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

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02277691
• Collaborator: (none)
• Enrollment: 341
• Locations: 38
• Arm: 1
• Actual Duration (Months): 17.6
• Patients Per Site: 9
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety of long-term administration of TAK-536, amlodipine (AML), and hydrochlorothiazide (HCTZ) in participants with essential hypertension.

Condition or Disease	Intervention/Treatment	Phase
Essential Hypertension	Drug: TAK-536TCH tablet; Drug: TAK-536CCB tablet; Drug: HCTZ 12.5 mg tablet	Phase 3

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 341 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Open-label, Multicenter, Long-term Study to Evaluate the Safety and Efficacy of TAK-536, Amlodipine and Hydrochlorothiazide in Subjects With Essential Hypertension
• Actual Study Start Date: Nov 7, 2014
• Actual Primary Completion Date: Apr 25, 2016
• Actual Study Completion Date: Apr 25, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: TAK-536TCH For 4 weeks during the run-in period, one tablet of TAK-536CCB (as TAK-536/AML, 20 mg/5 mg, respectively) orally, once daily, before or after breakfast. For 48 weeks during 52 weeks of the treatment period, one tablet of TAK-536TCH (as TAK-536/AML/HCTZ, 20 mg/5 mg/12.5 mg, respectively) orally, once daily, before or after breakfast. For the remaining 4 weeks of the treatment period, one tablet each of TAK-536CCB and HCTZ 12.5 mg orally, once daily, before or after breakfast.

Drug: TAK-536TCH tablet; TAK-536TCH tablets; Drug: TAK-536CCB tablet; TAK-536CCB tablets; Drug: HCTZ 12.5 mg tablet; HCTZ tablets

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Experience at Least One Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [Baseline up to Week 52]

   An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A Serious Adverse Event (SAE) A serious is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.

2. Number of Participants With Markedly Abnormal Vital Signs Values [Baseline up to Week 52]

   Vital signs included supine and standing systolic and diastolic blood pressure (SBP and DBP) respectively and office sitting pulse. Vital signs were considered abnormal if they were beyond the values defined in categories.

3. Number of Participants With Treatment Emergent Adverse Event (TEAE) Related to Body Weight [Baseline up to Week 52]

   Reported TEAE is categorized into investigations System Organ Class (SOC) related to body weight.

4. Number of Participants With Treatment Emergent Adverse Event (TEAE) Related to Electrocardiogram (ECG) [Baseline up to Week 52]

   Reported TEAE is categorized into cardiac disorders and investigations system organ class (SOC) related to ECG.

5. Number of Participants With Markedly Abnormal Clinical Laboratory Tests [Baseline up to Week 52]

   The number of participants with any markedly abnormal clinical laboratory test values collected throughout study. RBC = Red blood cells, ALT = alanine aminotransferase, AST = aspartate aminotransferase, GGT = gamma-glutamyl transferase, LLN = lower limit of normal or lower reference limit, ULN = upper limit of normal or upper reference limit. Laboratory vallues were considered abnormal if they were beyond the values defined in categories.

Secondary Outcome Measures

1. Change From Baseline in Office Trough Sitting Clinic Systolic and Diastolic Blood Pressure at Each Visit [Baseline (End of Run-in Period, Week 0) and Weeks 12 (LOCF) and 52 (LOCF)]

   The change in office trough SBP and DBP measured at Weeks 12 last observation was carried forward (LOCF) and 52 (LOCF) relative to baseline. Sitting blood pressure was measured at least 3 times. Each measurement session ended once blood pressure was found stable at 2 consecutive measurements. The average of the last 2 measurements of office sitting blood pressure was used.

2. Change From Baseline in Home Sitting Clinic Systolic and Diastolic Blood Pressure at Each Visit [Baseline (End of Run-in Period, Week 0), End of Week 12 and End of Treatment (Up to Week 52)]

   The change in home morning SPB and DBP measured at End of Week 12, End of Treatment (Up to Week 52) relative to baseline.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. In the opinion of the investigator or subinvestigator, the participant is capable of understanding and complying with protocol requirements.

2. The participant signs and dates a written informed consent form prior to the initiation of any study procedures.

3. The participant has essential hypertension.

4. 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.

5. 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.

1. 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).

2. The participant is male or female, aged 20 years or older at the time of providing informed consent.

3. The participant is an outpatient.

4. 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:

1. The participant has received any study drugs within 12 weeks prior to the start of the run-in period.

2. 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.

3. 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.

4. The participant requires taking prohibited concomitant drugs during the study.

5. 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.

6. 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.

7. The participant received combination therapy with antihypertensive drugs of the 3 ingredients contained in TAK-536TCH.

8. 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.

9. The participant has secondary or malignant hypertension.

10. 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).

11. The participant has apparent white coat hypertension or exhibits a white coat effect.

12. . The participant has a day-night reversed lifestyle, such as those working during the night.

13. The participant has sleep apnea syndrome requiring treatment.

14. 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

1. 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).

2. 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).

3. The participant's body fluid sodium or potassium level is markedly low* or high*.

*Based on normal ranges

1. 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.

2. The participant has uncontrolled diabetes (e.g., HbA1c ≥ 7.4% in laboratory tests performed at Week -2 of the run-in period).

3. The participant has a malignant tumor.

4. 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.

5. 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.

6. The participant who, in the opinion of the investigator or subinvestigator, is unsuitable for any other reason.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Nagoya-shi	Aichi	Japan
2		Chiba-shi	Chiba	Japan
3		Itojima-shi	Fukuoka	Japan
4		Kouriyama-shi	Fukushima	Japan
5		Sapporo-shi	Hokkaido	Japan
6		Amagasaki-shi	Hyougo	Japan
7		Tsukuba-shi	Ibaragi	Japan
8		Morioka-shi	Iwate	Japan
9		Sakaide-shi	Kagawa	Japan
10		Takamatsu-shi	Kagawa	Japan
11		Kawasaki-shi	Kanagawa	Japan
12		Kyoto-shi	Kyoto	Japan
13		Uji-shi	Kyoto	Japan
14		Sendai-shi	Miyagi	Japan
15		Hirakata-shi	Osaka	Japan
16		Osaka-shi	Osaka	Japan
17		Takatsuki-shi	Osaka	Japan
18		Saitama-shi	Saitama	Japan
19		Tokorozawa-shi	Saitama	Japan
20		Yaizu-shi	Shizuoka	Japan
21		Chiyoda-ku	Tokyo	Japan
22		Choufu-shi	Tokyo	Japan
23		Kodaira-shi	Tokyo	Japan
24		Koutou-ku	Tokyo	Japan
25		Setagaya-ku	Tokyo	Japan
26		Shinagawa-ku	Tokyo	Japan
27		Shinjuku-ku	Tokyo	Japan
28		Choufu-shi		Japan
29		Kawasaki-shi		Japan
30		Koutou-ku		Japan
31		Morioka-shi		Japan
32		Sakaide-shi		Japan
33		Setagaya-ku		Japan
34		Shinagawa-ku		Japan
35		Shinjuku-ku		Japan
36		Tsukuba-shi		Japan
37		Uji-shi		Japan
38		Yaizu-shi		Japan

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director Clinical Science, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT02277691
• Other Study ID Numbers: TAK-536TCH/OCT-001; U1111-1163-0169; JapicCTI-142689
• First Posted: Oct 29, 2014
• Last Update Posted: Aug 2, 2017
• Last Verified: Jun 1, 2017

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Takeda: Pharmacological therapy; Drug Therapy
• Additional relevant MeSH terms: Hypertension; Essential Hypertension; Azilsartan medoxomil

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 31 investigative sites in Japan, from 07 November 2014 to 25 April 2016.
Pre-assignment Detail	Participants with diagnosis of essential hypertension were enrolled in 1 treatment group:TAK-536CCB (TAK-536/ AML,20 mg/5 mg) in run-in period (Week -4 to 0).

Arm/Group Title	TAK-536TCH
Arm/Group Description	For 4 weeks during the run-in period, one tablet of TAK-536CCB (as TAK-536/AML, 20 mg/5 mg, respectively) orally, once daily, before or after breakfast. For 48 weeks during 52 weeks of the treatment period, one tablet of TAK-536TCH (as TAK-536/AML/HCTZ, 20 mg/5 mg/12.5 mg, respectively) orally, once daily, before or after breakfast. For the remaining 4 weeks of the treatment period, one tablet each of TAK-536CCB and HCTZ 12.5 mg, orally, once daily, before or after breakfast.
Period Title: Overall Study
STARTED	341
COMPLETED	295
NOT COMPLETED	46

Baseline Characteristics

Arm/Group Title	TAK-536TCH
Arm/Group Description	For 4 weeks during the run-in period, one tablet of TAK-536CCB (as TAK-536/AML, 20 mg/5 mg, respectively) orally, once daily, before or after breakfast. For 48 weeks during 52 weeks of the treatment period, one tablet of TAK-536TCH (as TAK-536/AML/HCTZ, 20 mg/5 mg/12.5 mg, respectively) orally, once daily, before or after breakfast. For the remaining 4 weeks of the treatment period, one tablet each of TAK-536CCB and HCTZ 12.5 mg, orally, once daily, before or after breakfast.
Overall Participants	341
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.8 (11.44)
Sex: Female, Male (Count of Participants)
Female	97 28.4%
Male	244 71.6%
Region of Enrollment (Count of Participants)
Japan	341 100%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	164.1 (8.51)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	70.80 (12.943)
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	26.20 (3.883)
Smoking Classification (Count of Participants)
Never Smoked	116 34%
Current Smoker	84 24.6%
Ex-Smoker	141 41.3%
History of Alcohol Consumption (Count of Participants)
Count of Participants [Participants]	120 35.2%
Duration of Hypertension (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	9.42 (7.728)
Concurrent Diabetes Mellitus (Count of Participants)
Count of Participants [Participants]	90 26.4%
Concurrent Chronic Kidney Disease (Count of Participants)
Count of Participants [Participants]	65 19.1%
Office Sitting Systolic Blood Pressure (SBP) (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	143.7 (8.23)
Office Sitting Diastolic Blood Pressure (DBP) (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	86.2 (9.28)
Estimated Glomerular Filtration Rate According To Creatinine (eGFRcreat) (mL/min/1.73 m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mL/min/1.73 m^2]	78.1 (16.73)
Medical History (Count of Participants)
Cerebrovascular Disorder	13 3.8%
Cardiac Disease	9 2.6%
Vascular Disorder	1 0.3%
Hepatic Disorder	2 0.6%
Dyslipidemia	1 0.3%
Other Medical History	52 15.2%
Concurrent Medical Conditions (Count of Participants)
Cerebrovascular Disorder	2 0.6%
Cardiac Disease	11 3.2%
Vascular Disorder	21 6.2%
Hepatic Disorder	43 12.6%
Dyslipidemia	174 51%
Other Concurrent Medical Conditions	292 85.6%
Medication History (Antihypertensives) (Count of Participants)
ARBs	310 90.9%
ACE Inhibitors	9 2.6%
CCBs	313 91.8%
Diuretics	66 19.4%
β-blockers	19 5.6%
Other Antihypertensives	14 4.1%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Experience at Least One Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Description	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A Serious Adverse Event (SAE) A serious is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.
Time Frame	Baseline up to Week 52

Outcome Measure Data

Analysis Population Description

The safety analysis set was defined as the participants who received at least 1 dose of the study drug for the treatment period.

Arm/Group Title	TAK-536TCH
Arm/Group Description	For 4 weeks during the run-in period, one tablet of TAK-536CCB (as TAK-536/AML, 20 mg/5 mg, respectively) orally, once daily, before or after breakfast. For 48 weeks during 52 weeks of the treatment period, one tablet of TAK-536TCH (as TAK-536/AML/HCTZ, 20 mg/5 mg/12.5 mg, respectively) orally, once daily, before or after breakfast. For the remaining 4 weeks of the treatment period, one tablet each of TAK-536CCB and HCTZ 12.5 mg, orally, once daily, before or after breakfast.
Measure Participants	341
TEAEs	289 84.8%
SAEs	20 5.9%

2. Primary Outcome

Title	Number of Participants With Markedly Abnormal Vital Signs Values
Description	Vital signs included supine and standing systolic and diastolic blood pressure (SBP and DBP) respectively and office sitting pulse. Vital signs were considered abnormal if they were beyond the values defined in categories.
Time Frame	Baseline up to Week 52

Outcome Measure Data

Analysis Population Description

The safety analysis set was defined as the participants who received at least 1 dose of the study drug for the treatment period.

Arm/Group Title	TAK-536TCH
Arm/Group Description	For 4 weeks during the run-in period, one tablet of TAK-536CCB (as TAK-536/AML, 20 mg/5 mg, respectively) orally, once daily, before or after breakfast. For 48 weeks during 52 weeks of the treatment period, one tablet of TAK-536TCH (as TAK-536/AML/HCTZ, 20 mg/5 mg/12.5 mg, respectively) orally, once daily, before or after breakfast. For the remaining 4 weeks of the treatment period, one tablet each of TAK-536CCB and HCTZ 12.5 mg, orally, once daily, before or after breakfast.
Measure Participants	341
SBP (Supine) (>180mmHg)	1 0.3%
SBP (Standing) (<85mmHg)	1 0.3%
SBP (Standing) (>180mmHg)	3 0.9%
DBP (Supine) (<50mmHg)	2 0.6%
DBP (Standing) (>110mmHg)	4 1.2%
Office, Sitting Pulse (<50bpm)	10 2.9%

3. Primary Outcome

Title	Number of Participants With Treatment Emergent Adverse Event (TEAE) Related to Body Weight
Description	Reported TEAE is categorized into investigations System Organ Class (SOC) related to body weight.
Time Frame	Baseline up to Week 52

Outcome Measure Data

Analysis Population Description

The safety analysis set was defined as the participants who received at least 1 dose of the study drug for the treatment period.

Arm/Group Title	TAK-536TCH
Arm/Group Description	For 4 weeks during the run-in period, one tablet of TAK-536CCB (as TAK-536/AML, 20 mg/5 mg, respectively) orally, once daily, before or after breakfast. For 48 weeks during 52 weeks of the treatment period, one tablet of TAK-536TCH (as TAK-536/AML/HCTZ, 20 mg/5 mg/12.5 mg, respectively) orally, once daily, before or after breakfast. For the remaining 4 weeks of the treatment period, one tablet each of TAK-536CCB and HCTZ 12.5 mg, orally, once daily, before or after breakfast.
Measure Participants	341
Weight decreased	2 0.6%
Weight increased	2 0.6%

4. Primary Outcome

Title	Number of Participants With Treatment Emergent Adverse Event (TEAE) Related to Electrocardiogram (ECG)
Description	Reported TEAE is categorized into cardiac disorders and investigations system organ class (SOC) related to ECG.
Time Frame	Baseline up to Week 52

Outcome Measure Data

Analysis Population Description

The safety analysis set was defined as the participants who received at least 1 dose of the study drug for the treatment period.

Arm/Group Title	TAK-536TCH
Arm/Group Description	For 4 weeks during the run-in period, one tablet of TAK-536CCB (as TAK-536/AML, 20 mg/5 mg, respectively) orally, once daily, before or after breakfast. For 48 weeks during 52 weeks of the treatment period, one tablet of TAK-536TCH (as TAK-536/AML/HCTZ, 20 mg/5 mg/12.5 mg, respectively) orally, once daily, before or after breakfast. For the remaining 4 weeks of the treatment period, one tablet each of TAK-536CCB and HCTZ 12.5 mg, orally, once daily, before or after breakfast.
Measure Participants	341
Atrial fibrillation	3 0.9%
Sinus bradycardia	1 0.3%
QRS axis abnormal	1 0.3%

5. Primary Outcome

Title	Number of Participants With Markedly Abnormal Clinical Laboratory Tests
Description	The number of participants with any markedly abnormal clinical laboratory test values collected throughout study. RBC = Red blood cells, ALT = alanine aminotransferase, AST = aspartate aminotransferase, GGT = gamma-glutamyl transferase, LLN = lower limit of normal or lower reference limit, ULN = upper limit of normal or upper reference limit. Laboratory vallues were considered abnormal if they were beyond the values defined in categories.
Time Frame	Baseline up to Week 52

Outcome Measure Data

Analysis Population Description

The safety analysis set was defined as the participants who received at least 1 dose of the study drug for the treatment period.

Arm/Group Title	TAK-536TCH
Arm/Group Description	For 4 weeks during the run-in period, one tablet of TAK-536CCB (as TAK-536/AML, 20 mg/5 mg, respectively) orally, once daily, before or after breakfast. For 48 weeks during 52 weeks of the treatment period, one tablet of TAK-536TCH (as TAK-536/AML/HCTZ, 20 mg/5 mg/12.5 mg, respectively) orally, once daily, before or after breakfast. For the remaining 4 weeks of the treatment period, one tablet each of TAK-536CCB and HCTZ 12.5 mg, orally, once daily, before or after breakfast.
Measure Participants	341
RBC (< 0.8×LLN×10^6cells/μL)	5 1.5%
Hemoglobin (<0.8 × LLN g/dL)	2 0.6%
Hematocrit (<0.8 × LLN Percent)	2 0.6%
ALT (>3 × ULN U/L)	4 1.2%
AST (>3 × ULN U/L)	4 1.2%
Total Bilirubin (>2.0 mg/dL)	2 0.6%
Creatinine (>2.0 mg/dL)	1 0.3%
Blood Urea Nitrogen (>30 mg/dL)	20 5.9%
GGT (>3 × ULN U/L)	14 4.1%
Eosinophils (>2 × ULN×10^3cells/μL)	4 1.2%
Uric Acid (>13.0 mg/dL)	1 0.3%
Total Cholesterol (>300 mg/dL)	2 0.6%
Triglycerides (>2.5 × ULN mg/dL)	29 8.5%
Potassium (<3.0 mEq/L)	3 0.9%
Sodium (<130 mEq/L)	3 0.9%

6. Secondary Outcome

Title	Change From Baseline in Office Trough Sitting Clinic Systolic and Diastolic Blood Pressure at Each Visit
Description	The change in office trough SBP and DBP measured at Weeks 12 last observation was carried forward (LOCF) and 52 (LOCF) relative to baseline. Sitting blood pressure was measured at least 3 times. Each measurement session ended once blood pressure was found stable at 2 consecutive measurements. The average of the last 2 measurements of office sitting blood pressure was used.
Time Frame	Baseline (End of Run-in Period, Week 0) and Weeks 12 (LOCF) and 52 (LOCF)

Outcome Measure Data

Analysis Population Description

The full analysis set is defined as the participants who received at least 1 dose of the study drug for the treatment period. Here 'n' is number of participants analyzed at the given timepoint.

Arm/Group Title	TAK-536TCH
Arm/Group Description	For 4 weeks during the run-in period, one tablet of TAK-536CCB (as TAK-536/AML, 20 mg/5 mg, respectively) orally, once daily, before or after breakfast. For 48 weeks during 52 weeks of the treatment period, one tablet of TAK-536TCH (as TAK-536/AML/HCTZ, 20 mg/5 mg/12.5 mg, respectively) orally, once daily, before or after breakfast. For the remaining 4 weeks of the treatment period, one tablet each of TAK-536CCB and HCTZ 12.5 mg, orally, once daily, before or after breakfast.
Measure Participants	341
Change at Week 12 (LOCF), SBP	-14.4 (12.72)
Change at Week 52 (LOCF), SBP	-13.9 (12.14)
Change at Week 12 (LOCF), DBP	-8.6 (8.97)
Change at Week 52 (LOCF), DBP	-8.3 (9.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TAK-536TCH
	Comments	P-value has been estimated for change from baseline in office trough SBP at Week 12 (LOCF).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	One sample t-test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	TAK-536TCH
	Comments	P-value has been estimated for change from baseline in office trough SBP at Week 52 (LOCF).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	One sample t-test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	TAK-536TCH
	Comments	P-value has been estimated for change from baseline in office trough sitting DBP at Week 12 (LOCF).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	One sample t-test
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	TAK-536TCH
	Comments	P-value has been estimated for change from baseline in office trough sitting DBP at Week 52 (LOCF).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	One sample t-test
	Comments

7. Secondary Outcome

Title	Change From Baseline in Home Sitting Clinic Systolic and Diastolic Blood Pressure at Each Visit
Description	The change in home morning SPB and DBP measured at End of Week 12, End of Treatment (Up to Week 52) relative to baseline.
Time Frame	Baseline (End of Run-in Period, Week 0), End of Week 12 and End of Treatment (Up to Week 52)

Outcome Measure Data

Analysis Population Description

The full analysis set is defined as the participants who received at least 1 dose of the study drug for the treatment period. Here 'n' is number of participants analysed at the given time-point.

Arm/Group Title	TAK-536TCH
Arm/Group Description	For 4 weeks during the run-in period, one tablet of TAK-536CCB (as TAK-536/AML, 20 mg/5 mg, respectively) orally, once daily, before or after breakfast. For 48 weeks during 52 weeks of the treatment period, one tablet of TAK-536TCH (as TAK-536/AML/HCTZ, 20 mg/5 mg/12.5 mg, respectively) orally, once daily, before or after breakfast. For the remaining 4 weeks of the treatment period, one tablet each of TAK-536CCB and HCTZ 12.5 mg, orally, once daily, before or after breakfast.
Measure Participants	341
Change at End of Week 12, Morning SBP	-13.9 (10.67)
Change at EOT (Up to Week 52), Morning SBP	-12.4 (11.75)
Change at End of Week 12, Morning DBP	-7.9 (6.59)
Change at EOT (Up to Week 52), Morning DBP	-6.9 (7.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TAK-536TCH
	Comments	P-value has been estimated for change from baseline in home SBP, morning at End of Week 12.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	One sample t-test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	TAK-536TCH
	Comments	P-value has been estimated for change from baseline in home SBP, morning at EOT (Up to Week 52).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	One sample t-test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	TAK-536TCH
	Comments	P-value has been estimated for change from baseline in home DBP, morning at End of Week 12.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	One sample t-test
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	TAK-536TCH
	Comments	P-value has been estimated for change from baseline in home DBP, morning at EOT (Up to Week 52).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	One sample t-test
	Comments

Adverse Events

Time Frame	Baseline up to Week 52
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	TAK-536TCH
Arm/Group Description	For 4 weeks during the run-in period, one tablet of TAK-536CCB (as TAK-536/AML, 20 mg/5 mg, respectively) orally, once daily, before or after breakfast. For 48 weeks during 52 weeks of the treatment period, one tablet of TAK-536TCH (as TAK-536/AML/HCTZ, 20 mg/5 mg/12.5 mg, respectively) orally, once daily, before or after breakfast. For the remaining 4 weeks of the treatment period, one tablet each of TAK-536CCB and HCTZ 12.5 mg, orally, once daily, before or after breakfast.
All Cause Mortality
	TAK-536TCH
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	TAK-536TCH
	Affected / at Risk (%)	# Events
Total	20/341 (5.9%)
Cardiac disorders
Angina pectoris	1/341 (0.3%)
Arteriosclerosis coronary artery	1/341 (0.3%)
Gastrointestinal disorders
Large intestine polyp	2/341 (0.6%)
Acute abdomen	1/341 (0.3%)
General disorders
Chest discomfort	1/341 (0.3%)
Injury, poisoning and procedural complications
Clavicle fracture	1/341 (0.3%)
Concussion	1/341 (0.3%)
Contusion	1/341 (0.3%)
Fall	1/341 (0.3%)
Post procedural inflammation	1/341 (0.3%)
Spinal cord injury cervical	1/341 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer	1/341 (0.3%)
Gastric cancer	1/341 (0.3%)
Lymphoma	1/341 (0.3%)
Oesophageal carcinoma	1/341 (0.3%)
Prostate cancer	1/341 (0.3%)
Uterine cancer	1/341 (0.3%)
Nervous system disorders
Carotid artery stenosis	1/341 (0.3%)
Subarachnoid haemorrhage	1/341 (0.3%)
VIIth nerve paralysis	1/341 (0.3%)
Renal and urinary disorders
Cystitis interstitial	1/341 (0.3%)
Vascular disorders
Peripheral arterial occlusive disease	2/341 (0.6%)
Other (Not Including Serious) Adverse Events
	TAK-536TCH
	Affected / at Risk (%)	# Events
Total	195/341 (57.2%)
Infections and infestations
Nasopharyngitis	106/341 (31.1%)
Investigations
Blood uric acid increased	86/341 (25.2%)
Metabolism and nutrition disorders
Hyperuricaemia	18/341 (5.3%)
Musculoskeletal and connective tissue disorders
Back pain	18/341 (5.3%)
Respiratory, thoracic and mediastinal disorders
Upper respiratory tract inflammation	18/341 (5.3%)
Skin and subcutaneous tissue disorders
Eczema	19/341 (5.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.