A study to evaluate the effectiveness and safety of TAK-491 and Chlorthalidone combined in one tablet (40/12.5 and 40/25 mg) in patients with high blood pressure who do not achieve target blood pressure on treatment with TAK-491 40 mg alone”
- Conditions
- Essential HypertensionMedDRA version: 14.1Level: PTClassification code 10015488Term: Essential hypertensionSystem Organ Class: 10047065 - Vascular disordersTherapeutic area: Diseases [C] - Cardiovascular Diseases [C14]
- Registration Number
- EUCTR2011-000220-16-DE
- Lead Sponsor
- Takeda Global Research & Development Centre (Europe) Ltd.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 390
Subject eligibility is determined according to the following criteria:
At Screening
1. The subject has grade 2-3 essential hypertension which is not adequately controlled, as defined by mean, trough, sitting, clinic SBP:
* =160 to =180 mm Hg in subjects who have not received any antihypertensive medication in the 14 days prior to Visit 1.
* =150 to =170 mm Hg in subjects taking 1 antihypertensive medication at Visit 1.
* =140 to =160 mm Hg in subjects taking 2 antihypertensive medications at Visit 1.
2. The subject 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 relevant for precluding entry in to the study in this
hypertensive population.
3. The subject is willing to discontinue current antihypertensive medications.
4. In the opinion of the investigator, the subject is capable of understanding and complying with protocol requirements.
5. The subject or, when applicable, the subject’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.
6. The subject is a man or woman and aged 18 years or older, inclusive.
7. A female subject 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.
NOTE: Women NOT of childbearing potential are defined as those who have been surgically sterilized (hysterectomy, bilateral oophorectomy, tubal ligation [performed more than one 1 year prior to Screening]) or who are postmenopausal (defined as at least 1 year since last regular menses).
Post-placebo run-in:
8. The subject must have a post-placebo run-in, 24-hour mean SBP by ABPM of 140-175 mm Hg inclusive, and a clinic SBP measurement of 160 to 190 mm Hg inclusive (determined by the mean of 3 sitting, trough, measurements on Day -29) to qualify for entry in to the 4 week
single-blind TAK-491 40 mg monotherapy treatment period.
Post-4 week, single-blind TAK-491 40 mg monotherapy treatment:
9. The subject does not achieve target blood pressure (defined as clinic SBP =140 mm Hg as determined by the mean of 3 sitting, trough, measurements) following 4 weeks single-blind treatment with TAK-491 40 mg monotherapy at Day -1, prior to randomization to double-blind
treatment.
Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 312
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 78
Any subject who meets any of the following criteria will not qualify for entry into the study:
At Screening
1. The subject has clinic DBP >110 mm Hg.
2. The subject’s 3 SBP measurements differ by more than 15 mm Hg (confirmed by a second set of three measurements).
3. The subject has received any investigational compound within 30 days prior to Screening or is currently participating in another investigational study.
NOTE: Subjects participating in observational studies (per local definition) may enter Screening provided that the last intervention or invasive procedure was >30 days prior to Visit 1.
4. The subject has been randomized/enrolled in a previous TAK-491 or TAK-491CLD study.
NOTE: This criterion does not apply to subjects who entered screening or placebo run-in in another TAK-491 or TAK-491CLD study but were not randomized/enrolled.
5. The subject is a 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.
6. The subject is currently treated with more than 2 antihypertensive medications.
7. The subject works a night (third) shift (defined as 11 PM [2300] to 7 AM [0700]).
8. The subject has an upper arm circumference <24 cm or >42 cm.
9. The subject has secondary hypertension of any etiology (eg, renovascular disease, pheochromocytoma, Cushing’s syndrome).
10. The subject has any history of myocardial infarction, heart failure, unstable angina, coronary artery bypass graft, percutaneous coronary intervention, hypertensive encephalopathy, cerebrovascular accident, persistent or permanent atrial fibrillation or transient ischemic attack.
11. The subject has clinically significant cardiac conduction defects (eg, third-degree atrioventricular block, sick sinus syndrome).
12. The subject has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease or hypertrophic cardiomyopathy.
13. The subject has severe renal dysfunction or disease [based on eGFR <30 mL/min/1.73m2 at screening], prior renal transplantation or nephrotic syndrome (defined as a urinary albumin/creatinine ratio >2000 mg/g at Screening).
14. Subject has known haemodynamically significant bilateral renal artery stenosis or unilateral disease in a single kidney.
15. The subject has a history of cancer that has not been in remission for at least 5 years prior to the first dose of single-blind TAK-491 monotherapy study drug. (This criterion does not apply to those subjects with basal cell or Stage 1 squamous cell carcinoma of the skin).
16. The subject has poorly-controlled type 1 or 2 diabetes mellitus (hemoglobin A1c [HbA1c] >8.5%) at Screening.
17. The subject has hypokalemia or hyperkalemia (defined as serum potassium outside of the normal reference range of the central laboratory) at Screening.
18. The subject has an alanine aminotransferase or aspartate aminotransferase level >2.5 times the upper limit of normal, active liver disease, or jaundice at Screening.
19. The subject 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 subject according to the protocol.
20. The subject has a history of hypersensitivity or allergies to ARBs or thiazide-type diuretics or other sulfonamide-derived compounds.
21. The subject has a history of drug abuse (defined as any i
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: The Primary objective of this phase-3 randomized, double-blind, active controlled, study of 8 weeks duration is to evaluate the efficacy and safety of the fixed dose combinations of TAK-491 plus chlorthalidone (40/12.5 mg and 40/25 mg) in subjects with grades 2 or 3 essential hypertension who do not reach target blood pressure following treatment with TAK-491 40 mg monotherapy.;Secondary Objective: Not Applicable;Primary end point(s): Change from baseline to Week 8 in trough, sitting, clinic systolic blood pressure (SBP).;Timepoint(s) of evaluation of this end point: Week 8
- Secondary Outcome Measures
Name Time Method Secondary end point(s): Change from baseline to Week 8 in trough, sitting, clinic diastolic blood pressure (DBP).<br>-Change from baseline to Week 8 in trough (22 to 24 hours after dosing) SBP as measured by<br>ambulatory blood pressure monitoring (ABPM).<br>-Change from baseline to Week 8 in trough DBP as measured by ABPM.<br>-Change from baseline to week 8 in the following ABPM parameters:<br>-24-hour mean SBP and DBP.<br>-Mean daytime (6 AM to 10 PM) SBP and DBP.<br>-Mean nighttime (12 AM to 6 AM) SBP and DBP.<br>-Mean SBP and DBP at 0 to 12 hours after dosing.<br>-Proportion of subjects who achieve target blood pressure at Week 8 as defined by the<br>following:<br>a) Trough, sitting clinic SBP <140 mm Hg (or <130 mm Hg for patients with diabetes or<br>CKD).<br>b) Trough, sitting, clinic DBP <90 mm Hg (or <80 mm Hg for patients with diabetes or<br>CKD).<br>c) Achieving both trough, sitting clinic SBP and DBP targets above.;Timepoint(s) of evaluation of this end point: Week 8