Safety
Conditions
Keywords
Renal Insufficiency, Kidney Diseases, Hypertension, Drug Therapy
Brief summary
The purpose of this study is to evaluate long term safety and tolerability of azilsartan medoxomil and chlorthalidone, once daily (QD), compared with olmesartan medoxomil and hydrochlorothiazide in hypertensive participants with moderate renal impairment.
Detailed description
A major component of blood pressure regulation is the renin-angiotensin-aldosterone system (RAAS). Drugs that modulate the RAAS are used commonly worldwide for the treatment of hypertension. TAK-491 (azilsartan medoxomil) is a prodrug of TAK-536 (azilsartan), an angiotensin II receptor blocker (ARB). Azilsartan medoxomil is being evaluated by Takeda to treat participants with essential hypertension. Chlorthalidone is an orally administered thiazide-like diuretic agent, and long-term outcomes trials show blood pressure reductions associated with chlorthalidone treatment reduce risk of cardiovascular morbidity and mortality. Hypertensive patients with moderate renal impairment are a relatively more severe and resistant hypertension population, and may benefit from effective fixed-dose combination treatments such as an ARB plus a diuretic for blood pressure control. Participants will be randomized to receive azilsartan medoxomil and chlorthalidone or olmesartan medoxomil and hydrochlorothiazide for up to 52 weeks to evaluate long term safety of azilsartan medoxomil and chlorthalidone. A titration-to-target blood pressure approach will be used to guide the titration of study medication in this trial.
Interventions
Fixed-dose combination tablets.
Fixed-dose combination tablets.
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
1. Is treated with 2 or 3 antihypertensive medications and on stable therapy, defined as ≥6 weeks on medication, and has a mean sitting clinic systolic blood pressure ≥135 and ≤160 mm Hg at the Screening Visit and on Day 1. 2. Has an estimated glomerular filtration rate (eGFR) in the range of ≥30 to \<60 mL/min/1.73 m\^2 (Stage 3 chronic kidney disease) at the Screening Visit. 3. Is a man or woman and aged 18 years or older. 4. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to routinely use adequate contraception from signing of the informed consent through 30 days after the last study drug dose. 5. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements. 6. 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. 7. Has clinical laboratory test results (clinical chemistry, hematology, and complete urinalysis) that the investigator does not consider to be clinically significant in this moderate renal impaired population. 8. Is willing to discontinue the current antihypertensive medications 2 days prior to randomization.
Exclusion criteria
1. Has received any investigational compound within 30 days prior to Screening or is currently participating in another investigational study. 2. Has been randomized/enrolled in a previous TAK-491 or TAK-491CLD study. NOTE: This criterion does not apply to participants who began participation in another TAK-491 or TAK-491CLD study but were not randomized/enrolled, nor does it apply to participants who participated in observational studies that lacked an intervention or invasive procedure. 3. Is receiving a combination of olmesartan and hydrochlorothiazide at the Screening Visit. 4. 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 (eg, spouse, parent, child, sibling) or may consent under duress. 5. Has a mean clinic diastolic (sitting, trough) \>110 mm Hg on Day 1. 6. Has secondary hypertension of any etiology (eg, renovascular disease, pheochromocytoma, Cushing's syndrome). 7. 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. 8. Has clinically significant cardiac conduction defects (ie, third-degree atrioventricular block, sick sinus syndrome). 9. Has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease. 10. Has severe renal dysfunction or disease (based on eGFR \<30 mL/min/1.73m\^2 at Screening) prior renal transplantation or nephrotic syndrome (defined as a urinary albumin/creatinine ratio \>2000 mg/g at Screening). 11. Has known or suspected unilateral or bilateral renal artery stenosis. 12. 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 I squamous cell carcinoma of the skin.) 13. Has poorly-controlled type 1 or 2 diabetes mellitus (glycosylated hemoglobin A \[HbA1c\] \>8.5%) at Screening. 14. Has hypokalemia or hyperkalemia (defined as serum potassium outside of the normal reference range of the central laboratory). 15. Has an alanine aminotransferase or aspartate aminotransferase level of \>2.5 times the upper limit of normal, active liver disease, or jaundice. 16. 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 the participant according to the protocol. 17. has a history of hypersensitivity or allergies to ARBs or thiazide-type diuretics or other sulfonamide-derived compounds. 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 required to take excluded medications. 20. If female, 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With at Least 1 Adverse Event (AE) | From the first dose of open-label study drug until 14 days (or 30 days for a serious adverse event) after the last dose of open- label study drug (up to 56 weeks). | An AE is any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have a causal relationship with this treatment. A serious AE is defined as any untoward medical occurrence that resulted in death, was life threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability or incapacity, led to a congenital anomaly/birth defect or was an important medical event that may have required intervention to prevent any of items above. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants at Final Visit Who Achieve Target Systolic Blood Pressure <130 mm Hg | Week 52 | Systolic blood pressure is the arithmetic mean of the 3 serial sitting systolic blood pressure measurements. Percentage of participants who achieve a sitting clinic systolic blood pressure response defined as less than 130 mm Hg at Week 52. |
| Percentage of Participants at Final Visit Who Achieved Target Diastolic Blood Pressure <80 mm Hg | Week 52 | Diastolic blood pressure is the arithmetic mean of the 3 serial sitting diastolic blood pressure measurements. Percentage of participants at Week 52 who achieved a sitting clinic diastolic blood pressure response, defined as less than 80 mm Hg. |
| Percentage of Participants at Final Visit Who Achieved Both a Clinic Systolic and Diastolic Blood Pressure Response | Week 52 | Systolic/diastolic blood pressure is the arithmetic mean of the 3 serial sitting systolic/diastolic blood pressure measurements. Percentage of participants who achieved both a sitting clinic systolic and diastolic blood pressure response, defined as systolic blood pressure less than 130 mm Hg and diastolic blood pressure less than 80 mm Hg at Week 52. |
Countries
Bulgaria, Germany, Latvia, Lithuania, Netherlands, Poland, Slovakia, Ukraine
Participant flow
Recruitment details
Participants took part in the study at 46 investigative sites in the United States, Germany, Latvia, Lithuania, Poland, Slovakia, and the Ukraine from 02 March 2011 to 11 October 2012.
Pre-assignment details
Participants with high blood pressure and moderate renal impairment were enrolled in 1 of 2 once-daily (QD) treatment groups.
Participants by arm
| Arm | Count |
|---|---|
| Azilsartan Medoxomil + Chlorthalidone United States and Europe: Azilsartan medoxomil 20 mg plus chlorthalidone 12.5 mg fixed dose combination tablets (TAK-491CLD), titrated up to azilsartan medoxomil 40 mg plus chlorthalidone 25 mg orally, once daily for up to 52 weeks. | 77 |
| Olmesartan Medoxomil + Hydrochlorothiazide United States: Olmesartan medoxomil 20 mg plus hydrochlorothiazide 12.5 mg fixed dose combination tablets (OLM/HCTZ), titrated up to olmesartan medoxomil 40 mg plus hydrochlorothiazide 25 mg orally, once daily for up to 52 weeks. Europe: Olmesartan medoxomil 20 mg plus hydrochlorothiazide 12.5 mg fixed dose combination tablets, titrated up to olmesartan medoxomil 20 mg plus hydrochlorothiazide 25 mg orally, once daily for up to 52 weeks. | 76 |
| Total | 153 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 11 |
| Overall Study | Major Protocol Deviation | 0 | 1 |
| Overall Study | Other | 1 | 0 |
| Overall Study | Voluntary Withdrawal | 5 | 4 |
Baseline characteristics
| Characteristic | Azilsartan Medoxomil + Chlorthalidone | Olmesartan Medoxomil + Hydrochlorothiazide | Total |
|---|---|---|---|
| Age Continuous | 67.9 years STANDARD_DEVIATION 8.24 | 68.9 years STANDARD_DEVIATION 9.1 | 68.4 years STANDARD_DEVIATION 8.66 |
| Age, Customized ≥45 to <65 years | 21 participants | 18 participants | 39 participants |
| Age, Customized <45 years | 0 participants | 1 participants | 1 participants |
| Age, Customized ≥65 to <75 years | 38 participants | 39 participants | 77 participants |
| Age, Customized ≥75 years | 18 participants | 18 participants | 36 participants |
| Baseline estimated glomerular filtration rate (eGFR) category ≥30 and <45 mL/min/1.73 m^2 | 31 participants | 33 participants | 64 participants |
| Baseline estimated glomerular filtration rate (eGFR) category ≥45 and <60 mL/min/1.73 m^2 | 40 participants | 39 participants | 79 participants |
| Baseline estimated glomerular filtration rate (eGFR) category ≥60 mL/min/1.73 m^2 | 6 participants | 4 participants | 10 participants |
| Body Mass Index (BMI) | 30.44 kg/m^2 STANDARD_DEVIATION 6.226 | 31.57 kg/m^2 STANDARD_DEVIATION 6.524 | 31.00 kg/m^2 STANDARD_DEVIATION 6.38 |
| Diabetes Status No | 44 participants | 44 participants | 88 participants |
| Diabetes Status Yes | 33 participants | 32 participants | 65 participants |
| Diastolic blood pressure | 84.8 mm Hg STANDARD_DEVIATION 10.31 | 84.7 mm Hg STANDARD_DEVIATION 9.68 | 84.7 mm Hg STANDARD_DEVIATION 9.97 |
| Diastolic blood pressure categories <90 mm Hg | 52 participants | 50 participants | 102 participants |
| Diastolic blood pressure categories ≥90 mm Hg | 25 participants | 26 participants | 51 participants |
| Estimated glomerular filtration rate (eGFR) | 48.25 mL/min/1.73 m^2 STANDARD_DEVIATION 10.205 | 47.73 mL/min/1.73 m^2 STANDARD_DEVIATION 8.761 | 47.99 mL/min/1.73 m^2 STANDARD_DEVIATION 9.487 |
| Height | 165.7 cm STANDARD_DEVIATION 9.65 | 168.7 cm STANDARD_DEVIATION 9.48 | 167.2 cm STANDARD_DEVIATION 9.65 |
| Race/Ethnicity, Customized Asian | 2 participants | 2 participants | 4 participants |
| Race/Ethnicity, Customized Black or African American | 18 participants | 12 participants | 30 participants |
| Race/Ethnicity, Customized White | 57 participants | 62 participants | 119 participants |
| Region of Enrollment Germany | 10 participants | 9 participants | 19 participants |
| Region of Enrollment Latvia | 4 participants | 5 participants | 9 participants |
| Region of Enrollment Lithuania | 5 participants | 2 participants | 7 participants |
| Region of Enrollment Poland | 7 participants | 6 participants | 13 participants |
| Region of Enrollment Slovakia | 6 participants | 6 participants | 12 participants |
| Region of Enrollment Ukraine | 6 participants | 11 participants | 17 participants |
| Region of Enrollment United States | 39 participants | 37 participants | 76 participants |
| Sex: Female, Male Female | 45 Participants | 31 Participants | 76 Participants |
| Sex: Female, Male Male | 32 Participants | 45 Participants | 77 Participants |
| Smoking Classification Current Smoker | 11 participants | 11 participants | 22 participants |
| Smoking Classification Ex-smoker | 20 participants | 25 participants | 45 participants |
| Smoking Classification Never Smoked | 46 participants | 40 participants | 86 participants |
| Systolic blood pressure | 151.1 mm Hg STANDARD_DEVIATION 10.3 | 149.0 mm Hg STANDARD_DEVIATION 7.8 | 150.1 mm Hg STANDARD_DEVIATION 9.18 |
| Systolic blood pressure categories <140 mm Hg | 11 participants | 10 participants | 21 participants |
| Systolic blood pressure categories ≥140 to <160 mm Hg | 60 participants | 64 participants | 124 participants |
| Systolic blood pressure categories ≥160 to <180 mm Hg | 5 participants | 2 participants | 7 participants |
| Systolic blood pressure categories ≥180 mm Hg | 1 participants | 0 participants | 1 participants |
| Weight | 83.54 kg STANDARD_DEVIATION 17.894 | 90.14 kg STANDARD_DEVIATION 21.587 | 86.82 kg STANDARD_DEVIATION 20.025 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 52 / 77 | 41 / 76 |
| serious Total, serious adverse events | 8 / 77 | 9 / 76 |
Outcome results
Primary
Number of Participants With at Least 1 Adverse Event (AE)
An AE is any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have a causal relationship with this treatment. A serious AE is defined as any untoward medical occurrence that resulted in death, was life threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability or incapacity, led to a congenital anomaly/birth defect or was an important medical event that may have required intervention to prevent any of items above.
Time frame: From the first dose of open-label study drug until 14 days (or 30 days for a serious adverse event) after the last dose of open- label study drug (up to 56 weeks).
Population: Safety analysis set - All participants who received at least 1 dose of open-label study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Azilsartan Medoxomil + Chlorthalidone | Number of Participants With at Least 1 Adverse Event (AE) | Adverse Events Leading to Discontinuation | 17 participants |
| Azilsartan Medoxomil + Chlorthalidone | Number of Participants With at Least 1 Adverse Event (AE) | Serious Adverse Events Leading to Discontinuation | 5 participants |
| Azilsartan Medoxomil + Chlorthalidone | Number of Participants With at Least 1 Adverse Event (AE) | Serious Adverse Events | 8 participants |
| Azilsartan Medoxomil + Chlorthalidone | Number of Participants With at Least 1 Adverse Event (AE) | Death | 0 participants |
| Azilsartan Medoxomil + Chlorthalidone | Number of Participants With at Least 1 Adverse Event (AE) | Adverse Events | 68 participants |
| Olmesartan Medoxomil + Hydrochlorothiazide | Number of Participants With at Least 1 Adverse Event (AE) | Death | 1 participants |
| Olmesartan Medoxomil + Hydrochlorothiazide | Number of Participants With at Least 1 Adverse Event (AE) | Adverse Events | 58 participants |
| Olmesartan Medoxomil + Hydrochlorothiazide | Number of Participants With at Least 1 Adverse Event (AE) | Adverse Events Leading to Discontinuation | 15 participants |
| Olmesartan Medoxomil + Hydrochlorothiazide | Number of Participants With at Least 1 Adverse Event (AE) | Serious Adverse Events | 9 participants |
| Olmesartan Medoxomil + Hydrochlorothiazide | Number of Participants With at Least 1 Adverse Event (AE) | Serious Adverse Events Leading to Discontinuation | 4 participants |
Secondary
Percentage of Participants at Final Visit Who Achieved Both a Clinic Systolic and Diastolic Blood Pressure Response
Systolic/diastolic blood pressure is the arithmetic mean of the 3 serial sitting systolic/diastolic blood pressure measurements. Percentage of participants who achieved both a sitting clinic systolic and diastolic blood pressure response, defined as systolic blood pressure less than 130 mm Hg and diastolic blood pressure less than 80 mm Hg at Week 52.
Time frame: Week 52
Population: Full analysis set participants (all randomized participants who received at least 1 dose of open-label study drug) with both Baseline and a post-baseline value; last observation carried forward was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azilsartan Medoxomil + Chlorthalidone | Percentage of Participants at Final Visit Who Achieved Both a Clinic Systolic and Diastolic Blood Pressure Response | 58.7 percentage of participants |
| Olmesartan Medoxomil + Hydrochlorothiazide | Percentage of Participants at Final Visit Who Achieved Both a Clinic Systolic and Diastolic Blood Pressure Response | 73.0 percentage of participants |
Secondary
Percentage of Participants at Final Visit Who Achieved Target Diastolic Blood Pressure <80 mm Hg
Diastolic blood pressure is the arithmetic mean of the 3 serial sitting diastolic blood pressure measurements. Percentage of participants at Week 52 who achieved a sitting clinic diastolic blood pressure response, defined as less than 80 mm Hg.
Time frame: Week 52
Population: Full analysis set participants (all randomized participants who received at least 1 dose of open-label study drug) with both Baseline and a post-baseline value; last observation carried forward was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azilsartan Medoxomil + Chlorthalidone | Percentage of Participants at Final Visit Who Achieved Target Diastolic Blood Pressure <80 mm Hg | 80.0 percentage of participants |
| Olmesartan Medoxomil + Hydrochlorothiazide | Percentage of Participants at Final Visit Who Achieved Target Diastolic Blood Pressure <80 mm Hg | 87.8 percentage of participants |
Secondary
Percentage of Participants at Final Visit Who Achieve Target Systolic Blood Pressure <130 mm Hg
Systolic blood pressure is the arithmetic mean of the 3 serial sitting systolic blood pressure measurements. Percentage of participants who achieve a sitting clinic systolic blood pressure response defined as less than 130 mm Hg at Week 52.
Time frame: Week 52
Population: Full analysis set participants (all randomized participants who received at least 1 dose of open-label study drug) with both Baseline and a post-baseline value; last observation carried forward was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azilsartan Medoxomil + Chlorthalidone | Percentage of Participants at Final Visit Who Achieve Target Systolic Blood Pressure <130 mm Hg | 69.3 percentage of participants |
| Olmesartan Medoxomil + Hydrochlorothiazide | Percentage of Participants at Final Visit Who Achieve Target Systolic Blood Pressure <130 mm Hg | 78.4 percentage of participants |