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