Hypertension, essential

- Male and female subjects 18 years or older. Female subjects must be either post-menopausal for one year, surgically sterile, or using an effective contraceptive method. Hormonal contraceptive use is disallowed.
- Subjects must have mild to moderate essential hypertension (Grade 1 and 2 WHO classifications) as measured by calibrated standard sphygmomanometer. (MSDBP of ≥90 mmHg and < 110 mmHg at Visit 1 (placebo run-in), and MSDBP of ≥95 mmHg and < 110 mmHg at visit 2 (randomization)
- Subjects must have an absolute difference in their MSDBP of less than 10 mmHg between Visit 1 (placebo run- in) and Visit 2 (randomization).

- Severe hypertension (Grade 3 WHO classification; MSDBP ≥110 mmHg and/or MSSBP ≥ 180 mmHg)
- Inability to washout of antihypertensive drugs (even if prescribed for another indication) safely for a period of 14 weeks.
- History of hypertensive retinopathy – known Keith-Wagener Grade III or IV
- History of hypertensive encephalopathy
- Cerebrovascular ischemic event (stroke, transient ischemic attack [TIA])within the previous 12 months
- History of intracerebral hemorrhage or subarachnoid hemorrhage
- Evidence of secondary hypertension such as coarchation of the aorta, pheochromocytoms, hypersaldosteronism, etc.
- Type I diabetes mellitus (DM) or poorly controlled DM Type II as evidenced by a glycosylated hemoglobin [HbA1C] of greater than 9% on visit 1.
- Allergies or known intolerance to one of the investigational drugs/drug class or to one of their ingredients
- Any history of heart failure, New York Heart Association (NYHA) classification III or IV
- Severe coronary heart disease as manifest by a history of myocardial infarction or unstable angina in the last 6 months prior to visit 1.
- Clinically significant cardiac valvular disease
- History of malignancy in the last 5 years, excluding basal or skin cancer
- Uncorrected hypokalemia or hyperkalemia: potassium outside 3.0-5.0 mmol/L
- Surgical or medical conditions that might alter the metabolism, excretion or distribution or absorption of any drug
a) Gastrointestinal disease or surgery resulting in the potential for malabsorption
b) Severe gastrointestinal tract narrowing; kock pouch (ileostomy after proctocolectomy)
c) Cholestasis or biliary obstruction or history of pancreatic injury or clinical significant increase of lipase, amylase, or bilirubin.
d) Liver disease or AST/ALT levels >3 x ULN
e) Renal insufficiency, defined as eGFR of < 50 mL/min (computed using the
Cockroft-Gault formula), or on hemodialysis
- Investigation trial participation with receipt of investigational study drug within the last month
- Previous assignment to treatment in this study
- Female subjects who are pregnant or lactating.
- Subjects who have night employment (night shift).
- Subjects with an aortic aneurysm that, in the opinion of the investigator, will be unsuitable to be enrolled in the study.
- Thought by the investigator for any reason to be unsuitable for participation in a clinical study
- Systemic use of known cytochrome P450-3A4 inhibitors (e.g cimetidine, anti-human immunodeficiency virus [HIV] protease inhibitors e.g. ritonavir, azole anti-mycotics eg. ketoconazole,) or inducers (e.g rifampicin, anti-epileptic drugs eg. phenytoin, carbamazepine and phenobarbitone) or some P450-3A4 substrates (e.g quinidine, digoxin, tacrolimus)
- Present severe rhythm or conduction disorder:
- Atrial fibrillation
- Second or third degree heart block without a pacemaker.
- Baseline QTc >450 msec
- History of non-compliance, alcoholism or drug abuse that in the opinion of the investigator will compromise successful completion of the study.
- If differences greater than 20 mmHg for SBP and 10 mmHg for DBP are present on 3 consecutive BP readings, the subject should be excluded from the study.