Parallel-Group Comparison of Olmesartan (OLM), Amlodipine (AML) and Hydrochlorothiazid (HCTZ) in Hypertension

Randomised, Double-Blind, Parallel-Group Study Evaluating Efficacy and Safety of Co-Administration of Triple Combinations of Olmesartan Medoxomil, Amlodipine Besylate, and Hydrochlorothiazide Compared With Corresponding Olmesartan - Amlodipine Combination in Subjects With Hypertension

This study is to determine the change in blood pressure from the administration of Olmesartan/Amlodipine/Hydrochlorothiazide triple combinations compared to dual combinations with Olmesartan/Amlodipine.

Inclusion Criteria:

• Male or female subjects aged 18 years or older.
• Subjects with mean trough seated blood pressure (SeBP) ≥ 160/100 mmHg, (seated systolic blood pressure(SeSBP) ≥ 160 mmHg and seated diastolic blood pressure (SeDBP) ≥ 100 mmHg) at Screening if not currently on antihypertensive medication (newly diagnosed subjects or subjects who are not taking any antihypertensive medication for at least 3 weeks); Or Subjects with mean trough SeBP ≥ 160/100 mmHg, SeSBP ≥ 160 mmHg and SeDBP ≥ 100 mmHg) after washout of prior antihypertensive medication in subjects who discontinued their previous antihypertensive medication.

The difference in mean SeSBP/SeDBP between the visit prior to randomisation and the randomisation visit must be ≤ 20/10 mmHg. Subjects not currently on antihypertensive (HTN) medication may meet this requirement at the screening visit (Visit 1) and the randomization visit (Visit 3). Subjects washing out of HTN medication must meet this requirement at least by Visit 2 (or Visit 2.1, if needed) and Visit 3. All subjects undergoing washout of their prior antihypertensive medication will have the opportunity to re-visit the study sites for additional visits during washout (Visits 2 and 2.1) to assess eligibility for randomisation.

• Subjects freely sign the informed consent form (ICF) after the nature of the study and the disclosure of his/her data has been explained.
• Female subjects of childbearing potential must be using adequate contraception (female of childbearing potential is defined as one who has not been postmenopausal for at least one year, or has not been surgically sterilised, or has not had a hysterectomy at least three months prior to the start of this study [Visit 1]). Adequate contraceptives include hormonal intra-uterine devices, hormonal contraceptives (oral, depot, patch or injectable), and double barrier methods such as condoms or diaphragms with spermicidal gel or foam.

Exclusion Criteria:

• Female subjects of childbearing potential who are pregnant or lactating.

• Subjects with serious disorders which may limit the ability to evaluate the efficacy or safety of the investigational products, including cerebrovascular, cardiovascular, renal, respiratory, hepatic, gastrointestinal, endocrine or metabolic, haematologic or, neurologic, and psychiatric diseases. The same applies for immunocompromised and/or neutropenic subjects.

• Subjects having a history of the following within the last six months: myocardial infarction (MI), unstable angina pectoris, percutaneous coronary intervention, heart failure, hypertensive encephalopathy, cerebrovascular accident (stroke), or transient ischaemic attack.

• Subjects with clinically significant abnormal laboratory values at Screening, including subjects with one or more of the following:

  • Aspartate aminotransferase (AST) > 3 times upper limit of normal (ULN).
  • Alanine aminotransferase (ALT) > 3 times ULN.
  • Gamma-glutamyl transferase (GGT) > 3 times ULN.
  • Potassium above ULN (unless high value is due to haemolytic blood sample).

• Subjects with secondary hypertension of any aetiology such as renal disease, phaeochromocytoma, or Cushing's syndrome.

• Subjects with contraindication to olmesartan, amlodipine, hydrochlorothiazide, or any of the tablet's excipients.

• Newly diagnosed subjects with a mean trough SeSBP > 200 mmHg or mean trough SeDBP > 115 mmHg or any subjects with bradycardia (heart rate < 50 beats/min at rest documented by mean radial pulse rate [PR] or electrocardiogram [ECG]) at Screening (Visit 1) or immediately before taking Period I study medication (Visit 3).

• Subjects already taking four or more antihypertensive medications.

• Subjects with a mean trough SeSBP > 145 mmHg or mean trough SeDBP > 95 mmHg while taking three antihypertensive medications.

• Subjects with a mean trough SeSBP > 160 mmHg or mean trough SeDBP > 100 mmHg while taking two antihypertensive medications.

• Subjects with a mean trough SeSBP > 180 mmHg or mean trough SeDBP > 110 mmHg while taking one antihypertensive medication.

• Subjects with electrocardiogram evidence of 2nd or 3rd degree atrio ventricular (AV) block, atrial fibrillation, or other cardiac arrhythmia (requiring treatment).

• Subjects with severe heart failure (New York Heart Association stage III-IV), clinically significant aortic or mitral valve stenosis, uncorrected coarctation of the aorta, obstruction of cardiac outflow (obstructive, hypertrophic cardiomyopathy) or symptomatic coronary disease.

• Subjects with clinical evidence of renal disease including reno-vascular occlusive disease, nephrectomy and/or renal transplant, bilateral renal artery stenosis, unilateral renal artery stenosis in a solitary kidney, or severe renal impairment as evidenced by CrCl of < 30 mL/min calculated using the Cockcroft and Gault formula.

• Subjects with clinically relevant hepatic impairment.

• Subjects with biliary obstruction.

• Subjects with uncontrolled Type 1 or Type 2 diabetes defined as HbA1c > 9.0%. Diabetics must have documentation of HbA1c within 6 months of the Screening Visit, or must have their HbA1c assessed prior to randomisation. Note: subjects with Type 1 or Type 2 diabetes controlled with insulin, diet or oral hypoglycaemic agents on a stable dose for at least 30 days may be included.

• Subjects with a history of a wasting disease (e.g. cancer), autoimmune diseases, connective tissue diseases, major allergies or angioneurotic oedema.

• Subjects who require or are taking any concomitant medication which may interfere with the objectives of the study.

• Subjects on beta blockers or calcium channel blockers (CCBs) for both hypertension and either ischemia, post-MI prophylaxis or tachyarrhythmias.

• Subjects with known malabsorption syndromes.

• Subjects with psychiatric or emotional problems, which would invalidate the giving of informed consent or limit the ability of the subject to comply with study requirements.

• Subjects with a history of alcohol and/or drug abuse.

• Subjects who have received any investigational agent within 30 days prior to Screening.

• Subjects who are unwilling or unable to provide informed consent or to participate satisfactorily for the entire study.

• Subjects with malignancy during the past 2 years excluding squamous cell or basal cell carcinoma of the skin.

• Subjects with signs or symptoms which could exacerbate the occurrence of hypotension such as volume and salt depletion.

• Subjects with any medical condition, which in the judgment of the Investigator would jeopardise the evaluation of efficacy or safety and/or constitute a significant safety risk to the subject.