Study Description
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.
Interventions
LCZ
LCZ/AML 200 mg/10 mg
LCZ/AML 200 mg/2.5 mg
LCZ/AML 200 mg/5 mg
Eligibility Criteria
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.
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