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.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: LCZ; Drug: LCZ/AML 200 mg/2.5 mg; Drug: LCZ/AML 200 mg/5 mg; Drug: LCZ/AML 200 mg/10 mg; Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 718
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Chuoh-ku, Japan, 104-0031
    • Novartis Investigative Site
  • Fukuoka, Japan, 810-0021
    • Novartis Investigative Site
  • Hiroshima, Japan, 732-0053
    • Novartis Investigative Site
  • Kyoto, Japan, 615-8125
    • Novartis Investigative Site
  • Osaka, Japan, 536-0008
    • Novartis Investigative Site
  • Osaka, Japan, 550-0013
    • Novartis Investigative Site
  • Osaka, Japan, 5300002
    • Novartis Investigative Site
  • Osaka, Japan, 5320003
    • Novartis Investigative Site
  • Aichi-ken
    • Nagoya, Aichi-ken, Japan, 4518511
      • Novartis Investigative Site
    • Nagoya, Aichi-ken, Japan, 453-0804
      • Novartis Investigative Site
    • Nagoya, Aichi-ken, Japan, 4540933
      • Novartis Investigative Site
    • Nagoya, Aichi-ken, Japan, 4578511
      • Novartis Investigative Site
  • Fukuoka
    • Itoshima, Fukuoka, Japan, 8191104
      • Novartis Investigative Site
  • Hokkaido
    • Chitose, Hokkaido, Japan, 066-0032
      • Novartis Investigative Site
    • Sapporo, Hokkaido, Japan, 30026
      • Novartis Investigative Site
    • Sapporo, Hokkaido, Japan, 630826
      • Novartis Investigative Site
    • Sapporo, Hokkaido, Japan, 630842
      • Novartis Investigative Site
  • Hyōgo
    • Akashi, Hyōgo, Japan, 674-0081
      • Novartis Investigative Site
    • Amagasaki, Hyōgo, Japan, 660-0861
      • Novartis Investigative Site
  • Ibaraki
    • Tsukuba, Ibaraki, Japan, 3050861
      • Novartis Investigative Site
  • Kanagawa
    • Kamakura, Kanagawa, Japan, 247-0055
      • Novartis Investigative Site
    • Kawasaki-shi, Kanagawa, Japan, 211-0041
      • Novartis Investigative Site
    • Yokohama, Kanagawa, Japan, 232-0064
      • Novartis Investigative Site
    • Yokohama, Kanagawa, Japan, 231-0023
      • Novartis Investigative Site
  • Miyagi
    • Sendai, Miyagi, Japan, 980-0011
      • Novartis Investigative Site
    • Sendai, Miyagi, Japan, 9830039
      • Novartis Investigative Site
    • Ōsaki, Miyagi, Japan, 989-6143
      • Novartis Investigative Site
  • Osaka
    • Suita, Osaka, Japan, 5650853
      • Novartis Investigative Site
  • Tokyo
    • Chiyoda City, Tokyo, Japan, 101-0041
      • Novartis Investigative Site
    • Chuo Ku, Tokyo, Japan, 104-0031
      • Novartis Investigative Site
    • Chuo-ku, Tokyo, Japan, 1030027
      • Novartis Investigative Site
    • Hachiōji, Tokyo, Japan, 192-0046
      • Novartis Investigative Site
    • Kiyose, Tokyo, Japan, 204-0021
      • Novartis Investigative Site
    • Musashino, Tokyo, Japan, 1800022
      • Novartis Investigative Site
    • Nerima Ku, Tokyo, Japan, 1770051
      • Novartis Investigative Site
    • Setagaya-ku, Tokyo, Japan, 1550031
      • Novartis Investigative Site
    • Shibuya City, Tokyo, Japan, 150-0013
      • Novartis Investigative Site
    • Shinagawa-Ku, Tokyo, Japan, 141-0032
      • Novartis Investigative Site
    • Shinjuku Ku, Tokyo, Japan, 160-0008
      • Novartis Investigative Site
    • Shinjuku-ku, Tokyo, Japan, 1600017
      • Novartis Investigative Site
    • Shinjuku-ku, Tokyo, Japan, 1690072
      • Novartis Investigative Site
    • Suginami-ku, Tokyo, Japan, 166-0003
      • Novartis Investigative Site
    • Toshima-Ku, Tokyo, Japan, 171-0021
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: LCZ 200mg; Oral administration, 1 tablet of LCZ 200 mg daily, 4 capsules of Amlodipine placebo daily.	Drug: LCZ; LCZ 200 mg; Other Names: LCZ696; Other: Placebo; Matching placebo of Amlodipine.
Experimental: LCZ 200mg + AML 2.5mg; Oral administration, 1 tablet of LCZ 200 mg daily, 1 capsule of Amlodipine 2.5 mg daily and 3 capsules of Amlodipine placebo daily.	Drug: LCZ/AML 200 mg/2.5 mg; LCZ/AML 200 mg/2.5 mg; Other Names: LCZ696/Amlodipine; Other: Placebo; Matching placebo of Amlodipine.
Experimental: LCZ 200mg + AML 5mg; Oral administration, 1 tablet of LCZ 200 mg daily, 2 capsules of Amlodipine 2.5 mg daily and 2 capsules of Amlodipine placebo daily.	Drug: LCZ/AML 200 mg/5 mg; LCZ/AML 200 mg/5 mg; Other Names: LCZ696/Amlodipine; Other: Placebo; Matching placebo of Amlodipine.
Experimental: LCZ 200mg + AML 10mg; Oral administration, 1 tablet of LCZ 200 mg daily, 4 capsules of Amlodipine 2.5 mg daily.	Drug: LCZ/AML 200 mg/10 mg; LCZ/AML 200 mg/10 mg; Other Names: LCZ696/Amlodipine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
[Core Part] Change from baseline to Week 8 in msSBP	Change from baseline to Week 8 in mean sitting systolic blood pressure (msSBP)	Baseline, Week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
[Core Part] Change from baseline to Week 8 in maSBP	Change from baseline to Week 8 in mean 24-hour ambulatory systolic blood pressure (maSBP)	Baseline, Week 8
[Core Part] Proportion of patients achieving a blood pressure control after 8 weeks of treatment	Proportion of patients achieving a blood pressure control (msSBP <140 mmHg and msDBP <90 mmHg) after 8 weeks of treatment	8 weeks
[Core Part] Change from baseline to Week 8 in msDBP	Change from baseline to Week 8 in mean sitting diastolic blood pressure (msDBP)	Baseline, Week 8
[Core Part] Change from baseline to Week 8 in maDBP	Change from baseline to Week 8 in mean 24-hour ambulatory diastolic blood pressure (maDBP)	Baseline, Week 8
[Core Part] Proportion of patients achieving a msSBP response after 8 weeks of treatment	Proportion of patients achieving a msSBP response (<140 mmHg or a reduction ≥20 mmHg from baseline) after 8 weeks of treatment	8 weeks
[Core Part] Proportion of patients achieving a msDBP response after 8 weeks of treatment	Proportion of patients achieving a msDBP response (<90 mmHg or a reduction ≥10 mmHg from baseline) after 8 weeks of treatment	8 weeks
[Core Part] Change from baseline to Week 8 in daytime, nighttime and early morning maSBP	Change from baseline to Week 8 in daytime, nighttime and early morning maSBP	Baseline, Week 8
[Core Part] Change from baseline to Week 8 in daytime, nighttime and early morning maDBP	Change from baseline to Week 8 in daytime, nighttime and early morning maDBP	Baseline, Week 8
[Core Part] Number of patients with treatment-emergent adverse events	Number of patients experiencing treatment-emergent adverse events including (but not limited to) any unfavorable and unintended signs, symptoms or disease, abnormal vital signs, electrocardiogram data, safety lab measurements that induce clinical signs or symptoms, are considered clinically significant or require therapy	Up to 8 weeks
[OLE Part] Number of patients with treatment-emergent adverse events	Number of patients experiencing treatment-emergent adverse events including (but not limited to) any unfavorable and unintended signs, symptoms or disease, abnormal vital signs, electrocardiogram data, safety lab measurements that induce clinical signs or symptoms, are considered clinically significant or require therapy	Up to 52 weeks
[OLE Part] Change from baseline in msSBP and msDBP	Change from baseline in msSBP and msDBP by visit in OLE part	Baseline, Week 4, Week 8, Week 13, Week 26, Week 39, and Week 52 of OLE part
[OLE Part] Proportion of patients achieving blood pressure control, msSBP response and msDBP response	Proportion of patients achieving blood pressure control (msSBP <140 mmHg and msDBP <90 mmHg), msSBP response (<140 mmHg or a reduction ≥20 mmHg from baseline) and msDBP response (<90 mmHg or a reduction ≥10 mmHg from baseline) by visit	Over 52 weeks

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): April 8, 2024
• Primary Completion (Actual): May 28, 2025
• Study Completion (Actual): December 23, 2025

Study Registration Dates

• First Submitted: January 23, 2024
• First Submitted That Met QC Criteria: January 23, 2024
• First Posted (Actual): February 1, 2024

Study Record Updates

• Last Update Posted (Actual): January 13, 2026
• Last Update Submitted That Met QC Criteria: January 12, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Phase 3; Amlodipine; LCZ696; grade 1 and 2 hypertension
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Hemic and Lymphatic Diseases; Hypertension; Lymphoma, Follicular; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Dihydropyridines; Amlodipine; sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: CLAZ696B11302

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No