Study of Efficacy and Safety of LCZ696/Amlodipine in Grade 1 and 2 Hypertension Patients Uncontrolled by LCZ696 Monotherapy

A Multicenter, Randomized, Double-blind, Parallel-group, Active-controlled Study to Evaluate the Efficacy and Safety of LCZ696/Amlodipine 200/2.5 mg, 200/5 mg and 200/10 mg Compared to LCZ696 200 mg Alone in Patients With Grade 1 and 2 Hypertension Not Adequately Controlled by LCZ696 200 mg Monotherapy

This CLAZ696B11302 study is composed of two parts; the Core part including double-blind period, and the open-label extension (OLE) part which is an open-label extension of the Core part.

The purpose of the Core part is to demonstrate that LCZ696 (LCZ) when used in combination with amlodipine (AML), denoted as LCZ/AML, will provide greater blood pressure lowering benefit compared to LCZ monotherapy in patients with grade 1 and 2 hypertension not adequately controlled with LCZ monotherapy. The purpose of the OLE part is to assess the long-term safety, tolerability and efficacy of the treatment with LCZ/AML.

This study is designed to provide efficacy and safety data for combinations of LCZ 200 mg and AML (2.5 mg, 5 mg or 10 mg) as compared to LCZ monotherapy in patients with grade 1 and 2 hypertension not adequately controlled with LCZ monotherapy, and also the long-term safety, tolerability and efficacy of the treatment with LCZ/AML. The Core part is a multicenter, randomized, double-blind, parallel-group, active-controlled study which is comprised of the following three periods: Screening / washout period, Single-blind active run-in period, Double-blind treatment period (8 weeks). A 52 week, open-label extension part will be conducted following the completion of the Core part. Those participants that complete the Core part without permanent study drug discontinuation will be offered continued participation in an additional 1 year safety extension to the protocol. Of the patients completed the Core part, approximately 278 participants who are eligible and agree to participate and sign a new informed consent form will start the OLE part, and receive the open-label LCZ/AML combination drug through the OLE part. At start of the OLE part, all participants will be switched to the open-label LCZ/AML 200 mg/5 mg combination drug from double-blinded study medication. After 4 weeks of OLE part, the dosage will be titrated up to LCZ/AML 200 mg/10 mg if an adequate control in blood pressure is not achieved [msSBP ≥ 130 mmHg or msDBP ≥ 80 mmHg, or the Investigator's judgement basically in accordance with the current local hypertension treatment guideline (JSH2019)] and when there is no safety concern on up-titration judged by the Investigator. If the blood pressure is controlled optimally, the participants will continue to receive LCZ/AML 200 mg/5 mg. Down-titration from LCZ/AML 200 mg/5 mg to LCZ/AML 200 mg/2.5 mg is permitted after the start of OLE part if participants are having difficulty with the current treatment of LCZ/AML 200 mg/5 mg due to adverse events (AEs) etc. Dose adjustment (up or down-titration) is allowed if participants meet the criteria for dose adjustment (the same defined above as up-titration and down-titration). The Investigators should maintain the maximum tolerated dose as much as possible after 8 weeks of OLE part. Thiazide diuretics/thiazide-like diuretics are allowed as rescue medication(s) at the investigator's discretion on and after 8 weeks of OLE part, if blood pressure is not adequately controlled even with LCZ/AML 200 mg/10 mg or maximum tolerated dose and with no signs of hypovolemia. Initial dose of the concomitant diuretics should be low, then the dose can be adjusted.

Inclusion Criteria:

Core Part)

• Patients with grade 1 and 2 essential hypertension, untreated or currently taking antihypertensive therapy

  1. Untreated patients [either newly diagnosed with essential hypertension or those with a history of hypertension but have not been taking any antihypertensive drugs for 4 weeks prior to screening visit (Visit Scr)] must have a msSBP of ≥ 150 mmHg and < 180 mmHg at both screening (Visit Scr) and run-in visit (Visit Run-in)
  2. Pretreated patients (taking antihypertensive drugs within 4 weeks prior to screening visit (Visit Scr)) must have msSBP < 180 mmHg at screening visit (Visit Scr), and msSBP ≥ 150 mmHg and < 180 mmHg at run-in visit (Visit Run-in)

• Patients who are not adequately responsive to LCZ 200 mg treatment must have a msSBP ≥ 140 mmHg and < 180 mmHg at the end of run-in/randomization visit

• Patients who are able to communicate well with the Investigator, to understand and comply with all study requirements, and demonstrate good medication compliance (≥ 80% compliance rate) during the single-blind run-in period OLE part)

• Patients who have completed the Core part without permanent study drug discontinuation and who, as judged by the Investigator, are able to continue in the OLE part

• Patients who have msSBP < 160 mmHg and msDBP <100 mmHg at Visit W8 of the double-blind period

Exclusion Criteria:

Core part)

• Patients currently on one or more antihypertensive medications in whom the Investigator considers that the medications cannot be safely discontinued for the duration of the Core part
• Severe hypertension (msSBP ≥ 180 mmHg and/or msDBP ≥ 110 mmHg at any visit prior to or at randomization), or malignant hypertension
• 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, sleep apnea, and drug-induced hypertension
• Patients with Type 1 or Type 2 diabetes mellitus not well controlled based on the Investigator's clinical judgement
• Concomitant refractory angina pectoris [angina in setting of Coronary Artery Disease (CAD) which is uncontrolled by combination of optimal medical therapy, angioplasty or bypass surgery]
• Clinically significant valvular heart disease at screening
• Any history of stroke or hypertensive encephalopathy
• History of hypersensitivity to any of the study treatments or its excipients, ARBs or to drugs of similar chemical classes
• Use of other investigational drugs within 30 days or 5 half-lives of screening visit, whichever is longer OLE part)
• Any medical condition that in the opinion of the Investigator is likely to prevent the patient from safely tolerating LCZ/AML or complying with the requirements of the study
• Patients who have experience of angioedema event(s) which occurred and reported by the Investigator during the Core part of study
• 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 human chorionic gonadotropin (hCG) laboratory test
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for 10 days after stopping study treatment. Highly effective contraception methods are defined as same as the criteria for the Core part.

Other protocol-defined inclusion/exclusion criteria may apply.