| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate essential hypertension (WHO grade II) |
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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 | 10020772 |
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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 valsartan 160 mg plus HCTZ 25 mg in fixed dose combination provide an additional mean sitting diastolic blood pressure reduction in patients not adequately responding (i.e., MSDBP ≥ 90 mmHg) to 4 weeks of treatment with an angiotensin receptor blocker + HCTZ 25 mg in free combination (candesartan 32 mg plus HCTZ 25 mg). |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the effects of valsartan 160 mg plus HCTZ 25 mg on mean sitting systolic blood pressure, pulse pressure, heart rate, normalization and responder rate.
To assess the safety and tolerability of valsartan 160 mg plus HCTZ 25 mg.
To assess treatment compliance by pill count.
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
For inclusion into the study, patients must meet all of the following inclusion criteria:
1. Male or female patients >= 18 years
2. Patients with essential hypertension:
- At Visit 1, untreated patients must have a MSDBP >= 100 mmHg and < 110 mmHg and treated patients need to have a 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 a MSDBP >= 100 mmHg and < 110 mmHg for entrance into the first treatment phase. Patients previously treated for hypertension who have a 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 a MSDBP >= 100 mmHg and < 110 mmHg for entrance into the first treatment phase.
- At Visit 4, all patients need to have a MSDBP >= 90 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. 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 angiotensin II receptor blockers or to diuretics as described in the SmPC (particularly candesartan 16 - 32 mg, valsartan 160 mg, HCTZ 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 including but not limited to any of the following:
History of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection
Currently active, or active inflammatory bowel syndrome within 12 months prior to Visit 1
Currently active gastritis, ulcers or gastrointestinal/ rectal bleeding (hemorrhoids not included)
Any history of pancreatic injury, pancreatitis or evidence of impaired pancreatic function/ injury
Evidence of hepatic disease or cholestasis as determined by any one of the following: ALT or AST values > 2 x ULN at Visit 1, a history of hepatic encephalopathy, a history of esophageal varices, or a history of a portocaval shunt, obstruction of the biliary tract
Evidence of renal impairment as determined by any one of the following: serum creatinine > 1.5 x ULN or active acute glomerulonephritis at Visit 1, a history of dialysis, or a history of nephrotic syndrome
Current obstruction of the urinary tract or difficulty in voiding due to mechanical as well as inflammatory conditions which is likely to require intervention during the course of the study or is regarded as clinically meaningful by the investigator
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.
22. Unwillingness or inability to give informed consent
23. Persons directly involved in the execution of this protocol
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. 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 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), IUD. 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.
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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 MSDBP between Visit 4 (candesartan 32 mg plus HCTZ 25 mg in free combination) and Visit 5 (valsartan 160 mg plus HCTZ 25 mg in fixed dose combination). |
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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 | No |
| E.6.5 | Efficacy | No |
| 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 | Yes |
| 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 | 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 | 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.8.5 | 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 | |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
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