| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10015488 |
| E.1.2 | Term | Essential hypertension |
| E.1.2 | System Organ Class | 10047065 - Vascular disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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. |
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| E.4 | Principal exclusion criteria |
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 illicit drug use) or a history of alcohol abuse per local guidelines within the past 2 years.
22. The subject is required to take excluded medications (see the Section 7.3 Excluded Medications and Treatments) at any point during the study.
23. If female, the subject is pregnant or lactating or intending to become pregnant before, during, or within 1 month after participating in this study; or intending to donate ova during such time period.
Post-placebo run-in period
24. The subject has a clinic SBP >190 mm Hg and DBP >115 mm Hg.
25. The subject is noncompliant (<70% or >130%) with study medication during the placebo run-in period.
26. The subject has a 24-hour mean eligibility ABPM reading of insufficient quality (as described in Appendix E).
Post-single-blind TAK-491 40 mg treatment period
27. The subject has a clinic SBP >180 mm Hg and DBP >110 mm Hg.
28. The subject is noncompliant (<70% or >130%) with study medication during the TAK-491 40 mg single-blind treatment period. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline to Week 8 in trough, sitting, clinic systolic blood pressure (SBP). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Change from baseline to Week 8 in trough, sitting, clinic diastolic blood pressure (DBP).
-Change from baseline to Week 8 in trough (22 to 24 hours after dosing) SBP as measured by
ambulatory blood pressure monitoring (ABPM).
-Change from baseline to Week 8 in trough DBP as measured by ABPM.
-Change from baseline to week 8 in the following ABPM parameters:
-24-hour mean SBP and DBP.
-Mean daytime (6 AM to 10 PM) SBP and DBP.
-Mean nighttime (12 AM to 6 AM) SBP and DBP.
-Mean SBP and DBP at 0 to 12 hours after dosing.
-Proportion of subjects who achieve target blood pressure at Week 8 as defined by the
following:
a) Trough, sitting clinic SBP <140 mm Hg (or <130 mm Hg for patients with diabetes or
CKD).
b) Trough, sitting, clinic DBP <90 mm Hg (or <80 mm Hg for patients with diabetes or
CKD).
c) Achieving both trough, sitting clinic SBP and DBP targets above. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 130 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Bulgaria |
| Estonia |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Serbia |
| Slovakia |
| Spain |
| Sweden |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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