| 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 of this trial is to evaluate the overall safety and tolerability profile of a regimen of amlodipine/valsartan 5/80 mg as compared to a regimen of amlodipine/valsartan 5/40 mg (with optional titration to amlodipine/valsartan 5/80 mg) after 8 weeks of treatment in elderly patients with essential hypertension not adequately controlled after four weeks on amlodipine 5 mg monotherapy. The intent of this study is to demonstrate that the safety profiles of the two amlodipine/valsartan regimens (5/80 mg and 5/40 mg optionally titrated to 5/80 mg) are comparable in elderly patients with essential hypertension. |
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| E.2.2 | Secondary objectives of the trial |
• To evaluate the overall safety and tolerability profile of a regimen of amlodipine/valsartan 5/80 mg and amlodipine/valsartan 5/40 mg (with optional titration to amlodipine/ valsartan 5/80 mg) as compared to a regimen of amlodipine 5 mg monotherapy in elderly patients with essential hypertension not adequately controlled after four weeks on amlodipine 5 mg monotherapy.
• To evaluate the blood pressure lowering effects of amlodipine/valsartan 5/80 mg as compared to a regimen of amlodipine/valsartan 5/40 mg (with optional titration to amlodipine/ valsartan 5/80 mg) or to a regimen of amlodipine 5 mg monotherapy.
• To evaluate changes in orthostatic blood pressure, sitting and standing pulse, and laboratory data.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients must give written informed consent before any assessment is performed.
2. Male or female ages 65 years and older.
3. Diagnosed as having hypertension:
• At Visit 1/Screening, naïve patients MUST have a mean seated SBP ≥ 155 mmHg and <180 mmHg; patients undergoing washout MUST have a mean seated SBP <180 mmHg.
• At Visit 2/Single-blind run-in entry, all patients MUST have a mean seated SBP ≥ 155 mmHg and <180 mmHg.
• At Visit 3/Core double-blind treatment period entry, all patients MUST have a mean seated SBP ≥145 mmHg and <180 mmHg.
4. Ability to communicate and comply with all study requirements including measuring their blood pressure at home, daily as instructed, using the home blood pressure monitor provided by the Sponsor.
5. Female patients must be post-menopausal for at least one year.
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| E.4 | Principal exclusion criteria |
1. Patients with severe hypertension (mean seated SBP ≥180 mmHg and/or a mean seated DBP ≥110 mmHg).
2. Patients who have a history of secondary hypertension (including primary aldosteronism, renovascular hypertension, pheocromocytoma, etc.).
3. Patients receiving three or more antihypertensive drugs. Dual fixed dose combination therapy will be considered as two antihypertensive drugs.
4. 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 Visit 1.
5. Known moderate or malignant retinopathy. Moderate defined as: retinal signs of hemorrhage, microaneurysm, cotton-wool spot, hard exudates, or a combination thereof; malignant defined as: signs of moderate retinopathy plus swelling of the optic disk.
6. Known or suspected contraindications, including history of allergy or hypersensitivity to ARBs, CCBs, or to drugs with similar chemical structures.
7. History of cerebrovascular accident, thrombotic stroke, or transient ischemic attack.
8. Significant history of coronary artery disease (CAD) such as any history of myocardial infarction (MI), angina pectoris, and all types of revascularization procedures.
9. History of or diagnosis of congestive heart failure Grade II-IV according to the NYHA classification.
10. Clinically significant valvular heart disease.
11. All patients with Type 1 diabetes mellitus and those patients with Type 2 diabetes mellitus who, in the opinion of the investigator, are not well controlled. Patients who need oral anti-diabetic medication to adequately control their Type 2 diabetes should be on a stable dose of oral anti-diabetic medication for at least 4 weeks prior to Visit 1.
12. Concomitant potentially life threatening arrhythmia or symptomatic arrhythmia.
13. Second or third degree heart block with or without a pacemaker.
14. Significant hepatic disease, as demonstrated by any one of the following: AST or ALT values greater than two times the upper limit of normal at Visit 1, a history of hepatic encephalopathy, a history of esophageal varices, or a history of a portocaval shunt.
15. Evidence of renal impairment as determined by any one of the following: GFR < 50 ml/min/1.73m2 as measured by the Modification of Diet in Renal Disease (MDRD) formula at Visit 1, a history of dialysis, or a history of nephrotic syndrome.
16. History of clinically significant allergies including asthma and/or multiple drug allergies.
17. Any surgical or medical condition 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 inactive 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.
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 requirement of the study or completing the trial period.
19. History of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin.
20. Any chronic inflammatory condition needing chronic anti-inflammatory therapy.
21. History of drug or alcohol abuse within the last 2 years.
22. Use of investigational drugs at the time of enrollment, or within 30 days prior to Visit 1 (Week -8).
23. Inability to communicate and comply with all study requirements including the unwillingness or inability to provide informed consent.
24. Persons directly involved in the execution of this protocol.
25. History of non-compliance to medical regimens, or patients unwilling to comply with the study protocol.
26. Any severe, life-threatening disease within the past five years.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary objective of this trial is to evaluate the overall safety and tolerability profile of a regimen of amlodipine/valsartan 5/80 mg as compared to a regimen of amlodipine/valsartan 5/40 mg (with optional titration to amlodipine/valsartan 5/80 mg) after 8 weeks of treatment in elderly patients with essential hypertension not adequately controlled after four weeks on amlodipine 5 mg monotherapy. The primary endpoint is at Week 8.
Variable
The parameters for the evaluation of the overall safety and tolerability profile include: the overall reporting of adverse events, serious adverse events (SAEs) including death, discontinuation due to adverse events, and notable laboratory abnormalities.
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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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| 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) | 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 125 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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