| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hypertensive patients not adequately responding to a 4 week therapy with candesartan 32 mg plus hydrochlorothiazide 25 mg |
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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 | 10015488 |
| E.1.2 | Term | Essential 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 |
| To demonstrate that 4 weeks of treatment with aliskiren 300mg plus hydrochlorothiazide 25mg in combination provide an additional mean sitting diastolic blood pressure reduction in hypertensive patients not adequately responding (i.e., MSDBP > 90 mmHg) to 4 weeks of treatment with an agiontensin receptor blocker plus hydrochlorothiazide 25mg in combination (candesartan 32mg plus HCTZ 25mg) |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the effects of 4 weeks of treatment with aliskiren 300mg plus HCTZ 25mg in combination in patients not adequately responding (i.e., MSDBP > 90 mmHg) to 4 weeks of treatment with candesartan 32mg plus HCTZ 25mg in combination on the difference in mean sitting systolic blood pressure, pulse pressure, heart rate, normalization and responder rate.
To assess the safety and tolerability of aliskiren 300mg plus HCTZ 25mg. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Extension 1:
An open-label, multicenter extension to evaluate the efficacy and safety of a 4 week therapy with amlodipine 5 mg and aliskliren 300mg plus HCTZ 25mg in hypertensive patients not adequately responding to a 4 week therapy each with the combination of candesartan 32mg plus HCTZ 25mg followed by aliskiren 300mg plus HCTZ 25mg |
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| E.3 | Principal inclusion criteria |
1. Male or female patients 18 years
2. Patients with essential hypertension:
- At Visit 1, untreated patients must have an MSDBP 100 mmHg and < 110 mmHg and treated patients need to have an MSDBP < 110 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 an MSDBP 100 mmHg and < 110 mmHg for entry into the first treatment phase. Patients previously treated for hypertension who have an MSDBP < 100 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 an MSDBP 100 mmHg and < 110 mmHg for entry into the first treatment phase.
- At Visit 4, all patients need to have an MSDBP 90 mmHg for entry 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. Patients with controlled blood pressure levels (MSSBP < 140 mmHg and MSDBP < 90 mmHg) under current antihypertensive therapy at Visit 1.
2. MSDBP 110 mmHg or MSSBP 180 mmHg at any time between visit 1 and baseline
3. Inability to completely discontinue all antihypertensive medications safely for a period of up to 2 weeks, as required by the protocol
4. Known Keith-Wagener grade III or IV hypertensive retinopathy
5. Evidence of a secondary form of hypertension, such as coarctation of the aorta, hyperaldosteronism, unilateral renal artery stenosis or pheochromocytoma
6. History of hypersensitivity to any of the study drugs or to drugs with similar chemical structures, known or suspected contraindications to the study drugs as described in the SmPC (particularly candesartan 16-32 mg, aliskiren 300 mg, hydrochlorothiazide 12.5-25 mg)
7. Heart failure NYHA II-IV
8. Second or third degree heart block without pacemaker
9. Concomitant refractory angina pectoris
10. Concomitant potentially life-threatening arrhythmia or symptomatic arrhythmia
11. Clinically significant valvular heart disease
12. Transient ischemic cerebral attack, stroke, hypertensive encephalopathy or myocardial infarction prior to Visit 1
13. Type 1 diabetes mellitus
14. 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.
15. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of any drug. 16. Therapy resistant hypokalemia, hypercalcemia, symptomatic hyperuricemia or sodium depletion (< 134 mmol/l), patients with volume depletion.
17. History of any severe, life-threatening disease
18. History of drug or alcohol abuse within the last 2 years
19. History of non-compliance to medical regimens, or those patients unwilling to comply with the trial protocol.
20. Any condition, which in the judgment of the investigator or medical monitor, would jeopardize the evaluation of efficacy or safety
21. Any surgical or medical conditions which, at the discretion of the investigator, place 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 it
22. Unwillingness or inability to give informed consent
23. Study personnel or first degree relatives of investigator(s) must not be included in the study
24. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer
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. Women
o who are pregnant or breast feeding (pregnancy 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))
o who are menstruating and capable of becoming pregnant* and not practicing a medically approved method of contraception (Pearl Index <1**) during and up to at least 4 weeks after the end of treatment. A negative pregnancy test (serum) for all women and for girls entering menarche is required with sufficient lead time before inclusion
*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
**examples of particularly reliable methods with Pearl Index (PI) <1, according to guidelines of Deutsche Gesellschaft für Gynäkologie und Geburtshilfe:
• Combination pill with estrogen and gestagen (no mini-pill, PI=0.1-0.9)
• Vaginal ring (NuvaRing®, PI=0.65 uncorr.; 0.4 corr.)
• Contraceptive patch (EVRA®, PI= 0.72 uncorr.; 0.9 corr.)
• Estrogen-free ovulation inhibitors (Cerazette®, PI=0.14)
• Progestin-containing contraceptives (Implanon®, PI=0-0.08)
• Injectable 3-month depot progestins (PI=0.3-1.4; 0.88 corr.)
• Intra-uterine progestine device (Mirena®, PI=0.16)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The aim of this multicenter open-label trial is to evaluate the reduction in trough MSDBP by a 4-week treatment with aliskiren 300 mg plus HCTZ 25 mg in hypertensive patients not adequately controlled by candesartan 32 mg plus HCTZ 25 mg. The main interest is the estimation and testing of the changes in BP between Visit 4 and Visit 5.
The primary efficacy parameter of this trial is the change in trough MSDBP between Visit 4 (candesartan 32 plus HCTZ 25 mg) and Visit 5 (aliskiren 300 mg plus HCTZ 25 mg). |
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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 | 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 | 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 40 |
| 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
| |
| 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 | 8 |
| E.8.9.1 | In the Member State concerned days | |
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