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

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

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.

Study Overview

• Status: Completed
• Conditions: Grade I or II Essential Hypertension
• Intervention / Treatment: Drug: TAK-536CCB; Drug: TAK-536CCB + Hydrochlorothiazide; Drug: TAK-536CCB + Hydrochlorothiazide; Drug: Hydrochlorothiazide; Drug: Hydrochlorothiazide

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 353
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Japan
  • Ehime
    • Touon-shi, Ehime, Japan
  • Fukuoka
    • Fukuoka-shi, Fukuoka, Japan
  • Hiroshima
    • Hiroshima-shi, Hiroshima, Japan
  • Hokkaido
    • Sapporo-shi, Hokkaido, Japan
  • Iwate
    • Hanamaki-shi, Iwate, Japan
    • Morioka-shi, Iwate, Japan
  • Kumamoto
    • Kumamoto-shi, Kumamoto, Japan
  • Kyoto
    • Kyoto-shi, Kyoto, Japan
  • Miyagi
    • Sendai-shi, Miyagi, Japan
  • Osaka
    • Osaka-shi, Osaka, Japan
    • Suita-shi, Osaka, Japan
  • Tokyo
    • Shinjuku-ku, Tokyo, Japan
  • Toyama
    • Toyama-shi, Toyama, Japan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Grade I or II essential hypertension.
2. 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.
3. Male or female aged 20 years or older at the time of providing informed consent.
4. Outpatient.

Exclusion Criteria:

1. Secondary hypertension, grade III hypertension or malignant hypertension.
2. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: TAK-536CCB 20 mg/5 mg ＋Placebo (dual therapy); TAK-536CCB 20 mg/5 mg and Hydrochlorothiazide (HCTZ) placebo for 10 weeks	Drug: TAK-536CCB; TAK-536CCB 20 mg/5 mg ＋Hydrochlorothiazide placebo tablets; Other Names: Fix-dose combination of Azilsartan and Amlodipine
Experimental: TAK-536CCB 20 mg/5 mg ＋HCTZ 6.25 mg (triple therapy); 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; TAK-536CCB 20 mg/5 mg and Hydrochlorothiazide 6.25 mg tablets; Other Names: Hydrochlorothiazide and fix-dose combination of Azilsartan and Amlodipine; Drug: TAK-536CCB + Hydrochlorothiazide; TAK-536CCB 20 mg/5 mg and Hydrochlorothiazide 6.25 mg tablets x2; Other Names: Hydrochlorothiazide and fix-dose combination of Azilsartan and Amlodipine
Experimental: TAK-536CCB 20 mg/5 mg ＋HCTZ 12.5 mg (triple therapy); 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; TAK-536CCB 20 mg/5 mg and Hydrochlorothiazide 6.25 mg tablets; Other Names: Hydrochlorothiazide and fix-dose combination of Azilsartan and Amlodipine; Drug: TAK-536CCB + Hydrochlorothiazide; TAK-536CCB 20 mg/5 mg and Hydrochlorothiazide 6.25 mg tablets x2; Other Names: Hydrochlorothiazide and fix-dose combination of Azilsartan and Amlodipine
Active Comparator: Placebo ＋HCTZ 6.25 mg (HCTZ monotherapy); TAK-536CCB placebo and Hydrochlorothiazide 6.25 mg (HCTZ monotherapy) for 10 weeks from the start of the treatment period.	Drug: Hydrochlorothiazide; TAK-536CCB placebo and Hydrochlorothiazide 6.25 mg tablets; Drug: Hydrochlorothiazide; TAK-536CCB placebo and Hydrochlorothiazide 6.25 mg tablets x2
Active Comparator: Placebo ＋Hydrochlorothiazide 12.5 mg (HCTZ monotherapy); TAK-536CCB placebo and Hydrochlorothiazide 12.5 mg (HCTZ monotherapy) for 10 weeks from the start of the treatment period.	Drug: Hydrochlorothiazide; TAK-536CCB placebo and Hydrochlorothiazide 6.25 mg tablets; Drug: Hydrochlorothiazide; TAK-536CCB placebo and Hydrochlorothiazide 6.25 mg tablets x2

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Takeda

Study record dates

Study Major Dates

• Study Start: March 1, 2013
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: February 24, 2014
• First Submitted That Met QC Criteria: February 24, 2014
• First Posted (Estimate): February 26, 2014

Study Record Updates

• Last Update Posted (Estimate): February 26, 2014
• Last Update Submitted That Met QC Criteria: February 24, 2014
• Last Verified: February 1, 2014

More Information

Terms related to this study

• Keywords: Hypertension, Drug therapy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Essential Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Sodium Chloride Symporter Inhibitors; Amlodipine; Hydrochlorothiazide; Azilsartan medoxomil
• Other Study ID Numbers: TAK-536TCH/CCT-001; JapicCTI-121962 (Registry Identifier: Japic CTI)