ESSENTIAL HYPERTENSION

The primary objective of this study is 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.

LCZ696

LCZ696

tablet

200 mg, 400 mg

Efficacy assessments
• Central Aortic Blood Pressures
• Central Pulse Pressure
• Aortic Pulse Wave Velocity
• Office Blood Pressure
• 24-hour Ambulatory Blood Pressure
Safety assessments
To evaluate the safety and tolerability of the LCZ696 treatment regimen
Other assessments
Plasma and urine biomarkers related to the pathophysiology of various
forms of hypertension, cardiovascular or renal function, or study drug
mechanism of action

Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1. Written informed consent must be obtained before any study-specific procedures are performed
2. Male and female patients ≥ 60 years of age.
3. Patients with essential hypertension, untreated or currently taking antihypertensive therapy.
4. 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.
5. 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 during the 4 weeks prior to Visit 1.
6. All patients must have pulse pressure >60 mmHg at Visit 201. Pulse pressure is defined as msSBP- msDBP.
7. Patients must have a difference in msSBP of +/-15 mmHg between Visit 201
(randomization) and the visit immediately prior to Visit 201.
8. 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).

Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No additional exclusions may be applied by the investigator, in order to ensure that the study population will be representative of all eligible patients.
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 • Herbal remedies or supplements used for treating high blood pressure.
• Other drugs which, in the opinion of the investigator or the medical monitor, could
affect BP
14. Known active liver disease or cirrhosis or evidence of hepatic disease as determined by
ALT or AST >2 times the upper limit of the normal (xULN) , or TBL >2 xULN or ALP
>1.5 xULN range at Visit 101, or a history of hepatic encephalopathy, a history of
esophageal varices, or a history of portocaval shunt.
15. Patients on renal dialysis or with history of renal transplantation
16. Evidence of severe renal impairment (stages 4 or 5 CKD): GFR <30 ml/min/1.73m2
as measured by the Modification of Diet in Renal Disease (MDRD) formula at Visit 101.
17. Other significant laboratory findings at Visit 101 such as serum potassium >5.5 mmol/L, or other clinically significant laboratory abnormalities confirmed by repeat measurements at Visit 101 (at the investigator’s discretion).
18. 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.
19. Any surgical or medical conditions that may significantly alter the absorption, distribution, metabolism or excretion of any drug substance, including but not limited to any of the following: history of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, bowel resection, gastric bypass, gastric stapling, or gastric banding, currently active or history of active inflammatory bowel disease within 12 months prior to Visit 1.
20. Any surgical or medical conditions that, in the opinion 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 the trial period.
21. Patients unwilling or not able to safely discontinue the use of current antihypertensive medications for a period, as required by the protocol. Administration of any agent indicated for the treatment of hypertension after Visit 101, with the permitted exception of those antihypertensive medications requiring tapering down commencing at Visit 101 and completing by Visit 102.
22. Any contraindication or history of hypersensitivity to any of the study drugs or to drugs with similar chemical structures.
23. History of drug or alcohol abuse within the last 1 year.
24. Patients with an inter-arm absolute value difference in msSBP >15 mmHg at Visit 101.
25. Upper thigh circumference >96 cm (maximum thigh cuff size for pulse wave velocity measurements).
26. Patients with night-shift employment (for ABPM measurements).
27. Upper arm circumference >42 cm (for ABPM measurements).
28. Use of other investigational drugs within 30 days or 5 half-lives of Visit 1, whichever is longer.
29. Patients who previously entered an LCZ696 study and had been randomized or enrolled into the active drug treatment epoch.
30. Persons directly involved in the execution of this clinical study