Azilsartan Medoxomil (TAK-491) Compared to Valsartan in Chinese Participants With Hypertension

A Phase 3, Double-Blind, Randomized, Parallel-Group Study to Compare the Efficacy and Safety of TAK-491 With Valsartan in Chinese Subjects With Essential Hypertension

The purpose of this study is to evaluate the antihypertensive effect of azilsartan medoxomil compared with valsartan in Chinese participants with essential hypertension.

Study Overview

• Status: Completed
• Conditions: Essential Hypertension
• Intervention / Treatment: Drug: Azilsartan medoxomil; Drug: Azilsartan medoxomil Placebo; Drug: Valsartan Placebo; Drug: Valsartan

Detailed Description

The drug being tested in this study is called TAK-491 (azilsartan medoxomil). Azilsartan medoxomil is being tested to treat Chinese people who have essential hypertension. This study will look at change in blood pressure after 8 weeks of treatment in people who take azilsartan medoxomil compared to people who take valsartan.

The study enrolled 612 patients. Prior to the start of study treatment, participants who have not received antihypertensive treatment within 28 days participated in a 2-week -run in period. Upon completion of the run-in period, participants were randomly assigned (by chance, like flipping a coin) to one of the three treatment groups-which remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

• azilsartan medoxomil 40 mg
• azilsartan medoxomil 80 mg
• Valsartan 160 mg

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

This multi-centre trial was conducted in China. The overall time to participate in this study is up to 14 weeks. Participants made 9 visits to the clinic and contacted by telephone 14 days after last dose of study drug for a follow-up assessment.

• Study Type: Interventional
• Enrollment (Actual): 612
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100050
      • Beijing Friendship Hospital, Capital Medical University
    • Beijing, Beijing, China, 100029
      • Beijing Anzhen Hospital
    • Beijing, Beijing, China, 100020
      • Beijing Chao Yang Hospital
    • Beijing, Beijing, China, 100730
      • Beijing Tong Ren Hospital, Capital Medical University
  • Fujian
    • Fuzhou, Fujian, China, 350001
      • Fujian Medical University Union Hospital
    • Fuzhou, Fujian, China, 350001
      • Fujian Provincial Hospital
    • Fuzhou, Fujian, China, 350005
      • The First Affiliated Hospital of Fujian Medical University
  • Guangdong
    • Guangzhou, Guangdong, China, 510080
      • The First Affiliated Hospital, Sun Yat-sen University
    • Guangzhou, Guangdong, China, 510080
      • Guangdong General Hospital
  • Guangxi
    • Nanning, Guangxi, China, 530021
      • The Peoples Hospital of Guangxi Zhuang Autonomous Region
  • Hainan
    • Haikou, Hainan, China, 570102
      • Affiliated Hospital of Hainan Medical University.
  • Hebei
    • Cangzhou, Hebei, China, 061001
      • Hebei Cangzhou Central Hospital
    • Shijiazhuang, Hebei, China, 50011
      • The 4th Hospital of Hebei Medical University
  • Hunan
    • Changsha, Hunan, China, 410013
      • The Third Xiangya Hospital of Central South University
    • Changsha, Hunan, China, 410002
      • Hunan Province People's Hospital
    • Fuzhou, Hunan, China, 421003
      • ZhuZhou Central Hospital
  • Jiangsu
    • Nanjing, Jiangsu, China, 210009
      • Cardiology/Zhong Da Hospital, Southeast University
    • Nanjing, Jiangsu, China, 210011
      • Nanjing Medical University Affiliated 2nd Hospital
    • Xuzhou, Jiangsu, China, 221002
      • The Affiliated Hospital of Xuzhou Medical College
    • Zhenjiang, Jiangsu, China, 212001
      • Affiliated Hospital of Jiangsu University
  • Jiangxi
    • Nanchang, Jiangxi, China, 330006
      • The First Affiliated Hospital of NanChang University
  • Jilin
    • Changchun, Jilin, China, 130031
      • China-Japan Union Hospital of Jilin University
  • Liaoning
    • Shenyang, Liaoning, China, 110015
      • People's Hospital of Liaoning Province
  • Shanghai
    • Shanghai, Shanghai, China, 200120
      • Shanghai East Hospital
    • Shanghai, Shanghai, China, 200003
      • Shanghai Changzheng Hospital
  • Shanxi
    • Taiyuan, Shanxi, China, 030001
      • Cardiology/The Second Hospital of Shanxi Medical University
    • Xi'an, Shanxi, China, 710061
      • First Affiliated Hospital of Xian Jiaotong University
  • Tianjin
    • Tianjin, Tianjin, China, 300121
      • Tianjin People's Hospital
    • Tianjin, Tianjin, China, 300457
      • TEDA International Cardiovascular Hospital
    • Tianjin, Tianjin, China, 300170
      • Tianjin Third Central Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Is treated with antihypertensive therapy and has a post-washout mean sitting clinic systolic blood pressure (SBP) ≥150 and ≤180 mm Hg on Day 1; or the participant has not received antihypertensive treatment within 28 days prior to Screening and has a mean sitting clinic SBP ≥150 and ≤180 mm Hg at the Screening Visit and on Day 1.
2. Is a man or woman aged 18 years or older.
3. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
4. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.
5. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent through 30 days after last study drug dose.
6. Has clinical laboratory test results (clinical chemistry, hematology, and complete urinalysis) within the reference range for the testing laboratory or the investigator does not consider the results to be clinically significant.
7. Is willing to discontinue current antihypertensive medications on Day -21 or on Day -28 if the participant is on amlodipine or chlorthalidone.

Exclusion Criteria:

1. Has a mean, sitting clinic diastolic blood pressure (DBP) greater than 110 mm Hg at Day 1 (after placebo run in).
2. Is non-compliant (less than 70% or greater than 130%) with study medication during placebo run-in period.
3. Has secondary hypertension of any etiology (eg, renovascular disease documented as the cause of hypertension, pheochromocytoma, Cushing's syndrome).
4. Has a history of myocardial infarction, heart failure, unstable angina, coronary artery bypass graft, percutaneous coronary intervention, hypertensive encephalopathy, cerebrovascular accident, or transient ischemic attack.
5. Has clinically significant cardiac conduction defects (eg, third-degree atrioventricular block, sick sinus syndrome).
6. Has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease and hypertrophic obstructive cardiomyopathy (HOCM).
7. Has severe renal dysfunction or disease (based on estimated glomerular filtration rate [GFR] <30 mL/min/1.73 m^2) at Screening.
8. Has known or suspected unilateral or bilateral renal artery stenosis.
9. Has a history of cancer that has not been in remission for at least 5 years prior to the first dose of study drug. (This criterion does not apply to those participants with basal cell or Stage 1 squamous cell carcinoma of the skin).
10. Has type 1 or poorly controlled type 2 diabetes mellitus (hemoglobin A1c [HbA1c] >8.5%) at Screening.
11. Has hyperkalemia (defined as serum potassium above the normal reference range of the central laboratory) at Screening.
12. Has an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level of greater than 2.5 times the upper limit of normal (ULN), active liver disease, or jaundice at Screening.
13. Has any other known serious disease or condition at Screening (or Randomization) that would compromise participant safety, might affect life expectancy, or make it difficult to successfully manage and follow the participant according to the protocol.
14. Has a history of hypersensitivity or allergies to TAK-491 (azilsartan medoxomil), any of its excipients or other angiotension II (AII) receptor blockers (ARBs).
15. If female, the participant is pregnant or lactating or intending to become pregnant before, during, or within 30 days after participating in this study; or intending to donate ova during such time period.

16. Is currently participating in another investigational study or is receiving or has received any investigational compound within 30 days prior to the first dose of study medication.

    Note: This criterion does not apply to participants who participated in observational studies that lacked an intervention or invasive procedure.

17. Is an immediate family member, study site employee, or is in a dependant relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.
18. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within the past 2 years.
19. Is taking or expected to take an excluded medication.
20. Works a night (third) shift (defined as 11 PM [2300] to 7 AM [0700]). (Only for participants with ambulatory blood pressure monitoring [ABPM].)
21. Has an upper arm circumference <24 cm or >42 cm. (Only for participants with ABPM.)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Azilsartan medoxomil 40 mg; Run-in Period: azilsartan medoxomil 40 mg placebo-matching tablets, azilsartan medoxomil 80 mg placebo-matching tablets, and valsartan two 80 mg placebo-matching capsules, orally, once daily, for 2 weeks prior to the start of the treatment period. Treatment Period: azilsartan medoxomil 40 mg tablets, orally, once daily, azilsartan medoxomil 80 mg placebo-matching tablets, orally, once daily, and valsartan two 80 mg placebo-matching capsules, orally, once daily, for up to 8 weeks.	Drug: Azilsartan medoxomil; Azilsartan medoxomil tablets; Other Names: Edarbi; TAK-491; Drug: Azilsartan medoxomil Placebo; Azilsartan medoxomil placebo-matching tablets; Drug: Valsartan Placebo; Valsartan placebo-matching capsules
Experimental: Azilsartan medoxomil 80 mg; Run-in Period: azilsartan medoxomil 40 mg placebo-matching tablets, azilsartan medoxomil 80 mg placebo-matching tablets, and valsartan two 80 mg placebo-matching capsules, orally, once daily, for 2 weeks prior to the start of the treatment period. Treatment Period: azilsartan medoxomil 80 mg tablets, orally, once daily, azilsartan medoxomil 40 mg placebo-matching tablets, orally, once daily, and valsartan two 80 mg placebo-matching capsules, orally, once daily, for up to 8 weeks.	Drug: Azilsartan medoxomil; Azilsartan medoxomil tablets; Other Names: Edarbi; TAK-491; Drug: Azilsartan medoxomil Placebo; Azilsartan medoxomil placebo-matching tablets; Drug: Valsartan Placebo; Valsartan placebo-matching capsules
Active Comparator: Valsartan 160 mg; Run-in Period: azilsartan medoxomil 40 mg placebo-matching tablets, azilsartan medoxomil 80 mg placebo-matching tablets, and valsartan two 80 mg placebo-matching capsules, orally, once daily, for 2 weeks prior to the start of the treatment period. Treatment Period: valsartan two 80 mg capsules, orally, once daily, azilsartan medoxomil 40 mg placebo-matching tablets, orally, once daily, and azilsartan medoxomil 80 mg placebo-matching tablets, orally, once daily, for up to 8 weeks.	Drug: Azilsartan medoxomil Placebo; Azilsartan medoxomil placebo-matching tablets; Drug: Valsartan Placebo; Valsartan placebo-matching capsules; Drug: Valsartan; Valsartan 80 mg capsules; Other Names: Diovan®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Trough Sitting Clinic Systolic Blood Pressure (SBP)	The change in trough clinic sitting SBP measured at Week 8 relative to baseline. The trough is the average of the non-missing values of 3 serial trough sitting SBP measurements. Blood pressure was measured using a validated, automated device after the participant had been sitting for at least 5 minutes. Week 8 blood pressure was measured approximately 24 hours after the previous day's dose.	Baseline and Week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Trough Sitting Clinic Diastolic Blood Pressure (DBP)	The change in trough clinic sitting DBP measured at Week 8 relative to baseline. The trough is the average of the non-missing values of 3 serial trough sitting DBP measurements. Blood pressure was measured using a validated, automated device after the participant had been sitting for at least 5 minutes. Week 8 blood pressure was measured approximately 24 hours after the previous day's dose.	Baseline and Week 8
Percentage of Participants Who Achieved a Clinic SBP Response at Week 8	Clinic SBP response was defined as clinic SBP <140 mm Hg and/or reduction of ≥20 mm Hg from Baseline. Blood pressure was measured using a validated, automated device after the participant had been sitting for at least 5 minutes. Week 8 blood pressure was measured approximately 24 hours after the previous day's dose.	Week 8
Percentage of Participants Who Achieved a Clinic DBP Response at Week 8	Clinic DBP response was defined as clinic DBP <90 mm Hg and/or reduction of ≥10 mm Hg from Baseline. Blood pressure was measured using a validated, automated device after the participant had been sitting for at least 5 minutes. Week 8 blood pressure was measured approximately 24 hours after the previous day's dose.	Week 8
Percentage of Participants Who Achieved Both Clinic SBP and DBP Response at Week 8	Clinic SBP response was defined as clinic SBP <140 mm Hg and/or reduction of ≥20 mm Hg from Baseline and clinic DBP response was defined as clinic DBP <90 mm Hg and/or reduction of ≥10 mm Hg from Baseline. Blood pressure was measured using a validated, automated device after the participant had been sitting for at least 5 minutes. Week 8 blood pressure was measured approximately 24 hours after the previous day's dose.	Week 8
Percentage of Participants Who Achieved Target Clinic SBP <140 mm Hg, Clinic DBP <90 mm Hg or Both at Week 8	Blood pressure was measured using a validated, automated device after the participant had been sitting for at least 5 minutes. Week 8 blood pressure was measured approximately 24 hours after the previous day's dose.	Week 8
Percentage of Participants Who Achieved Target Clinic SBP <130 mm Hg, Target Clinic DBP <80 mm Hg or Both at Week 8	Blood pressure was measured using a validated, automated device after the participant had been sitting for at least 5 minutes. Week 8 blood pressure was measured approximately 24 hours after the previous day's dose.	Week 8

Collaborators and Investigators

• Sponsor: Takeda

Publications and helpful links

General Publications

• Wu J, Du X, Lv Q, Li Z, Zheng Z, Xia Y, Tang C, Yao Z, Zhang J, Long M, Hisada M, Wu J, Zhou W, Ma C. A phase 3 double-blind randomized (CONSORT-compliant) study of azilsartan medoxomil compared to valsartan in Chinese patients with essential hypertension. Medicine (Baltimore). 2020 Aug 7;99(32):e21465. doi: 10.1097/MD.0000000000021465. Erratum In: Medicine (Baltimore). 2020 Sep 4;99(36):e22168.

Study record dates

Study Major Dates

• Study Start (Actual): August 27, 2015
• Primary Completion (Actual): September 22, 2017
• Study Completion (Actual): October 13, 2017

Study Registration Dates

• First Submitted: June 22, 2015
• First Submitted That Met QC Criteria: June 22, 2015
• First Posted (Estimate): June 24, 2015

Study Record Updates

• Last Update Posted (Actual): March 5, 2019
• Last Update Submitted That Met QC Criteria: February 15, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: Drug therapy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Essential Hypertension; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Valsartan; Azilsartan medoxomil
• Other Study ID Numbers: TAK-491_305; U1111-1159-5579 (Registry Identifier: WHO)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Takeda makes patient-level, de-identified data sets and associated documents available after applicable marketing approvals and commercial availability have been received, an opportunity for the primary publication of the research has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com/Approach for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.