Study of Nifedipine GITS and Candesartan Combination Compared to Monotherapy in Patients With Essential Hypertension

Inclusion criteria

• 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).

Exclusion criteria

• 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

• Gastrointestinal disease or surgery resulting in the potential for malabsorption
• Severe gastrointestinal tract narrowing; kock pouch (ileostomy after proctocolectomy)
• Cholestasis or biliary obstruction or history of pancreatic injury or clinical significant increase of lipase, amylase, or bilirubin.
• Liver disease or AST/ALT levels >3 x ULN
• 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.