Efficacy and Safety of LCZ696 Compared to Valsartan on Cognitive Function in Patients With Chronic Heart Failure and Preserved Ejection Fraction

NCT ID: NCT02884206

Last Updated: 2024-08-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 592 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-11-23
• Study Completion Date: 2022-05-16

Brief Summary

This study was a multi-center, randomized, double-blind, parallel group, active comparator trial designed to evaluate the overall effect of LCZ696 compared to valsartan on cognitive function as assessed by the CogState comprehensive cognitive battery in patients with Heart failure and preserved ejection fraction (HFpEF).

Detailed Description

The Screening epoch of approximately 3 weeks was used to assess eligibility. Eligible patients then entered the single-blind treatment run-in epoch (Active Run-In Epoch), which was designed to assess patient's tolerability to study drug and to determine patients who were likely to stay on study drug for the duration of the trial. The treatment run-in consisted of valsartan 40 mg bid (if necessary), followed by valsartan 80 mg bid, and then followed by LCZ696 100 mg bid, over 3 to 8 weeks duration. Patients unable to tolerate either valsartan or LCZ696 at the prescribed doses during the treatment run-in were not eligible for randomization and were discontinued from the study.

At randomization (Visit 199/201), eligible patients were randomized 1:1 to receive either LCZ696 200 mg bid or valsartan 160 mg bid (double-blind period).

Patients who terminated the study early were expected, and were encouraged, to attend all the protocol specified study visits, to perform all measurements as stipulated in the visit schedule and to remain in follow up for the duration of the trial.

Conditions

Chronic Heart Failure (CHF)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

LCZ696 200 mg bid

Patients who were able to tolerate the treatment during the single-blind treatment run-in epoch. Following the run-in period, patients randomized in this arm were given LCZ696 at 200 mg twice daily for three years

Group Type: EXPERIMENTAL

LCZ696

Intervention Type: DRUG

LCZ696 50, 100, and 200 mg tablets taken orally twice daily with matching placebo for valsartan

Placebo of Valsartan

Intervention Type: DRUG

Placebo to match valsartan 40 mg, 80 mg, and 160 mg tablets

Valsartan 160 mg bid

Patients who were able to tolerate the treatment during the single-blind treatment run-in epoch. Following the run-in period, patients randomized in this arm were given valsartan at 160 mg twice daily for three years.

Group Type: ACTIVE_COMPARATOR

Valsartan

Intervention Type: DRUG

Valsartan 40, 80, and 160 mg tablets taken orally twice daily with matching placebo for LCZ696

Placebo of LCZ696

Intervention Type: DRUG

Placebo to match LCZ696 50 mg, 100 mg, and 200 mg tablets

Interventions

LCZ696

LCZ696 50, 100, and 200 mg tablets taken orally twice daily with matching placebo for valsartan

Intervention Type: DRUG

Valsartan

Valsartan 40, 80, and 160 mg tablets taken orally twice daily with matching placebo for LCZ696

Intervention Type: DRUG

Placebo of LCZ696

Placebo to match LCZ696 50 mg, 100 mg, and 200 mg tablets

Intervention Type: DRUG

Placebo of Valsartan

Placebo to match valsartan 40 mg, 80 mg, and 160 mg tablets

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Chronic heart failure with current symptoms NYHA class II-IV
• Left ventricular ejection fraction > 40%
• NT-proBNP >= 125 pg/mL at screening visit
• Patient with evidence of adequate functioning to complete study assessments

Exclusion Criteria

• Patients with acute decompensated heart failure requiring augmented therapy with diuretics, vasodilators and/or inotropic drugs
• Acute coronary syndrome (including myocardial infarction (MI)), cardiac surgery, other major CV surgery, or urgent percutaneous coronary intervention (PCI), carotid surgery or carotid angioplasty, history of stroke or transient ischemic attack within the 3 months prior to Screening visit or an elective PCI within 30 days prior to Screening visit
• Patients with history of hereditary or idiopathic angioedema or angioedema related to previous ACEi or ARB therapies
• Patients who require treatment with 2 or more of the following: an ACEi, an ARB or a renin inhibitor
• Patients with one of the following:

1. Patients with serum potassium >5.2 mmol/L (mEq/L) at Screening visit

2. Patients with serum potassium >5.4 mmol/L (mEq/L) at any visit during run-in treatment period or at randomization visit

3. Systolic blood pressure (SBP) ≥180 mmHg at Screening visit, or

4. SBP <110 mmHg at Screening visit, or

5. SBP <100 mmHg or symptomatic hypotension as determined by the investigator at Visit 103 or at randomization visit

6. Body mass index (BMI) >45 kg/m^2

• Patients with

1. known pericardial constriction, genetic hypertrophic cardiomyopathy, infiltrative cardiomyopathy

2. hemodynamically significant obstructive valvular disease

• Life-threatening or uncontrolled dysrhythmia, including symptomatic or sustained ventricular tachycardia and atrial fibrillation or flutter with a resting ventricular rate >110 beats per minute
• Inability to perform cognitive battery or other study evaluations based on significant motor (e.g. hemiplegia, muscular-skeletal injury) or sensory (blindness, decreased or uncorrected visual or auditory acuity) skill
• Clinically significant cerebral pathology for example large cerebral aneurysm or space occupying lesion that may impact cognition as assessed by central MRI reader
• Mini mental state examination score less than 24 at screening
• Patients with a clinical diagnosis of Alzheimer's disease or other dementia syndromes or any indication for or current treatment with cholinesterase inhibitors and/or another prescription AD treatment (e.g. memantine).

• Minimum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Novartis Investigative Site

Andalusia, Alabama, United States

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Glendale, Arizona, United States

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Mesa, Arizona, United States

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Phoenix, Arizona, United States

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Sun City West, Arizona, United States

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Tucson, Arizona, United States

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Beverly Hills, California, United States

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Fresno, California, United States

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Loma Linda, California, United States

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Long Beach, California, United States

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Newport Beach, California, United States

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Santa Ana, California, United States

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Santa Ana, California, United States

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Torrance, California, United States

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Danbury, Connecticut, United States

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Clearwater, Florida, United States

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Edgewater, Florida, United States

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Hollywood, Florida, United States

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Homestead, Florida, United States

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Inverness, Florida, United States

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Jacksonville Beach, Florida, United States

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Miami, Florida, United States

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Miami, Florida, United States

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Miami, Florida, United States

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Naples, Florida, United States

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Port Orange, Florida, United States

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Tampa, Florida, United States

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Lombard, Illinois, United States

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Springfield, Illinois, United States

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Topeka, Kansas, United States

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Eunice, Louisiana, United States

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Baltimore, Maryland, United States

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Saginaw, Michigan, United States

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St Louis, Missouri, United States

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Kalispell, Montana, United States

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Reno, Nevada, United States

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Elmer, New Jersey, United States

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Buffalo, New York, United States

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Gastonia, North Carolina, United States

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Cincinnati, Ohio, United States

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Oregon City, Oregon, United States

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Springfield, Oregon, United States

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Fort Mill, South Carolina, United States

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Rock Hill, South Carolina, United States

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Summerville, South Carolina, United States

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Dallas, Texas, United States

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Dallas, Texas, United States

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Gonzales, Texas, United States

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Houston, Texas, United States

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Lufkin, Texas, United States

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San Antonio, Texas, United States

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Tacoma, Washington, United States

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Buenos Aires, ARG, Argentina

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CABA, Buenos Aires, Argentina

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Ciudad Autonoma de Bs As, Buenos Aires, Argentina

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Ramos Mejía, Buenos Aires, Argentina

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CABA, Buenos Aires F.D., Argentina

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Chemside, Queensland, Australia

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Milton, Queensland, Australia

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Bedford Park, South Australia, Australia

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Geelong, Victoria, Australia

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Aalst, , Belgium

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Sofia, BGR, Bulgaria

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Sofia, , Bulgaria

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Hamilton, Ontario, Canada

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Greenfield Park, Quebec, Canada

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Rijeka, , Croatia

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Zagreb, , Croatia

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Paris, , France

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Tourcoing, , France

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Regensburg, Bavaria, Germany

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Dresden, Saxony, Germany

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Berlin, , Germany

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Berlin, , Germany

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Bielefeld, , Germany

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Bitburg, , Germany

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Buch, , Germany

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Cologne, , Germany

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Cologne, , Germany

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Dessau, , Germany

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Dresden, , Germany

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Elsterwerda, , Germany

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Frankfurt, , Germany

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Ulm, , Germany

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Wuppertal, , Germany

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Würzburg, , Germany

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Ancona, AN, Italy

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Bergamo, BG, Italy

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Cona, FE, Italy

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Florence, FI, Italy

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Pozzilli, IS, Italy

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Rozzano, MI, Italy

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Modena, MO, Italy

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Pisa, PI, Italy

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Kaunas, LTU, Lithuania

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Vilnius, , Lithuania

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's-Hertogenbosch, , Netherlands

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Amsterdam, , Netherlands

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Tarnów, Lesser Poland Voivodeship, Poland

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Krakow, Maloposkie, Poland

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Bialystok, , Poland

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Katowice, , Poland

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Krakow, , Poland

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Warsaw, , Poland

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Lodz, Łódź Voivodeship, Poland

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Moscow, , Russia

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Saint Petersburg, , Russia

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Saint Petersburg, , Russia

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Saint Petersburg, , Russia

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Saratov, , Russia

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Wŏnju, Gangwon-do, South Korea

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Seongnam-si, Gyeonggi-do, South Korea

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Seoul, , South Korea

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San Sebastián de los Reyes, Madrid, Spain

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Valencia, Valencia, Spain

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Madrid, , Spain

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Madrid, , Spain

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Madrid, , Spain

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Valencia, , Spain

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Zaragoza, , Spain

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Basel, , Switzerland

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Tainan City, , Taiwan

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Taipei, , Taiwan

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Taipei, , Taiwan

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Meselik, Eskişehir, Turkey (Türkiye)

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Sivas, , Turkey (Türkiye)

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Axbridge, Somerset, United Kingdom

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Cardiff, Wales, United Kingdom

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Birmingham, , United Kingdom

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Bournemouth, , United Kingdom

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East Yorkshire, , United Kingdom

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Harrow, , United Kingdom

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Liverpool, , United Kingdom

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Newport, , United Kingdom

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Stevenage, , United Kingdom

Countries

United States; Argentina; Australia; Belgium; Bulgaria; Canada; Croatia; France; Germany; Italy; Lithuania; Netherlands; Poland; Russia; South Korea; Spain; Switzerland; Taiwan; Turkey (Türkiye); United Kingdom

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2016-001254-17

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CLCZ696B2320

Identifier Type: -

Identifier Source: org_study_id