Essential Hypertension
Conditions
Keywords
Hypertensive, Blood Pressure, High, Cardiovascular disease, Vascular Disease, Drug Therapy
Brief summary
The purpose of this study is to compare the safety and tolerability of azilsartan medoxomil plus chlorthalidone, once daily (QD), versus olmesartan medoxomil-hydrochlorothiazide in adults with essential hypertension.
Detailed description
High Blood Pressure (Hypertension) is the most common cause of preventable death in developed nations. Uncontrolled hypertension greatly increases the risk of heart disease, brain disease, and kidney failure. As the population ages, the incidence of hypertension will continue to increase if effective preventive measures are not implemented. Despite the availability of antihypertensive agents, hypertension is not adequately controlled; only about one in three patients successfully keep blood pressure normal. Treatment for high blood pressure includes thiazides or thiazide-like diuretics, either alone or as part of combination treatment. Chlorthalidone is a commercially available, orally administered thiazide-type diuretic agent. TAK-491 (azilsartan) is an angiotensin II receptor blocker being evaluated by Takeda to treat patients with high blood pressure (essential hypertension). This study will compare the safety and tolerability of azilsartan medoxomil plus chlorthalidone (TAK-491CLD) fixed-dose combination to olmesartan medoxomil-hydrochlorothiazide fixed-dose combination. Initially patients will undergo a Screening Visit to confirm that they are eligible to participate in the study. All participants will receive the study drug for up to 52 weeks. The dose of the study drug may be gradually increased throughout the study so that a target blood pressure value can be reached for each participant. Throughout the treatment period of the study, participants will be required to visit the research site for 11 visits. At these study visits participants will be required to undergo certain study procedures including physical examinations, vital sign measurements (blood pressure, heart rate, weight and height), electrocardiograms (monitoring of the heart), and blood and urine samples taken for clinical laboratory tests.
Interventions
Combination tablet.
Combination tablet.
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Is treated with antihypertensive therapy and has a post-washout mean sitting clinic systolic blood pressure greater than or equal to 160 and less than or equal to 190 mm Hg on Day, or has not received antihypertensive treatment within 14 days prior to Screening and has a mean sitting clinic systolic blood pressure greater than or equal to 160 and less than or equal to 190 mm Hg at the Screening Visit and on Day 1. * Females of childbearing potential who are sexually active agree to routinely use adequate contraception, and can neither be pregnant nor lactating from before study participation to Screening to 30 days after the last study drug dose. * Has clinical laboratory test results within the reference range for the testing laboratory or the investigator does not consider the results to be clinically significant. * Is willing to discontinue current antihypertensive medications up to 3 weeks before enrollment.
Exclusion criteria
* Has a mean clinic diastolic blood pressure (sitting, trough) greater than 119 mm Hg on Day 1. * Has secondary hypertension of any etiology (eg, renovascular disease, pheochromocytoma, Cushing's syndrome). * Has a recent history (within the last 6 months) of myocardial infarction, heart failure, unstable angina, coronary artery bypass graft, percutaneous coronary intervention, hypertensive encephalopathy, cerebrovascular accident or transient ischemic attack. * Has clinically significant cardiac conduction defects (ie, third-degree atrioventricular block, sick sinus syndrome). * Has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease. * Has severe renal dysfunction or disease. * Has known or suspected unilateral or bilateral renal artery stenosis. * Has a history of cancer that has not been in remission for at least 5 years prior to the first dose of study drug. * Has poorly-controlled type 1 or 2 diabetes mellitus at Screening. * Has hypokalemia or hyperkalemia at Screening. * Has an alanine aminotransferase or aspartate aminotransferase level of greater than 2.5 times the upper limit of normal, active liver disease, or jaundice at Screening. * Has any other known serious disease or condition that would compromise safety, might affect life expectancy, or make it difficult to successfully manage and follow according to the protocol. * Has known hypersensitivity to angiotensin II receptor blockers or thiazide-type diuretics or other sulfonamide-derived compounds. * Has been randomized/enrolled in a previous azilsartan or azilsartan medoxomil plus chlorthalidone study. * Currently is participating in another investigational study or has received any investigational compound within 30 days prior to Screening. * Has a history of drug abuse or a history of alcohol abuse within the past 2 years. * Is taking or expected to take any excluded medication, including: * Antihypertensive medications must be discontinued completely by Day -14, except antihypertensive medications used in the open-label treatment period in accordance with the titration-to-target blood pressure titration. * Angiotensin II receptor blockers or thiazide-type diuretics other than study medication. * Over-the-counter products not permitted by investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With at Least 1 Adverse Event | From Week 0 (Day 1) to Week 52. | An adverse event is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product without regard to causality. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Serum Creatinine Elevations Greater Than 50% From Baseline and Greater Than the Upper Limit of Normal (ULN) | Baseline and Week 52 | Serum creatinine was measured at every visit and evaluated as a laboratory parameter of special interest. The percentage of participants with creatinine increase ≥50% from Baseline and greater than ULN was summarized: - At any visit (includes transient and persistent elevations). - At the Final Visit (includes persistent elevations and participants whose first elevation may have been at the Final Visit). - At least 2 consecutive visits (includes only persistent elevations). |
Countries
Austria, Germany, Netherlands, Poland, United Kingdom
Participant flow
Recruitment details
Participants took part in the study at 79 investigative sites in the United States, Netherlands, Poland, the United Kingdom and Germany from 27 October 2009 to 17 November 2011.
Pre-assignment details
Participants with a diagnosis of essential hypertension were randomized to receive open-label treatment with either Azilsartan Medoxomil and Chlorthalidone or Olmesartan Medoxomil and Hydrochlorothiazide for up to 52 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Azilsartan Medoxomil and Chlorthalidone Azilsartan medoxomil 40 mg and chlorthalidone 12.5 mg combination tablet, orally, once daily for up to 52 weeks. For participants who did not achieve target blood pressure by Week 4, titration to a maximum dose of azilsartan medoxomil 80 mg and chlorthalidone 25 mg. Additional antihypertensive agents could be added as needed to achieve blood pressure control. | 418 |
| Olmesartan Medoxomil and Hydrochlorothiazide Participants in the United States: Olmesartan medoxomil 20 mg and hydrochlorothiazide 12.5 mg combination tablet, orally, once daily for up to 52 weeks. For participants who did not achieve target blood pressure by Week 4, titration to a maximum dose of Olmesartan medoxomil 40 mg and hydrochlorothiazide 25 mg. Participants in Europe: Olmesartan medoxomil 20 mg and hydrochlorothiazide 12.5 mg combination tablet, orally, once daily for up to 52 weeks. For participants who did not achieve target blood pressure by Week 4, titration to a maximum dose of Olmesartan medoxomil 20 mg and hydrochlorothiazide 25 mg. Additional antihypertensive agents could be added as needed to achieve blood pressure control. | 419 |
| Total | 837 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 75 | 37 |
| Overall Study | Lack of Efficacy | 0 | 2 |
| Overall Study | Lost to Follow-up | 14 | 16 |
| Overall Study | Major Protocol Deviation | 6 | 7 |
| Overall Study | Other | 5 | 7 |
| Overall Study | Withdrawal by Subject | 31 | 20 |
Baseline characteristics
| Characteristic | Azilsartan Medoxomil and Chlorthalidone | Total | Olmesartan Medoxomil and Hydrochlorothiazide |
|---|---|---|---|
| Age Continuous | 58.5 years STANDARD_DEVIATION 10.79 | 58.1 years STANDARD_DEVIATION 10.8 | 57.6 years STANDARD_DEVIATION 10.8 |
| Age, Customized 45 to 64 years | 251 participants | 510 participants | 259 participants |
| Age, Customized <45 years | 46 participants | 94 participants | 48 participants |
| Age, Customized 65 to 74 years | 94 participants | 187 participants | 93 participants |
| Age, Customized ≥75 years | 27 participants | 46 participants | 19 participants |
| Body Mass Index (BMI) | 31.4 kg/m^2 STANDARD_DEVIATION 6.21 | 31.7 kg/m^2 STANDARD_DEVIATION 6.42 | 31.9 kg/m^2 STANDARD_DEVIATION 6.63 |
| Chronic Kidney Disease (CKD) status No | 359 participants | 727 participants | 368 participants |
| Chronic Kidney Disease (CKD) status Yes | 59 participants | 110 participants | 51 participants |
| Diabetes Status No | 354 participants | 714 participants | 360 participants |
| Diabetes Status Yes | 64 participants | 123 participants | 59 participants |
| Diastolic blood pressure < 90 mmHg | 107 participants | 210 participants | 103 participants |
| Diastolic blood pressure ≥90 mmHg | 311 participants | 627 participants | 316 participants |
| Estimated glomerular filtration rate Mild impairment: ≥60 and <90 ml/min/1.73 m^2 | 275 participants | 540 participants | 265 participants |
| Estimated glomerular filtration rate Missing | 2 participants | 3 participants | 1 participants |
| Estimated glomerular filtration rate Moderate impairment: ≥30 and <60 ml/min/1.73 m^2 | 54 participants | 97 participants | 43 participants |
| Estimated glomerular filtration rate Normal: ≥90 ml/min/1.73 m^2 | 87 participants | 197 participants | 110 participants |
| Height | 169.9 cm STANDARD_DEVIATION 10.2 | 169.8 cm STANDARD_DEVIATION 10.1 | 169.6 cm STANDARD_DEVIATION 10.1 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 4 participants | 9 participants | 5 participants |
| Race/Ethnicity, Customized Asian | 4 participants | 11 participants | 7 participants |
| Race/Ethnicity, Customized Black or African American | 72 participants | 146 participants | 74 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 40 participants | 81 participants | 41 participants |
| Race/Ethnicity, Customized Missing | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Multiracial | 3 participants | 6 participants | 3 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Non-Hispanic or Latino | 209 participants | 414 participants | 205 participants |
| Race/Ethnicity, Customized Not collected | 169 participants | 341 participants | 172 participants |
| Race/Ethnicity, Customized White | 341 participants | 677 participants | 336 participants |
| Region of Enrollment Germany | 22 participants | 43 participants | 21 participants |
| Region of Enrollment Netherlands | 56 participants | 114 participants | 58 participants |
| Region of Enrollment Poland | 52 participants | 106 participants | 54 participants |
| Region of Enrollment United Kingdom | 39 participants | 78 participants | 39 participants |
| Region of Enrollment United States | 249 participants | 496 participants | 247 participants |
| Sex: Female, Male Female | 192 Participants | 365 Participants | 173 Participants |
| Sex: Female, Male Male | 226 Participants | 472 Participants | 246 Participants |
| Smoking history Current smoker | 82 participants | 160 participants | 78 participants |
| Smoking history Ex-smoker | 122 participants | 258 participants | 136 participants |
| Smoking history Never smoked | 214 participants | 419 participants | 205 participants |
| Systolic blood pressure ≥140 - < 160 mmHg | 1 participants | 2 participants | 1 participants |
| Systolic blood pressure ≥160 - < 180 mmHg | 382 participants | 767 participants | 385 participants |
| Systolic blood pressure ≥180 mm Hg | 35 participants | 68 participants | 33 participants |
| Weight | 91.00 kg STANDARD_DEVIATION 21.025 | 91.50 kg STANDARD_DEVIATION 21.373 | 92.00 kg STANDARD_DEVIATION 21.727 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 217 / 418 | 183 / 419 |
| serious Total, serious adverse events | 24 / 418 | 26 / 419 |
Outcome results
Primary
Percentage of Participants With at Least 1 Adverse Event
An adverse event is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product without regard to causality.
Time frame: From Week 0 (Day 1) to Week 52.
Population: Safety analysis set: All participants who received at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azilsartan Medoxomil and Chlorthalidone | Percentage of Participants With at Least 1 Adverse Event | 78.5 percentage of participants |
| Olmesartan Medoxomil and Hydrochlorothiazide | Percentage of Participants With at Least 1 Adverse Event | 76.4 percentage of participants |
Secondary
Percentage of Participants With Serum Creatinine Elevations Greater Than 50% From Baseline and Greater Than the Upper Limit of Normal (ULN)
Serum creatinine was measured at every visit and evaluated as a laboratory parameter of special interest. The percentage of participants with creatinine increase ≥50% from Baseline and greater than ULN was summarized: - At any visit (includes transient and persistent elevations). - At the Final Visit (includes persistent elevations and participants whose first elevation may have been at the Final Visit). - At least 2 consecutive visits (includes only persistent elevations).
Time frame: Baseline and Week 52
Population: Safety analysis set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Azilsartan Medoxomil and Chlorthalidone | Percentage of Participants With Serum Creatinine Elevations Greater Than 50% From Baseline and Greater Than the Upper Limit of Normal (ULN) | At any postbaseline visit | 14.2 percentage of participants |
| Azilsartan Medoxomil and Chlorthalidone | Percentage of Participants With Serum Creatinine Elevations Greater Than 50% From Baseline and Greater Than the Upper Limit of Normal (ULN) | at the Final Visit | 5.9 percentage of participants |
| Azilsartan Medoxomil and Chlorthalidone | Percentage of Participants With Serum Creatinine Elevations Greater Than 50% From Baseline and Greater Than the Upper Limit of Normal (ULN) | ≥2 consecutive elevations | 5.1 percentage of participants |
| Olmesartan Medoxomil and Hydrochlorothiazide | Percentage of Participants With Serum Creatinine Elevations Greater Than 50% From Baseline and Greater Than the Upper Limit of Normal (ULN) | At any postbaseline visit | 5.8 percentage of participants |
| Olmesartan Medoxomil and Hydrochlorothiazide | Percentage of Participants With Serum Creatinine Elevations Greater Than 50% From Baseline and Greater Than the Upper Limit of Normal (ULN) | at the Final Visit | 1.0 percentage of participants |
| Olmesartan Medoxomil and Hydrochlorothiazide | Percentage of Participants With Serum Creatinine Elevations Greater Than 50% From Baseline and Greater Than the Upper Limit of Normal (ULN) | ≥2 consecutive elevations | 1.2 percentage of participants |