Atacand Dose Range Finding Study in Pediatric Subjects 6 to <17 Years of Age

A Dose-Ranging and Safety Study of Candesartan Cilexetil in Hypertensive Pediatric Subjects 6 to <17 Years of Age: A 4-Week, Multinational, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study

Study 261A is a dose-ranging and safety study of candesartan cilexetil. It is a multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group study with a 4 week treatment period in hypertensive pediatric subjects.

Subjects undergo a screening evaluation, then a 1-week, single-blind, placebo run-in after which eligible subjects are allocated to receive 1 of 3 dose levels of candesartan cilexetil or placebo. The study includes 2 panels based on subject weight.

The primary efficacy analysis is based on the intent-to-treat population and tests for slope = 0 in a linear regression model with change in sitting systolic blood pressure as the dependent and non-zero dose pooled across weight panels as the independent variable. For subjects without a Double-Blind Week 4 blood pressure determination, carrying the last value forward assigns the value.

Additional analyses will include data pooled from a similar dose ranging study conducted in children 1 to < 6 years of age.

Inclusion Criteria:

• Male or female ages 6 to < 17 years-of-age after parent or guardian's signing of informed consent.

Subjects with hypertension that is either:

• Diagnosed and untreated with a mean sitting systolic and/or diastolic blood pressure ≥ 95th percentile and ≤ 20 mm Hg (systolic) and/or 10 mm Hg (diastolic) above the 95th percentile at randomisation based on height-adjusted charts for age and gender; or
• Previously diagnosed and currently treated with mean sitting systolic blood pressure and/or diastolic blood pressure ≥ 95th percentile and ≤ 20 mm Hg (systolic) and/or 10 mm Hg (diastolic) above the 95th percentile at randomisation (off treatment) based on height-adjusted charts for age and gender.

Females of childbearing potential (post-menarche) must have a negative urine pregnancy test prior to randomization and adhere to a pregnancy prevention method (abstinence, barrier method plus spermicidal foam, oral, or implanted contraceptive).

A signed informed consent by a parent or a legal guardian and an assent form signed by the subject (if applicable).

Exclusion Criteria:

• Any situation, clinical condition or laboratory abnormality that, in the opinion of the investigator or sponsor, may interfere with the subject's participation in the study or would pose a significant risk to the subject or interfere with the assessment of safety and efficacy endpoints.
• Hypertension secondary to coarctation of the aorta, pheochromocytoma, hyperthyroidism, Cushing's syndrome, or medications (eg: corticosteroids).
• Known history of bilateral renal artery stenosis, unilateral renal artery stenosis or a renal transplant.
• Glomerular filtration rate < 50 mL/min based on an estimated value using the Schwartz Formula.
• Nephrotic syndrome not in remission.
• Insulin dependent diabetes mellitus.
• Known bleeding, coagulation, or platelet disorder that could interfere with blood sampling.
• Clinically significant valvular heart disease.
• Clinical diagnosis of heart failure.
• Clinically significant arrhythmia (eg, any arrhythmia requiring medical therapy or that causes symptoms).
• Second or third degree AV block.
• Pregnant or breast-feeding an infant.
• Impaired liver function defined as either acute liver disease or chronic liver disease with persistent liver enzyme values greater than 1½ times the upper limit of the reference range for AST or ALT.
• Known hypersensitivity to ARBs.
• Unable to be off antihypertensive medication (diuretics, beta blockers, ACE Inhibitors, etc) for 6-weeks.
• Inability to discontinue medications which may contribute to elevated blood pressure e.g. systemic corticosteroids.
• Currently using, or used within 14 days prior to receiving double-blind medication, any concomitant medications which in the opinion of the investigator could negatively affect the subject.
• Unable or unwilling to comply with the study requirements including blood sampling and swallowing study drug tablets.
• Received an investigational agent within 30 days prior to receiving study medication.
• Alcohol or drug abuse.