| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10015488 |
| E.1.2 | Term | Essential hypertension |
| E.1.2 | System Organ Class | 10047065 - Vascular disorders |
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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 |
1. To evaluate the efficacy of the dual combination of low-dose aliskiren and amlodipine compared to low-dose aliskiren monotherapy in reducing mean sitting systolic blood pressure (MSSBP) from the baseline to week 8 in hypertensive patients ≥ 65 years of age by testing the hypothesis of superiority.
2. To evaluate the efficacy of low-dose aliskiren monotherapy compared to low-dose ramipril monotherapy in reducing mean sitting systolic blood pressure (MSSBP) from the baseline to week 8 in hypertensive patients ≥ 65 years of age by testing the hypothesis of (i) non-inferiority of aliskiren versus ramipril and (ii) superiority of aliskiren versus ramipril, if hypothesis of non-inferiority is achieved.
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| E.2.2 | Secondary objectives of the trial |
• To compare safety and tolerability (frequency of SAEs, AEs) of an aliskiren-based regimen (aliskiren monotherapy, dual combination of aliskiren and amlodipine and triple combination of aliskiren, amlodipine and hydrochlorothiazide) vs. a ramipril-based regimen (ramipril monotherapy, dual combination of ramipril and amlodipine and triple combination of ramipril, amlodipine and hydrochlorothiazide) at the end of the double-blind randomized treatment period (average follow-up of 2.5 years).
• To compare safety and tolerability (hyperkalemia, hypotension, reduction in estimated glomerular filtration rate [eGFR] and other AEs and SAEs) of aliskiren monotherapy, aliskiren dual therapy (aliskiren plus amlodipine) and ramipril monotherapy at the end of the initial double-blind randomized treatment period (8 weeks).
• for detailed list see fulll protocol |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria: -Patients ≥ 65 years of age with a clinical diagnosis of essential
hypertension at Visit 1.
-Mean sitting SBP (MSSBP) ≥ 140 mmHg and < 180 mmHg at Visit 2/Visit 201 and Visit 3. –Absolute MSSBP difference ≤ 20 mmHg between Visit 3 and the Visit immediately prior |
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| E.4 | Principal exclusion criteria |
1. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes.
2. Severe hypertension (MSSBP ≥ 180 mmHg or MSDBP ≥ 110 mmHg) at Visit 1, Visit 2, Visit 201 or Visit 3 or during patient self measured blood pressure (SMBP) monitoring in the pre-randomization period confirmed by office measurement.
3. Current treatment with any blocker of the RAAS (aliskiren, ACEI, ARB or an aldosterone antagonist) and unable to discontinue this therapy.
4. Concurrent use of any anti-hypertensive medications except a stable dose of 3 months prior to Visit 1 of alpha adrenergic blockers for benign prostatic hypertrophy (e.g., tamsulosin [Flomax®] for benign prostatic hypertrophy [BPH]), beta blockers for angina, or beta blocker ophthalmic preparations.
5. Contraindications to aliskiren, ramipril, amlodipine, or HCTZ.
6. History of renal artery stenosis.
7. Known retinopathy.
8. History of hypertensive encephalopathy.
9. Known ejection fraction ≤ 40%.
10. Current diagnosis of heart failure (NYHA Class III-IV).
11. History of transient ischemic cerebral attack (TIA) or cerebrovascular accident (CVA) within 6 months.
12. History of myocardial infarction, bypass surgery (CABG), or any percutaneous coronary intervention (PCI) within 6 months.
13. History of acute gouty arthritis within the last 3 years.
14. Serum sodium less than the lower limit of normal (minus 10 percent) or dehydration at Visit 1.
15. Serum potassium less than 3.5 mEq/L (corresponding to 3.5 mmol/L), or more than 5.2 mEq/L (corresponding to 5.2 mmol/L) at Visit 1.
16. Current unstable angina pectoris. Patients on a stable dose of oral or topical nitrates for angina are acceptable.
17. Concurrent potentially life threatening arrhythmia or symptomatic arrhythmia.
18. Clinically significant valvular heart disease.
19. Evidence of renal impairment: eGFR < 60 ml/min/1.73m2 as estimated by the Modification of Diet in Renal Disease (MDRD) or the Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) equations using serum creatinine measured by an Isotope Dilution Mass Spectrometry (IDMS)-traceable creatinine assay at Visit 1.
20. Evidence of nephrotic range proteinuria as indicated by proteinuria > 3500 mg/day per 1.73m2 body surface area or nephrotic syndrome.
21. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs.
22. Unstable type 2 diabetes mellitus (stable diabetes mellitus is defined as diabetes in patients on a stable regimen of diet and, if required, a stable dose of oral anti-diabetics and/or insulin during the last 3 month).
23. Concurrent treatment with cyclosporine, quinidine or systemic use of conazoles (e.g. itraconazole), except ketoconazole and voriconazole.
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. History of inflammatory bowel disease of the colon and small intestine (Crohn’s disease and ulcerative colitis).
26. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
27. History of chronic liver disease or abnormal ALT/SGPT (> 3 times the upper limit of the reference range) or total bilirubin (> 2 times the upper limit of the reference range).
28. History or evidence of drug or alcohol abuse within the last 12 months.
29. History of noncompliance to medical regimens or unwillingness to comply with the study protocol.
30. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer.
31. 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 the change from baseline to Week 8 endpoint in MSSBP.
The change from baseline to week 8 in mean sitting systolic blood pressure will be analyzed for aliskiren monotherapy, dual therapy of aliskiren and amlodipine and ramipril monotherapy using ANCOVA model in which treatment arm, region and age (less than 75 and greater than or equal to 75 years) will be included as factors |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Frequency of serious adverse events and adverse events; Safety and tolerability of study treatments will be analyzed by comparing the frequency of serious adverse events and adverse events at the time frames
Incidence of hyperkalemia, hypotension and reduction of eGFR , The incidence of hyperkalemia, hypotension and reduction of eGFR will be compared between aliskiren monotherapy, aliskiren dual therapy with amlodipine and ramipril monotherapy |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 73 |
| 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 | No |
| 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 |
| Romania |
| Slovakia |
| Argentina |
| Colombia |
| Finland |
| Germany |
| Guatemala |
| Hungary |
| Spain |
| Mexico |
| Peru |
| Poland |
| Russian Federation |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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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| Last patient last visit (LPLV) |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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