| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| 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 |
| •Evaluate the efficacy of the combination of aliskiren 300 mg and valsartan 320 mg in patients with essential hypertension by testing the hypothesis of superior reduction in MSDBP from baseline to end of study when compared to both monotherapy components. |
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| E.2.2 | Secondary objectives of the trial |
1. Evaluate efficacy of combination of aliskiren 300 mg and valsartan 320 mg in patients with essential hypertension by testing superior reduction in mean sitting systolic blood pressure from baseline to end of study when compared to both monotherapy components.
2. Evaluate efficacy of combination of aliskiren 150 mg and valsartan 160 mg in patients with essential hypertension by testing superior reduction in MSDBP and MSSBP from baseline when compared to both monotherapy components at 4 weeks of treatment.
3. Evaluate efficacy of aliskiren 150 mg and 300 mg given alone versus placebo in patients with essential hypertension by testing superior reduction in MSSBP and MSDBP from baseline when compared to placebo.
4. Evaluate safety and tolerability of combination of aliskiren and valsartan (150/160 mg and 300/320 mg) compared with their component monotherapies and placebo.
Other secondary objectives listed in the protocol.
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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 outpatients, 18 years of age and older.
2. Patients with a history of essential hypertension; newly diagnosed or patients who have not been treated within 4 weeks of Visit 1 must have an office cuff MSDBP ≥ 95 mmHg and < 110 mmHg at Visit 1.
3. Prior to the randomization,
• Patients must have an office cuff MSDBP ≥ 95 mmHg and < 110 mmHg at last two consecutive visits (at Visit 3 and Visit 4 or at Visit 4 and Visit 5) during the single-blind placebo run-in period.
• Patients must have a difference of ≤ 7 mmHg in their MSDBP during the last two consecutive visits (at Visit 3 and Visit 4 or at Visit 4 and Visit 5) of the single-blind placebo run-in period.
• Patients must have a mean 8-hour daytime ABPM DBP ≥ 90 mmHg at Visit 5.
4. Patients who are eligible and 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).
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| E.4 | Principal exclusion criteria |
1. Previously treated in an aliskiren study and who qualified to be randomized or enrolled into the active drug treatment period.
2. 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).
3. 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), hormonal contraception (implantable, patch, oral), and double-barrier methods. Reliable contraception should be maintained throughout the study and for 7 days after study drug discontinuation.
4. Severe hypertension (an office cuff MSDBP ≥ 110 mmHg and/or MSSBP ≥ 180 mmHg).
5. History or evidence of a secondary form of hypertension.
6. Known Keith-Wagener grade III or IV hypertensive retinopathy.
7. Previous and current diagnosis of heart failure (NYHA Class II-IV).
8. History of hypertensive encephalopathy or cerebrovascular accident, transient ischemic cerebral attack (TIA), myocardial infarction, coronary bypass surgery, or any percutaneous coronary intervention (PCI).
9. Serum sodium less than lower limit of normal, serum potassium < 3.5 mEq/L or ≥ 5.3 mEq/L at Visit 1.
10. History of Type 1, or Type 2 diabetes and glycosylated hemoglobin (HbA1c) > 8 % at Visit 1.
11. Current angina pectoris requiring pharmacological therapy.
12. Second or third degree heart block without a pacemaker.
13. Atrial fibrillation or atrial flutter at Visit 1, or potentially life threatening or any symptomatic arrhythmia during the 12 months prior to Visit 1.
14. Clinically significant valvular heart disease.
15. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs including, but not limited to, any of the following:
• History of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection.
• History of active inflammatory bowel disease during the 12 months prior to Visit 1.
• Currently active gastritis, duodenal or gastric ulcers, or gastrointestinal bleeding during the 3 months prior to Visit 1.
• Any history of pancreatic injury, pancreatitis, or evidence of impaired pancreatic function/injury as indicated by abnormal lipase or amylase during the 12 months prior to Visit 1.
• Evidence of hepatic disease as determined by any one of the following: SGOT or SGPT values exceeding 3 x ULN at Visit 1, a history of hepatic encephalopathy, a history of esophageal varices, or a history of portocaval shunt.
• Evidence of renal impairment as determined by any one of the following: serum creatinine > 1.5 x ULN at Visit 1, a history of dialysis, or a history of nephrotic syndrome.
• Current treatment with cholestyramine or colestipol resins.
16. History of hypersensitivity to any of the study drugs or to drugs belonging to the same therapeutic class (ARB’s or renin inhibitors) as the study drugs.
17. History of angioedema due to usage of an ARB or ACE.
18. 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.
19. History or evidence of drug or alcohol abuse within the last 12 months.
20. Any surgical or medical condition, which in the opinion of the investigator, may place the patient at higher risk from his/her participation in the study, or is likely to prevent the patient from complying with the requirements of the study or completing the study.
21. Arm circumference > 42 cm.
22. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer.
23. History of noncompliance to medical regimens or unwillingness to comply with the study protocol.
24. Any condition that in the opinion of the investigator or the Novartis Medical Monitor would confound the evaluation and interpretation of efficacy and/or safety data.
25. Persons directly involved in the execution of this protocol.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy variable is change from baseline (Visit 5) to the end of the study in mean sitting diastolic blood pressure (MSDBP). For each patient, the last post-baseline measurement during the double-blind period will be carried forward to Week 8 as the Week 8 endpoint measurement for the variable to be analyzed. The primary analysis time-point will be the Week 8 endpoint. At each visit, mean sitting diastolic blood pressure is calculated based on the average of the available readings of sitting diastolic blood pressure |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| 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) | Information not present in EudraCT |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| 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 |
| dose escalation; double-dummy |
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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 | Yes |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| 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 | 11 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
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