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CompletedNCT02277691Updated Aug 2, 2017Results posted

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

A Phase 3 interventional study of TAK-536TCH tablet and TAK-536CCB tablet in Essential Hypertension, sponsored by Takeda. Completed at 38 sites in Japan. Open to participants aged 20 Years and older. Per ClinicalTrials.gov, last updated 2017-08-02.

Sponsored by Takeda · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
341
Allocation
Not applicable
Ages
20 Years and older
Sex
All
01

Study 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.

Read the 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.

02

Conditions studied

  • Essential Hypertension

Keywords

  • Pharmacological therapy
  • Drug Therapy
03

In context

Hypertension

6,689 studies on the registry are indexed under Hypertension; 965 are open to participants now.

This study's enrollment of 341 is above the median of 90 across 4,995 interventional studies indexed under Hypertension.

Browse Hypertension studies →

Lead sponsor

Takeda is the lead sponsor of 1,002 studies on the registry; 92 are open to participants now.

Of its 173 completed or terminated interventional studies of FDA-regulated products, 149 (86%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
20 Years and older
Sexes eligible
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.
  6. 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).
  7. The participant is male or female, aged 20 years or older at the time of providing informed consent.
  8. The participant is an outpatient.
  9. 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

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
  15. 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).
  16. 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).

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

    *Based on normal ranges

  18. 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.
  19. The participant has uncontrolled diabetes (e.g., HbA1c ≥ 7.4% in laboratory tests performed at Week -2 of the run-in period).
  20. The participant has a malignant tumor.
  21. 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.
  22. 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.
  23. The participant who, in the opinion of the investigator or subinvestigator, is unsuitable for any other reason.
05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrollment
341 participants (actual)

Study arms

  • 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 · Drug: TAK-536CCB tablet · Drug: HCTZ 12.5 mg tablet

Interventions

  • DrugTAK-536TCH tablet

    TAK-536TCH tablets

  • DrugTAK-536CCB tablet

    TAK-536CCB tablets

  • DrugHCTZ 12.5 mg tablet

    HCTZ tablets

06

What researchers measure

Primary outcomes

  1. Number of Participants Who Experience at Least One Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

    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

  2. Number of Participants With Markedly Abnormal Vital Signs Values

    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

  3. Number of Participants With Treatment Emergent Adverse Event (TEAE) Related to Body Weight

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

    Time frame: Baseline up to Week 52

  4. Number of Participants With Treatment Emergent Adverse Event (TEAE) Related to Electrocardiogram (ECG)

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

    Time frame: Baseline up to Week 52

  5. Number of Participants With Markedly Abnormal Clinical Laboratory Tests

    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

Secondary outcomes

  1. Change From Baseline in Office Trough Sitting Clinic Systolic and Diastolic Blood Pressure at Each Visit

    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)

  2. Change From Baseline in Home Sitting Clinic Systolic and Diastolic Blood Pressure at Each Visit

    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)

07

Results

Posted Jun 26, 2017

Participant flow

Participants took part in the study at 31 investigative sites in Japan, from 07 November 2014 to 25 April 2016.

Participant flow — Overall Study
MilestoneTAK-536TCH
Started341
Completed295
Not completed46
Withdrew: Pretreatment event/adverse event33
Withdrew: Voluntary withdrawal7
Withdrew: Lack of efficacy5
Withdrew: Used other antihypertensive drug1

Outcome measures

PrimaryNumber of Participants Who Experience at Least One Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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
Reported as:
Count of participants · Participants
Number of Participants Who Experience at Least One Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
ParticipantsTAK-536TCH
TEAEs289
SAEs20
PrimaryNumber of Participants With Markedly Abnormal Vital Signs Values

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
Reported as:
Count of participants · Participants
Number of Participants With Markedly Abnormal Vital Signs Values
ParticipantsTAK-536TCH
SBP (Supine) (>180mmHg)1
SBP (Standing) (<85mmHg)1
SBP (Standing) (>180mmHg)3
DBP (Supine) (<50mmHg)2
DBP (Standing) (>110mmHg)4
Office, Sitting Pulse (<50bpm)10
PrimaryNumber of Participants With Treatment Emergent Adverse Event (TEAE) Related to Body Weight

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

Time frame:
Baseline up to Week 52
Reported as:
Count of participants · Participants
Number of Participants With Treatment Emergent Adverse Event (TEAE) Related to Body Weight
ParticipantsTAK-536TCH
Weight decreased2
Weight increased2
PrimaryNumber of Participants With Treatment Emergent Adverse Event (TEAE) Related to Electrocardiogram (ECG)

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

Time frame:
Baseline up to Week 52
Reported as:
Count of participants · Participants
Number of Participants With Treatment Emergent Adverse Event (TEAE) Related to Electrocardiogram (ECG)
ParticipantsTAK-536TCH
Atrial fibrillation3
Sinus bradycardia1
QRS axis abnormal1
PrimaryNumber of Participants With Markedly Abnormal Clinical Laboratory Tests

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
Reported as:
Count of participants · Participants
Number of Participants With Markedly Abnormal Clinical Laboratory Tests
ParticipantsTAK-536TCH
RBC (< 0.8×LLN×10^6cells/μL)5
Hemoglobin (<0.8 × LLN g/dL)2
Hematocrit (<0.8 × LLN Percent)2
ALT (>3 × ULN U/L)4
AST (>3 × ULN U/L)4
Total Bilirubin (>2.0 mg/dL)2
Creatinine (>2.0 mg/dL)1
Blood Urea Nitrogen (>30 mg/dL)20
GGT (>3 × ULN U/L)14
Eosinophils (>2 × ULN×10^3cells/μL)4
Uric Acid (>13.0 mg/dL)1
Total Cholesterol (>300 mg/dL)2
Triglycerides (>2.5 × ULN mg/dL)29
Potassium (<3.0 mEq/L)3
Sodium (<130 mEq/L)3
SecondaryChange From Baseline in Office Trough Sitting Clinic Systolic and Diastolic Blood Pressure at Each Visit

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)
Reported as:
Mean · mmHg
Change From Baseline in Office Trough Sitting Clinic Systolic and Diastolic Blood Pressure at Each Visit
mmHgTAK-536TCH
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
  • TAK-536TCH · One sample t-test · p = <0.0001
  • TAK-536TCH · One sample t-test · p = <0.0001
  • TAK-536TCH · One sample t-test · p = <0.0001
  • TAK-536TCH · One sample t-test · p = <0.0001
SecondaryChange From Baseline in Home Sitting Clinic Systolic and Diastolic Blood Pressure at Each Visit

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)
Reported as:
Mean · mmHg
Change From Baseline in Home Sitting Clinic Systolic and Diastolic Blood Pressure at Each Visit
mmHgTAK-536TCH
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
  • TAK-536TCH · One sample t-test · p = <0.0001
  • TAK-536TCH · One sample t-test · p = <0.0001
  • TAK-536TCH · One sample t-test · p = <0.0001
  • TAK-536TCH · One sample t-test · p = <0.0001

Adverse events

Collected over Baseline up to Week 52. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
TAK-536TCH—20/341 (5.9%)195/341 (57.2%)
Most frequent serious events
Showing 10 of 22
Most frequent serious events
EventTAK-536TCH
Large intestine polypGastrointestinal disorders2/341
Peripheral arterial occlusive diseaseVascular disorders2/341
Angina pectorisCardiac disorders1/341
Arteriosclerosis coronary arteryCardiac disorders1/341
Acute abdomenGastrointestinal disorders1/341
Chest discomfortGeneral disorders1/341
Clavicle fractureInjury, poisoning and procedural complications1/341
ConcussionInjury, poisoning and procedural complications1/341
ContusionInjury, poisoning and procedural complications1/341
FallInjury, poisoning and procedural complications1/341
Most frequent other events
Most frequent other events
EventTAK-536TCH
NasopharyngitisInfections and infestations106/341
Blood uric acid increasedInvestigations86/341
EczemaSkin and subcutaneous tissue disorders19/341
HyperuricaemiaMetabolism and nutrition disorders18/341
Back painMusculoskeletal and connective tissue disorders18/341
Upper respiratory tract inflammationRespiratory, thoracic and mediastinal disorders18/341

Baseline characteristics

Randomized set included all randomized participants.

Age, Continuous
Age, Continuous(years)TAK-536TCH
Mean60.8 ± 11.44
Sex: Female, Male
Sex: Female, Male(Participants)TAK-536TCH
Female97
Male244
Region of Enrollment
Region of Enrollment(Participants)TAK-536TCH
Japan341
Height
Height(cm)TAK-536TCH
Mean164.1 ± 8.51
Weight
Weight(kg)TAK-536TCH
Mean70.80 ± 12.943
BMI
BMI(kg/m^2)TAK-536TCH
Mean26.20 ± 3.883
Smoking Classification
Smoking Classification(Participants)TAK-536TCH
Never Smoked116
Current Smoker84
Ex-Smoker141
History of Alcohol Consumption
History of Alcohol Consumption(Participants)TAK-536TCH
Count of participants120

9 further baseline measures are reported on the registry.

08

Study locations

38 sites
  • Nagoya-shi, Aichi, Japan
  • Chiba-shi, Chiba, Japan
  • Itojima-shi, Fukuoka, Japan
  • Kouriyama-shi, Fukushima, Japan
  • Sapporo-shi, Hokkaido, Japan
  • Amagasaki-shi, Hyougo, Japan
  • Tsukuba-shi, Ibaragi, Japan
  • Morioka-shi, Iwate, Japan
  • Sakaide-shi, Kagawa, Japan
  • Takamatsu-shi, Kagawa, Japan
  • Kawasaki-shi, Kanagawa, Japan
  • Kyoto-shi, Kyoto, Japan
  • Uji-shi, Kyoto, Japan
  • Sendai-shi, Miyagi, Japan
  • Hirakata-shi, Osaka, Japan
  • Osaka-shi, Osaka, Japan
  • Takatsuki-shi, Osaka, Japan
  • Saitama-shi, Saitama, Japan
  • Tokorozawa-shi, Saitama, Japan
  • Yaizu-shi, Shizuoka, Japan
  • Chiyoda-ku, Tokyo, Japan
  • Choufu-shi, Tokyo, Japan
  • Kodaira-shi, Tokyo, Japan
  • Koutou-ku, Tokyo, Japan
  • Setagaya-ku, Tokyo, Japan
  • Shinagawa-ku, Tokyo, Japan
  • Shinjuku-ku, Tokyo, Japan
  • Choufu-shi, Japan
  • Kawasaki-shi, Japan
  • Koutou-ku, Japan
  • Morioka-shi, Japan
  • Sakaide-shi, Japan
  • Setagaya-ku, Japan
  • Shinagawa-ku, Japan
  • Shinjuku-ku, Japan
  • Tsukuba-shi, Japan
  • Uji-shi, Japan
  • Yaizu-shi, Japan
09

References and documents

Publications

  • Rakugi H, Shimizu K, Nishiyama Y, Sano Y, Umeda Y. A phase III, open-label, multicenter study to evaluate the safety and efficacy of long-term triple combination therapy with azilsartan, amlodipine, and hydrochlorothiazide in patients with essential hypertension. Blood Press. 2018 Jun;27(3):125-133. doi: 10.1080/08037051.2017.1412797. Epub 2017 Dec 13. Erratum In: Blood Press. 2018 Jun;27(3):184. doi: 10.1080/08037051.2018.1428781. PubMed 29235365 ↗
10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Aug 2, 2017, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT02277691
Lead sponsor
Takeda
Responsible party
Sponsor
First posted
Oct 29, 2014
Start date
Nov 7, 2014
Primary completion
Apr 25, 2016
Completion
Apr 25, 2016
Results posted
Jun 26, 2017
Last update
Aug 2, 2017

Study contacts

Medical Director Clinical Science
study director · Takeda

Oversight

Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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