of seated diastolic blood pressure of the Triple Combinations OM/AML/HCTZ 20/5/12.5mg vs.OM/HCTZ 20/12.5mg |  | from baseline to week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The changes of mean seated systolic blood pressure of the Triple Combinations OM/AML/HCTZ 20/5/12.5mg vs.OM/HCTZ 20/12.5mg |  | from baseline to Week 8 | 
| The changes of mean seated systolic and diastolic blood pressure of the Triple Combinations OM/AML/HCTZ 20/5/12.5mg vs.OM/HCTZ 20/12.5mg |  | from baseline to week 4 | 
| Percentage of subjects achieving blood pressure goal of the Triple Combinations OM/AML/HCTZ 20/5/12.5mg vs.OM/HCTZ 20/12.5mg |  | at Week 4, and Week 8 | 
| Percentage of subjects achieving blood pressure goal of the Triple Combinations OM/AML/HCTZ 40/5/12.5mg vs.OM/AML/HCTZ 20/5/12.5mg |  | At week 16 | 
| The changes of mean seated systolic and diastolic blood pressure of the Triple Combinations OM/AML/HCTZ 40/5/12.5mg vs.OM/AML/HCTZ 20/5/12.5mg |  | from Week 8 to Week 16 |