Study to Evaluate the Efficacy and Safety of Combined Administration of TAK-536CCB and Hydrochlorothiazide in Patients With Grade I or II Essential Hypertension.

Study Overview
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Brief Summary
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The objective of this study is to compare the efficacy and safety of combined administration of TAK-536CCB (Fix-dose combination of Azilsartan and Amlodipine) and Hydrochlorothiazide (HCTZ) with those of TAK-536CCB in patients with Grade I or II essential hypertension.

Detailed Description
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This study is a randomized, double-blind, multicenter, phase 2/3 study to evaluate the efficacy and safety of combined administration of TAK-536CCB and Hydrochlorothiazide (HCTZ) with those of TAK-536CCB or Hydrochlorothiazide in patients with grade I or II essential hypertension. This study consists of a 4-week single-blind placebo run-in period and a 10-week double-blind treatment period.

Official Title
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A Randomized, Double-Blind, Multicenter, Phase 2/3 Study to Evaluate the Efficacy and Safety of Combined Administration of TAK-536CCB (Fix-dose Combination of Azilsartan and Amlodipine) and Hydrochlorothiazide in Comparison With TAK-536CCB or Hydrochlorothiazide Monotherapy in Patients With Grade I or II Essential Hypertension

Conditions
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Grade I or II Essential Hypertension

Intervention / Treatment
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* Drug: TAK-536CCB
* Drug: TAK-536CCB + Hydrochlorothiazide
* Drug: Hydrochlorothiazide
* Drug: Hydrochlorothiazide
* Drug: TAK-536CCB + Hydrochlorothiazide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Grade I or II essential hypertension. An office sitting systolic blood pressure of ≥ 150 and < 180 mmHg, and an office sitting diastolic blood pressure of ≥ 95 and < 110 mmHg during the placebo run-in period at Week -2 and Week 0. Male or female aged 20 years or older at the time of providing informed consent. Outpatient. Exclusion Criteria: Secondary hypertension, grade III hypertension or malignant hypertension. An office sitting systolic blood pressure of ≥160 mmHg or sitting diastolic blood pressure of ≥100 mmHg recorded while on combined therapy with 3 or more antihypertensives within 4 weeks prior to the initiation of the placebo run-in period and at Week -4. 3 Evident white coat hypertension or white coat phenomenon. 4. Day-night reversed lifestyle, such as night-time workers. 5. Sleep apnea syndrome requiring treatment. 6. Have any of the cardiovascular disease or symptoms listed below: Heart disease: myocardial infarction (within 24 weeks before the placebo run-in period), coronary arterial revascularization (within 24 weeks before the placebo run-in period), severe valvular disease, atrial fibrillation, or following diseases which require medication: angina pectoris, congested heart failure, or arrhythmia. Cerebrovascular disease: cerebral infarction, cerebral hemorrhage (within 24 weeks before the placebo run-in period), or transient ischemic attack (within 24 weeks before the placebo run-in period). Vascular diseases: peripheral arterial disease with intermittent claudication, artery dissection, aneurysm Advanced hypertensive retinopathy: bleeding, exudation, or papilledema (within 24 weeks before the placebo run-in period). 7. Clinically significant hepatic disorder. 8. Clinically significant renal impairment. 9. Significantly low or high Potassium or Sodium levels. 10. Complicated by gout, or had a past history of gout within 24 weeks prior to the initiation of the placebo run-in period, or complicated by hyperuricemia requiring medication. 11. Diabetic subject on insulin treatment or poorly controlled type 2 diabetes mellitus. 12. Have a malignant tumor.

Ages Eligible for Study
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Minimum Age: 20 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 |
| --- | --- |
| Active Comparator: TAK-536CCB 20 mg/5 mg ＋Placebo (dual therapy)<br>TAK-536CCB 20 mg/5 mg and Hydrochlorothiazide (HCTZ) placebo for 10 weeks | Drug: TAK-536CCB<br>* TAK-536CCB 20 mg/5 mg ＋Hydrochlorothiazide placebo tablets<br>* Other names: Fix-dose combination of Azilsartan and Amlodipine;|
| Experimental: TAK-536CCB 20 mg/5 mg ＋HCTZ 6.25 mg (triple therapy)<br>TAK-536CCB 20 mg/5 mg and Hydrochlorothiazide placebo (triple therapy) for the first 2 weeks of the treatment period and TAK-536CCB 20 mg/5 mg and HCTZ 6.25 mg for the remaining 8 weeks. | Drug: TAK-536CCB + Hydrochlorothiazide<br>* TAK-536CCB 20 mg/5 mg and Hydrochlorothiazide 6.25 mg tablets<br>* Other names: Hydrochlorothiazide and fix-dose combination of Azilsartan and Amlodipine;|
| Experimental: TAK-536CCB 20 mg/5 mg ＋HCTZ 12.5 mg (triple therapy)<br>TAK-536CCB 20 mg/5 mg and Hydrochlorothiazide placebo for the first 2 weeks of the treatment period and TAK-536CCB 20 mg/5 mg and HCTZ 12.5 mg (triple therapy) for the remaining 8 weeks. | Drug: TAK-536CCB + Hydrochlorothiazide<br>* TAK-536CCB 20 mg/5 mg and Hydrochlorothiazide 6.25 mg tablets x2<br>* Other names: Hydrochlorothiazide and fix-dose combination of Azilsartan and Amlodipine;|
| Active Comparator: Placebo ＋HCTZ 6.25 mg (HCTZ monotherapy)<br>TAK-536CCB placebo and Hydrochlorothiazide 6.25 mg (HCTZ monotherapy) for 10 weeks from the start of the treatment period. | Drug: Hydrochlorothiazide<br>* TAK-536CCB placebo and Hydrochlorothiazide 6.25 mg tablets<br>|
| Active Comparator: Placebo ＋Hydrochlorothiazide 12.5 mg (HCTZ monotherapy)<br>TAK-536CCB placebo and Hydrochlorothiazide 12.5 mg (HCTZ monotherapy) for 10 weeks from the start of the treatment period. | Drug: Hydrochlorothiazide<br>* TAK-536CCB placebo and Hydrochlorothiazide 6.25 mg tablets x2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in the office trough sitting diastolic blood pressure (DBP) | Change in the office trough sitting DBP from the end of the placebo run-in period (baseline [Week 0]) to the end of the treatment period (Week 10, last observation carried forward [LOCF]) | Baseline and Week 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in the office trough sitting systolic blood pressure (SBP) | Change in the office trough sitting SBP from the end of the placebo run-in period (baseline [Week 0]) to the end of the treatment period (Week 10, last observation carried forward [LOCF]) | Baseline and Week 10 | 
| Proportion of patients achieving < 140/90 mmHg | Patients achieving < 140/90 mmHg refer to those meeting both of the following criteria: A decrease to < 90 mmHg in office trough sitting DBP A decrease to < 140 mmHg in office trough sitting SBP | 10 weeks | 
| Proportion of responders (140/90 mmHg criterion) | Patients who met either of the following conditions are regarded as responders (140/90 mmHg criterion). A ≥ 20 mmHg decrease in office trough sitting SBP and a ≥ 10 mmHg decrease in the office trough sitting DBP A decrease to < 140 mmHg in office trough sitting SBP and a decrease to < 90 mmHg in office trough sitting DBP | 10 weeks | 
| Frequency of adverse events( including vital sign, body weight, ECG findings and laboratory tests) | The frequency of adverse events by type, seriousness. Adverse events are defined as any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal product reported from first dose of study drug to the last dose of study drug | 10 weeks | 
| Time profile of office trough sitting diastolic blood pressure |  | 10 weeks | 
| Time profile of office trough sitting systolic blood pressure |  | 10 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypertension, Drug therapy