| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with essential hypertension |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | M15 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10015488 |
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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 |
| To demonstrate that 5 weeks of treatment with valsartan 160 mg plus amlodipine 10 mg provide an additional mean sitting systolic blood pressure reduction in patients not adequately responding to 5 weeks of treatment with ramipril 5 mg and felodipine 5 mg (i.e., MSSBP ≥ 140 mmHg). |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the effects of valsartan 160 mg plus amlodipine 10 mg on mean sitting diastolic blood pressure, normalization and responder rate.
To assess the safety and tolerability of valsartan 160 mg plus amlodipine 10 mg.
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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
2. Patients with essential hypertension:
- At Visit 1, untreated patients (not having been treated with antihypertensive drugs in the month priot to V1) need to have a MSSBP >= 160 mmHg and < 180 mmHg and treated patients need to have a MSSBP < 180 mmHg. Untreated patients can be included as soon as the safety laboratory parameters are available, but not at the day of Visit 1. This inclusion visit will be recorded as Visit 3 in the CRF.
- At Visit 2, patients previously treated for hypertension need to have a MSSBP >= 160 mmHg and < 180 mmHg for entrance into the first treatment phase. Patients previously treated for hypertension who have a MSSBP < 160 mmHg at Visit 2 will continue the wash-out phase and will be again evaluated with regard to BP criteria at Visit 3. Untreated patients do not perform Visit 2.
- At Visit 3, which is not performed for patients who entered the first treatment phase already at Visit 2, patients need to have a MSSBP >= 160 mmHg and < 180 mmHg for entrance into the first treatment phase.
- At Visit 4, all patients need to have a MSSBP >= 140 mmHg for entrance into the second treatment phase
3. Written informed consent to participate in the study prior to any study procedures
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| E.4 | Principal exclusion criteria |
1. MSSBP ≥ 180 mmHg and/or MSDBP ≥ 110 mmHg at any time between Visit 1 and Baseline
2. Inability to discontinue all antihypertensive medications safely for a period of up to two weeks prior to initiation of treatment
3. History of hypersensitivity to valsartan, ramipril, felodipine, amlodipine, inactive ingredients of these study drugs or to drugs with similar chemical structure, history of angioneurotic oedema
4. A history of cardiovascular disease, including angina pectoris, myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, transient ischemic attack, stroke, and peripheral artery disease
5. Known Keith-Wagener grade III or IV hypertensive retinopathy
6. Second or third degree heart block without a pacemaker, concurrent potentially life threatening arrhythmia or symptomatic arrhythmia, clinically significant valvular heart disease
7. Heart failure NYHA II -IV
8. Evidence of a secondary form of hypertension, to include coarctation of the aorta, hyperaldosteronism, Cushing’s disease, unilateral or bilateral renal artery stenosis, pheochromocytoma, polycystic kidney disease
9. Diabetes mellitus type I or type 2 diabetes mellitus with poor glucose control as defined by persistent fasting blood glucose > 11 mmol/l or > 200 mg/dl at Visit 1.
10. Evidence of hepatic disease as determined by AST (SGOT) or ALT (SGPT) values > 2 x ULN at Visit 1
11. Known bilateral kidney artery stenosis or unilateral stenosis of the kidney artery if patient has only a single kidney
12. Patients after kidney transplantation
13. Known hypertrophic obstructive cardiomyopathy
14. Known primary hyperaldosteronism
15. A history of hepatic encephalopathy, a history of esophageal varices, or a history of portocaval shunt
16. Evidence of renal impairment as determined by one of the followings: serum creatinine > 1.5 x ULN at Visit 1, a history of dialysis, or a history of nephrotic syndrome. If creatinine is found to be between 1.5 and 2 x UNL, a retest can be performed prior to initiation of treatment
17. Any severe, life-threatening disease within the past five years
18. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of any drug.
19. Any surgical or medical condition which, at the discretion of the investigator, places the patient at higher risk from his/her participation in the study, or are likely to prevent the patient from complying with the requirements of the study or completing the trial period
20. History of drug or alcohol abuse within the last 2 years
21. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 halflives before enrollment, whichever is longer
22. History of noncompliance with medical regimens, or patients unwilling to comply with the study protocol
23. Persons directly involved in the execution of this protocol/study
24. Inability to communicate and comply with all study requirements
25. 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.
26. 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).
27. Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, 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/m 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, vasectomy), hormonal contraception (implantable, patch, oral). Acceptable methods of contraception may include total abstinence at the discretion of the investigator in cases where the age, career, lifestyle, or sexual orientation of the patient ensures compliance. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Reliable contraception should be maintained throughout the study and for 7 days after study drug discontinuation.
28. Patients with controlled blood pressure levels (BP < 140/90 mmHg) under current antihypertensive therapy.
29. Patients with clinically relevant electrolyte disturbances, patients with salt and / or volume depletion.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy parameter of this trial is the change in trough MSSBP between Visit 4 (ramipril 5 mg plus felodipine 5 mg) and Visit 5 (valsartan 160 mg plus amlodipine 10 mg). The mean change will be calculated and tested against the null hypothesis of no change using a one-sample t-test. Point estimates, p-values and (95%) confidence intervals will be reported. The two-sided significance level is set to 5% The primary analysis will be performed using the ITT-population
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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 | 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| 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 | No |
| 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 | 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
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