| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| patients with mild-to-moderate hypertension and left ventricular hypertrophy |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049773 |
| E.1.2 | Term | Left ventricular hypertrophy |
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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 a noninferior or superior efficacy of the combination of valsartan 160mg and amlodipine 5mg compared with the combination of losartan 100mg and HCTZ 12.5mg by testing the hypothesis that the regression of LVH, as measured by the change in LVMI [g/m2] via MRI from baseline to end of study is at least irrelevantly smaller or even larger under valsartan/amlodipine compared to losartan/HCTZ in patients with mild-to moderate hypertension and LVH. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of the combination of valsartan/amlodipine compared with the combination of losartan/HCTZ on the change in LVH parameters (such as left ventricular wall thickness, left ventricular ejection fraction, left ventricular end-diastolic volume, left ventricular endsystolic volume) assessed by MRI.
• To evaluate the effect of both combinations on the change in LVH parameters and left ventricular diastolic function as assessed by centrally read ECHO.
• To evaluate the impact of both combinations on the change in NT-proBNP and High-Sensitivity C-Reactive Protein.
• To compare the effects of both combination therapies on the proportion of patients, who achieve without rescue medication the target blood pressure of MSSBP < 140 mm Hg and MSDBP < 90 mm Hg.
• To evaluate the overall safety and tolerability of the combination of valsartan/amlodipine compared with the combination of losartan/HCTZ in patients with essential hypertension and LVH.
|
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Caucasian; male or female outpatients and age between 18-80 years of age, inclusive.
2. Patients with a history of essential hypertension and who are actually treated either with an antihypertensive monotherapy (limited to one active compound) and with a MSDBP of >=90 and <= 110mmHg at visit 1
or
with a combination therapy (limited to up to 3 active compounds; patients treated with 3 active compounds can only be included when all the three compounds were not already given in the highest approved dose level prior to study entry) and with a MSDBP of >=90 and <= 105mmHg at visit 1. Patients who are currently not treated with antihypersensitive drugs may be included with a MSDBP of >=95 and <=110mmHg at visit 1.
3. Patients with LVH (LVWT >= 12.0mm and <= 16.0mm; determined by the highest value either by the posterior wall thickness [PWTd] or by the interventricular septal wall thickness [IVSTd]) confirmed by ECHO at Visit 2 prior to randomization.
4. Patients who are eligible, able to participate in the study, and who consent to do so after the purpose and nature of the investigation has been clearly explained to them (written informed consent).
|
|
| E.4 | Principal exclusion criteria |
1. Known or suspected contraindications as listed in the national prescribing information, to any of the study drugs (valsartan, losartan, amlodipine and HCTZ; Appendices 3-6) or to drugs with similar chemical structures or to drugs belonging to the same therapeutic class.
2. Severe refractory hypertension defined as confirmed reading of MSSBP > 180 mm Hg or MSDBP of > 110 mm Hg at any visit.
3. History of secondary form of hypertension, such as coarctation of the aorta, hyperaldosteronism, unilateral or bilateral renal artery stenosis, Cushing’s disease, pheochromocytoma, polycystic kidney disease, etc..
4. Hypertrophic cardiomyopathies due to etiologies other than hypertension (i.e., idiopathic or valvular). Hemodynamically significant mitral stenosis or lesions of the left ventricular outflow tract including aortic stenosis or hypertrophic obstructive cardiomyopathy.
5. History of symptomatic heart failure (NYHA classes II-IV) or a LVEF < 50% confirmed by ECHO prior to randomization.
6. A history of stroke, transient ischemic cerebral attack, hypertensive encephalopathy, coronary artery bypass surgery, percutaneous transluminal angioplasty or myocardial infarction anytime prior to visit 1.
7. Concurrent life threatening arrhythmia or symptomatic arrhythmia.
8. Known history of angioneurotic oedema.
9. Evidence of hepatic disease or cholestasis as determined by any one of the following: AST (SGOT) or ALT (SGPT) values exceeding 3 x ULN at Visit 1.
10. Insulin dependent Diabetes mellitus or uncontrolled treated Type 2 Diabetes mellitus with poor glucose control defined as HbA1c > 7.0 % at Visit 1.
11. Documented history of clinically significant peripheral edema.
12. Second or third degree heart block, sick sinus syndrome or sinuatrial block.
13. Patients with non-sinus rhythm or frequent extrasystoles (>6/min).
14. Known or suspected contraindication for MRI
• use of pacemakers, ICD, defibrillators or any device which interferes with an MRI or presence of cranial aneurysm clips or ocular metallic shards.
• Patients who cannot lie supine for at least 30 minutes, who cannot hold their breath for 15 seconds, who are suffering from significant claustrophobia (not responsive to light intravenous anxiolytics or whose body structure (e.g., weight, height, body circumference, etc.) exceeds the restrictions of the local MRI site instrument.
15. Significant non-cardiovascular illness or condition likely to result in death prior to trial completion, e.g., major organ transplant (life expectancy < 1 year).
16. 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.
17. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs.
18. 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).
19. 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 a highly effective method of birth control. A highly effective method of birth control is defined as those which result in a low failure rate (i.e. less than 1% a year) when used consistently and correctly. The following methods are fulfilling the criteria of a highly effective method of birth control:
• Implants
• Injectables
• Combined oral contraception
• Some IUDs
• 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 4 weeks after study drug discontinuation.
20. Persons directly involved in the execution of this protocol.
21. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer.
22. Current abuse or recent history of alcohol or other drug substance abuse (past 12 months).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy variable is the change from baseline of the left ventricular mass index (LVMI). |
|
| 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 | 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 14 |
| 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 | 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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