E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020772 |
E.1.2 | Term | Hypertension |
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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 (Period II, Week 8 to Week 16) is to demonstrate the additional antihypertensive efficacy for SeDBP gained by adding HCTZ 12.5 or 25 mg to the treatment regimen in subjects with moderate to severe HTN not adequately controlled on OM/AML 40/10 mg alone, at Week 16 (after 8 weeks of double-blind treatment) using conventional BP measurement. |
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E.2.2 | Secondary objectives of the trial |
Period II: 1. Evaluate antihypertensive efficacy for SeDBP of triple combination OM/AML/HCTZ 40/10/12.5 & 40/10/25 mg vs OM/AML 40/10 mg at Wk(week)12. 2. Evaluate antihypertensive efficacy for SeSBP of OM/AML/HCTZ 40/10/12.5 & 40/10/25mg vs OM/AML 40/10mg at Wk12&16. 3. Evaluate antihypertensive efficacy from baseline to Wk16 (see protocol p36). 4. Evaluate % no. subjects achieving BP goal (SeBP, see protocol p36) and % no. subjects achieving SeBP thresholds (see protocol p.36) at Wk12&16. 5. Evaluate safety & tolerability of triple combination therapy at Wk8-16. Period III&IV: 1. Evaluate antihypertensive efficacy of up titration of dose to 40/10/25mg in subjects not reaching BP goal on dose 40/10/12.5mg based on changes from Wk24-32 (see protocol p36). 2. Evaluate % no. subjects achieving BP goal & BP thresholds (defined point 4 above) at Wk32. 3. Evaluate safety & tolerability of triple combination therapy during Wk16-32. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female aged 18 years or older. 2. Mean trough SeBP of ≥ 160/100 mmHg (SeSBP of ≥ 160 mmHg and SeDBP ≥ 100 mmHg) at Screening if not currently on antihypertensive medication (e.g. newly diagnosed subjects) and a mean 24-hour DBP of at least 85 mmHg with at least 30% of daytime DBP readings over 90 mmHg. OR: For subjects on monotherapy: mean trough SeBP of ≥ 150/95 mmHg (SeSBP of ≥ 150 mmHg and SeDBP ≥ 95 mmHg) at Screening and mean 24-hour DBP of at least 80 mmHg and with at least 30% of daytime DBP readings over 85 mmHg. OR: For subjects on any combination of antihypertensive medications that includes either HCTZ, OM or AML for a duration of at least four weeks: mean trough SeBP of ≥ 140/90 mmHg (SeSBP of ≥ 140 mmHg and SeDBP ≥90 mmHg) at Screening and mean 24-hour DBP of at least 80 mmHg and with at least 30% of daytime DBP readings over 85 mmHg. OR: For subjects on any other combination of antihypertensive medications that includes neither HCTZ, OM nor AML: mean trough SeSBP ≥ 160 mmHg, mean trough SeDBP ≥ 100mmHg, at the end of the taper-off period and a mean 24-hour DBP of at least 85 mmHg, assessed by 24-hour ABPM, with at least 30% of daytime DBP readings above 90 mmHg. 3. Subject freely signs ICF after the nature of the study and the disclosure of his/her data has been explained. 4. 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]). Females taking oral contraceptives should have been on therapy for at least three months. 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. If a female becomes pregnant during the study, she has to be withdrawn immediately.
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E.4 | Principal exclusion criteria |
1. Female subjects of childbearing potential who are pregnant or lactating. 2. 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, haematological or oncological, neurological, and psychiatric diseases. The same applies for immunocompromised and/or neutropenic subjects. 3. Subjects having a history of the following within the last six months: MI, unstable angina pectoris, percutaneous coronary intervention, heart failure, hypertensive encephalopathy, cerebrovascular accident (stroke), or transient ischaemic attack. 4. 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) • ALT > 3 times ULN • Gamma-glutamyltransferase (GGT) > 3 times ULN • Potassium above ULN (unless high value is due to haemolytic blood sample) 5. Subjects with secondary HTN of any aetiology such as renal disease, phaechromocytoma, or Cushing’s syndrome. 6. Subjects with contraindication to OM, AML, HCTZ, or any of the excipients. 7. Subjects with a mean SeSBP > 200 mmHg or SeDBP > 115 mmHg or bradycardia (heart rate < 50 beats/min at rest documented by mean radial PR or ECG at Screening (Visit 1) or immediately before taking Period I study medication (Visit 2). 8. Subjects already taking four or more antihypertensive medications. 9. Subjects with ECG evidence of 2nd or 3rd degree atrio-ventricular (AV) block, atrial fibrillation, or other cardiac arrhythmia (requiring treatment). 10. 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. 11. Subjects with clinical evidence of renal disease including renovascular 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. 12. Subjects with clinically relevant hepatic impairment. 13. Subjects with biliary obstruction. 14. Subjects with a history of a wasting disease (e.g. cancer), autoimmune diseases, connective tissue diseases, major allergies or angioneurotic oedema. 15. Subjects who require or are taking any concomitant medication which may interfere with the objectives of the study. 16. Subjects with known malabsorption syndromes. 17. 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. 18. Subjects with a current history of alcohol and/or drug abuse. 19. Subjects who have received any investigational drug within 30 days prior to Screening. 20. Subjects who are unwilling or unable to provide informed consent or to participate satisfactorily for the entire study. 21. Signs or symptoms which could exacerbate the occurrence of hypotension such as volume and salt depletion. 22. Uncontrolled Type 1 or Type 2 diabetes defined as an HbA1c > 9.0%. Diabetics must have documentation of an HbA1c level within 6 months of the Screening Visit, or must have their HbA1c level documented 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. 23. Subjects with malignancy during the past 2 years excluding squamous cell or basal cell carcinoma of the skin. 24. A subject 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. 25. Subjects on beta blockers or calcium channel blockers (CCBs) for both HTN and either ischemia, post-MI prophylaxis or tachyarrhythmias.
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E.5 End points |
E.5.1 | Primary end point(s) |
The mean change in trough SeDBP from the randomisation visit (end of the OM/AML run-in period [Week 8]) to the end of the double-blind Period II (Week 16). |
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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 | Yes |
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 | No |
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 | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 143 |
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 | Information not present in EudraCT |
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 |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 17 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 19 |