A Phase III Long-term Study of TAK-536TCH in Participants With Essential Hypertension

The drug being tested in this study is called TAK-536TCH. TAK-536TCH is being tested to treat people who have essential hypertension. The study looked at effectiveness and long-term safety of TAK-536TCH in people who took TAK-536CCB in addition to standard care.

The study enrolled 341 patients. Participants received:

• TAK-536CCB (as TAK-536/AML, 20 mg/5 mg) in run-in period,
• TAK-536TCH (as TAK-536/ AML/HCTZ, 20 mg/5 mg/12.5 mg) in treatment period
• TAK-536CCB and HCTZ 12.5 mg in treatment period

All participants were asked to take tablets at the same time each day throughout the study.

This multi-center trial was conducted in Japan. The overall time to participate in this study was 56 weeks (4 weeks run-in period and 52 weeks treatment period). Participants made multiple visits to the clinic during the study.

Inclusion criteria

• In the opinion of the investigator or subinvestigator, the participant is capable of understanding and complying with protocol requirements.
• The participant signs and dates a written informed consent form prior to the initiation of any study procedures.
• The participant has essential hypertension.
• The participant has an office sitting systolic blood pressure (SBP) of <180 mmHg and office sitting diastolic blood pressure (DBP) of < 110 mmHg at the start of the run-in period (Week -4). Participants receiving combined therapy with a 3-drug antihypertensive within 4 weeks prior to the start of the run-in period is required to have an office sitting SBP of < 160 mmHg and an office sitting DBP of < 100 mmHg.
• The participant's office sitting blood pressure at Week -2 and at the end of the run-in period (Week 0) need to be either:

• Participants without concurrent diabetes mellitus or chronic kidney disease (CKD)*: Sitting SBP of ≥ 140 mmHg or sitting DBP of ≥ 90 mmHg
• Participants with concurrent diabetes mellitus or CKD*: Sitting SBP of ≥ 130 mmHg or sitting DBP of ≥ 80 mmHg.

• Estimate glomerular filtration rate according to creatinine (eGFRcreat) of <60 mL/min/1.73 m^2, or urinary albumin (spot urine) of ≥30 μg/mL in laboratory tests performed at Week -2 of the run-in period, and diagnosed with CKD by the investigator or subinvestigator.
• The participant has an office sitting SBP of < 160 mmHg and office sitting DBP of < 100 mmHg at the end of the run-in period (Week 0).
• The participant is male or female, aged 20 years or older at the time of providing informed consent.
• The participant is an outpatient.
• A female participant of childbearing potential who is sexually active with a nonsterilized male partner agree to use routinely adequate contraception from signing of informed consent through 1 month following the end of the study.

Exclusion criteria

• The participant has received any study drugs within 12 weeks prior to the start of the run-in period.
• The participant has participated in another clinical study or a post-marketing study within 30 days prior to the start of the run-in period.
• The participant is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (e.g. spouse, parent, child, sibling), or may consent under duress.
• The participant requires taking prohibited concomitant drugs during the study.
• The participant has a history of hypersensitivity or allergies to TAK-536, AML, HCTZ, any thiazide diuretic or analog, any dihydropyridine drug, or any analog of TAK-536TCH.
• The participant is judged by the investigator or subinvestigator to be in danger of experiencing an excessive increase in blood pressure when changing or discontinuing premedication.
• The participant received combination therapy with antihypertensive drugs of the 3 ingredients contained in TAK-536TCH.
• The participant received combined therapy with antihypertensive drugs, including 4 or more components, within 4 weeks prior to the start of the run-in period.
• The participant has secondary or malignant hypertension.
• The participant has a difference of ≥ 20 mmHg between left and right arms in office sitting SBP at the start of the run-in period (Week -4).
• The participant has apparent white coat hypertension or exhibits a white coat effect.
• . The participant has a day-night reversed lifestyle, such as those working during the night.
• The participant has sleep apnea syndrome requiring treatment.
• The participant has any of the following cardiovascular diseases:

• Cardiac disease: Myocardial infarction*, coronary arterial revascularization*, severe valvular disorder, atrial fibrillation, any of the following conditions requiring treatment: angina pectoris, congestive heart failure, arrhythmia
• Cerebrovascular disorders: Cerebral infarction/cerebral hemorrhage*, transient ischemic attack*
• Vascular disease: Peripheral artery disease with intermittent claudication, artery dissection, aneurysm
• Advanced hypertensive retinopathy: With bleeding or exudate/papilledema** * Occurring or performed within 24 weeks of the start of the run-in period ** Observed within 24 weeks of the start of the run-in period
• The participant has a clinically apparent hepatic disorder (e.g., aspartate aminotransferase (AST) or alanine aminotransferase (ALT) at Week -2 of the run-in period ≥ 2.5 times the upper limit of normal (ULN).
• The participant has a clinically severe renal disorder (e.g., eGFRcreat in laboratory tests performed at Week -2 of run-in period < 30 mL/minute/1.73 m^2).
• The participant's body fluid sodium or potassium level is markedly low* or high*.

*Based on normal ranges

• The participant has gout or a history of gout within 24 weeks of the start of the run-in period or has hyperuricemia requiring drug treatment.
• The participant has uncontrolled diabetes (e.g., HbA1c ≥ 7.4% in laboratory tests performed at Week -2 of the run-in period).
• The participant has a malignant tumor.
• If female, the participant is pregnant or lactating or before giving informed consent, intending to become pregnant or donate ova during or within 1 month after participating in the study.
• The participant has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 2 years prior to the run-in period.
• The participant who, in the opinion of the investigator or subinvestigator, is unsuitable for any other reason.