| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Elderly patients with Essential Hypertension |
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| E.1.1.1 | Medical condition in easily understood language |
| Elderly patients with Essential Hypertension |
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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 | 15.1 |
| 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 |
To demonstrate superiority of an LCZ696 regimen compared to an olmesartan regimen, as measured by change from baseline in mean Central Aortic Systolic Blood Pressure (CASP) after 12 weeks of treatment in elderly patients with essential hypertension.
Key Secondary Objective: To demonstrate superiority of an LCZ696 regimen compared to an olmesartan regimen, as measured by change from baseline in mean Central Pulse Pressure (CPP) after 12 weeks of treatment. |
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| E.2.2 | Secondary objectives of the trial |
1: To evaluate the efficacy of the LCZ696 regimen in comparison to the olmesartan regimen in reducing mean aortic Pulse Wave Velocity (PWV) after 12 weeks and 52 weeks of treatment
2: To demonstrate superiority of an LCZ696 regimen compared to an olmesartan regimen, as measured by change from baseline in mean CASP after 52 weeks of treatment
3: To demonstrate superiority of an LCZ696 regimen compared to an olmesartan regimen, as measured by change from baseline in mean CPP after 52 weeks of treatment
4: To evaluate the efficacy of the LCZ696 regimen in comparison to the olmesartan regimen in reducing mean sitting systolic blood pressure (msSBP), mean sitting diastolic blood pressure (msDBP) and mean sitting pulse pressure (msPP) after 12 weeks and 52 weeks of treatment
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Written informed consent must be obtained before any assessment is performed
• Male and female patients ≥ 60 years of age.
• Patients with essential hypertension, untreated or currently taking antihypertensive therapy.
• Untreated patients must have an office msSBP ≥150 mmHg and <180 mmHg at Visit 101 and Visit 201 if they are newly diagnosed or have not been treated with antihypertensive drugs for the 4 weeks prior to Visit 1.
• Treated patients must have an office msSBP ≥140 mmHg and <180 mmHg at Visit 102 (or Visit 103) and msSBP ≥150 mmHg and <180 mmHg at Visit 201 if they have been treated with antihypertensive drugs for the 4 weeks prior to Visit 1.
• All patients must have pulse pressure >60 mmHg at Visit 201. Pulse pressure is defined as msSBP- msDBP.
• Patients must have a difference in msSBP of +/-15 mmHg betweenv Visit 201 (randomization) and the visit immediately prior to Visit 201.
• Patients with the ability to communicate and comply with all study requirements and demonstrate good medication compliance (≥80% compliance rate) during the run-in epoch (Epoch 2). |
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| E.4 | Principal exclusion criteria |
1. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 5 times the terminal half-life of study treatment. Highly effective contraception methods include:
• Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
• Male sterilization (at least 6 m prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject
• Combination of any two of the following (a+b or a+c, or b+c):
a. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.
• In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository
• Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
2. Malignant or severe hypertension (grade 3 of WHO classification; msDBP ≥110 mmHg and/or msSBP ≥180 mmHg).
3. History of angioedema, drug-related or otherwise.
4. History or evidence of a secondary form of hypertension, including but not limited to any of the following: renal parenchymal hypertension, renovascular hypertension (unilateral or bilateral renal artery stenosis), coarctation of the aorta, primary hyperaldosteronism, Cushing’s disease, pheochromocytoma, polycystic kidney disease, and drug-induced hypertension.
5. Transient ischemic cerebral attack (TIA) during the 12 months prior to Visit 1 or any history of stroke.
6. History of myocardial infarction, coronary bypass surgery or any percutaneous coronary intervention (PCI) during the 12 months prior to Visit 1.
7. Current angina pectoris requiring pharmacological therapy (other than patients on a stable dose of oral or topical nitrates).
8. Type 1 or Type 2 diabetes mellitus not well controlled based on the investigator’s clinical judgment. Patients currently being treated for diabetes mellitus should be on stable dose of anti-diabetic medication for at least 4 weeks prior to Visit 1.
9. Previous or current diagnosis of heart failure (NYHA Class II-IV).
10. Clinically significant valvular heart disease at Visit 1.
11. History of atrial fibrillation or atrial flutter during the 3 months prior to Visit 1, or active atrial fibrillation or atrial flutter on the ECG at Visit 101.
12. History or current diagnosis of the following cardiac abnormalities:
• Second or third degree AV block without a pacemaker.
• History of familial long QT syndrome or family history of torsade de pointe.
13. The following medications are prohibited at any time during the study:
• Other angiotensin receptor blockers (ARBs), ACE inhibitors, β-adrenergic antagonists (Beta-blocker ophthalmic preparations are permitted), potassium sparing diuretics (e.g., spironolactone, triamterene, amiloride), and any other antihypertensive(s) not specified in the protocol.
• Anti-arrhythmic drugs
• Antianginal medication of any kind, including other calcium channel blockers, nitrates (oral, sublingual, or transdermal)
• α-adrenergic antagonists unless for medical condition other than hypertension (e.g., tamsulosin for benign prostatic hyperplasia)
• Digitalis glycosides
• Ergot and serotonin (5-hydroxytryptamine) receptor agonist preparations.
• Drugs for the treatment of attention deficit hyperactivity disorder (ADHD), including bupropion, desipramine, methylphenidate, amphetamine and atomoxetine
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint for this phase 2 study is change from baseline in central aortic systolic
pressure (CASP) after 12 weeks of treatment with LCZ696 (4 weeks of 200 mg with an
additional 8 weeks of 400 mg) or olmesartan (4 weeks of 20 mg with an additional 8 weeks of
40 mg). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Primary endpoint at Week 12 |
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| E.5.2 | Secondary end point(s) |
1. Change from baseline in mean central pulse pressure
2. Change from baseline in mean aortic pulse wave velocity
3. Change from baseline in mean central aortic systolic blood pressure at 52 weeks
4. Change from baseline in mean sitting systolic blood pressure
5. Change from baseline in mean sitting diastolic blood pressure
6. Change from baseline in mean sitting pulse pressure
7. Change from baseline in mean arterial pressure
8. Change from baseline in mean 24-hour systolic blood pressure
9. Change from baseline in mean 24-hour diastolic blood pressure
10. Change from baseline in mean 24-hour ambulatory pulse pressure
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Baseline, 12 weeks, and 52 weeks (Endpoints 1, 2, 4, 5, 6, 7, 8, 9, 10)
Baseline, 52 weeks (Endpoints 3)
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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 | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 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 | 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.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 |
| Argentina |
| Brazil |
| Colombia |
| France |
| Germany |
| Greece |
| Italy |
| Japan |
| Korea, Republic of |
| Russian Federation |
| Spain |
| Taiwan |
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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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| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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