| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| 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 |
• A once daily dosing regimen of the triple combination of valsartan/HCTZ/amlodipine is superior to the dual combinations of valsartan/HCTZ, valsartan/amlodipine, and HCTZ/amlodipine in lowering mean sitting diastolic blood pressure (MSDBP) in patients with moderate to severe hypertension.
• A once daily dosing regimen of the triple combination of valsartan/HCTZ/amlodipine is superior to the dual combinations of valsartan/HCTZ, valsartan/amlodipine, and HCTZ/amlodipine in lowering mean sitting systolic blood pressure (MSSBP) in patients with moderate to severe hypertension.
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| E.2.2 | Secondary objectives of the trial |
• To evaluate the blood pressure control rates (MSSBP/MSDBP < 140/90 mmHg) of the triple combination of valsartan/HCTZ/amlodipine in patients with moderate to severe hypertension and test the hypothesis that the percentage of patients controlled on the triple therapy is greater than the percentage of patients controlled on any of the dual therapies, valsartan/HCTZ, valsartan/amlodipine, or HCTZ/amlodipine.
• To evaluate the diastolic blood pressure control rates (MSDBP < 90 mmHg) of the triple combination of valsartan/HCTZ/amlodipine in patients with moderate to severe hypertension and test the hypothesis that the percentage of patients controlled on the triple therapy is greater than the percentage of patients controlled on any of the dual therapies, valsartan/HCTZ, valsartan/amlodipine, or HCTZ/amlodipine.
For detailed list of secondary objectives see full protocol |
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Male or female patients ≥ 18 years and < 86 years of age are eligible.
2. Systolic and diastolic blood pressure requirements:
• Diagnosis of moderate to severe hypertension (MSDBP ≥ 100 mmHg and < 120 mmHg, MSSBP ≥ 145 mmHg and < 200 mmHg) at Visit 3
• Patients must also meet the blood pressure requirements (MSDBP ≥ 95 mmHg and < 110 mmHg, MSSBP < 180 mmHg) at Visit 2
or
• MSDBP ≥ 110 mmHg and < 120 mmHg, and MSSBP ≥ 145 mmHg and < 200 mmHg, or MSDBP ≥ 100 mmHg and < 110 mmHg and MSSBP ≥ 180 mmHg and < 200 mmHg after one week of treatment with placebo (blood pressure check) or at any subsequent scheduled study visit or blood pressure evaluation during the single-blind run-in period (designated Visit 3)
3. Written informed consent to participate in the study prior to any study procedures.
4. Ability to communicate and comply with all study requirements.
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| E.4 | Principal exclusion criteria |
1. Inability to discontinue all prior antihypertensive medications safely for a period of 1 to 5 weeks as required by the protocol.
2. Patients with an MSSBP ≥ 180 mmHg and MSDBP < 100 mmHg at any time between one week (7 ± 3 days) and four weeks of treatment with placebo must be discontinued from the study. Patients with an MSDBP ≥ 120 mmHg or an MSSBP ≥ 200 mmHg at screening or any time during the single-blind run-in period.
3. Patients on two or more antihypertensive drugs with MSSBP ≥ 180 mmHg and/or MSDBP ≥ 110 mmHg at Visit 1 (see Table 4-2).
4. Patients on three or more antihypertensive drugs with MSDBP ≥ 90 mmHg and < 110 mmHg, and/or MSSBP ≥ 140 mmHg and < 180 mmHg at Visit 1(see Table 4-2).
5. Patients on four or more antihypertensive drugs at Visit 1 (see Table 4-2).
6. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/ml).
7. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner, UNLESS they meet the following definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels >40 mIU/ml or 6 weeks post surgical bilateral oophorectomy with or without hysterectomy OR are using one or more of the following acceptable methods of contraception: surgical sterilization (e.g., bilateral tubal ligation, hysterectomy), double-barrier methods. Reliable contraception should be maintained throughout the study and for 7 days after study drug discontinuation.
• Hormonal contraceptive use is disallowed.
8. Known moderate or malignant retinopathy. Defined as: moderate (retinal signs of hemorrhage, microaneurysm, cotton-wool spot, hard exudates, or a combination thereof) or malignant (signs of moderate retinopathy plus swelling of the optic disk).
9. Any history of hypertensive encephalopathy, cerebrovascular accident or transient ischemic attack.
10. Any history of myocardial infarction or all types of revascularization procedures.
11. Heart failure requiring treatment.
12. Second or third degree heart block with or without a pacemaker.
13. Angina pectoris of any type.
14. Concurrent potentially life threatening arrhythmia or symptomatic arrhythmia.
15. Clinically significant valvular heart disease.
16. Evidence of a secondary form of hypertension, including but not limited to any of the following: coarctation of the aorta, hyperaldosteronism, unilateral or bilateral renal artery stenosis, Cushing disease, pheochromocytoma, polycystic kidney disease.
17. All patients with Type 1 diabetes mellitus and those patients with Type 2 diabetes mellitus who are not well controlled based on the Investigator’s clinical judgement. It is recommended that Type 2 diabetic patients are adequately controlled and, if treated with medication, be on a stable dose of oral anti-diabetic medication for at least 4 weeks prior to Visit 1.
18. Any condition, not identified in the protocol, that in the opinion of the Investigator or the Novartis monitor, places the patient at higher risk from his/her participation in the study, or is likely to prevent the patient from complying with the requirements of the study or completing the trial period.
19. Administration of any agent indicated for the treatment of hypertension after Visit 1, with the permitted exception of those antihypertensive medications requiring tapering down (e.g. beta-blocker and/or clonidine) commencing with the washout period that precedes Visit 1 and continuing at Visit 1.
20. Known or suspected contraindications, including a history of hypersensitivity to angiotensin receptor blockers, thiazide diuretics, dihydropyridine calcium antagonists, or drugs with similar chemical structures.
21. Any surgical or medical conditions which might significantly alter the absorption, distribution, metabolism, or excretion of any drug including but not limited to any of the following: history of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, bowel resection, gastric bypass, gastric stapling, or gastric banding, currently active or active inflammatory bowel syndrome within 12 months prior to Visit 1, currently active gastritis, ulcers, or gastrointestinal/rectal bleeding, or urinary tract obstruction regarded as clinically meaningful by the Investigator.
22. Any history of pancreatic injury, pancreatitis or evidence of impaired pancreatic function/injury within 1 year of Visit 1.
For detailed list of exclusion criteris see full protocol |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Change from baseline in MSDBP. MSDBP is the average of available readings of sitting diastolic blood pressure for a given visit.
Change from baseline in MSSBP. MSSBP is the average of available readings of sitting systolic blood pressure for a given visit.
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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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| 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.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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 | 16 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 14 |
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