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

NCT02884206 | Completed Phase 3 Results DMC

• 2 other identifiers: CLCZ696B23202016-001254-17
• Study Type: interventional
• Target: 592
• Locations: 20 countries
• Sites: 135

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).

Conditions

Chronic Heart Failure (CHF)

Keywords

heart failure; cognition; positron emission tomography; magnetic resonance imaging; LCZ696; valsartan; Chronic heart failure; CHF

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in the CogState Global Cognitive Composite Score (GCCS)

  The CogState cognitive battery was composed of 7 tests, which were administered electronically by the patients at scheduled visits. For each test, a standardized z-score was calculated. The GCCS was the average of the non-missing individual test z-scores. A higher score indicated better cognitive function. CogState GCCS changes from baseline (randomization) were analyzed using a repeated measures ANCOVA in which treatment, age stratification factor, Mini mental state examination stratification factor, education level, Apolipoprotein E ε4 allele status, cerebrovascular disease burden at screening, visit and treatment-by-visit interaction are included as fixed-effect factor, and baseline (randomization) GCCS and visit-by- baseline GCCS as covariates with a common unstructured covariance matrix among visits between treatment groups. The analysis was based on a direct likelihood method with an assumption of Missing at random.

  Baseline, month 36

Secondary Outcomes (3)

• Change From Baseline in Cortical Composite Standardized Uptake Value Ratio (SUVr)

  Baseline, month 36

• Change From Baseline in Individual Cognitive Domains

  Baseline, month 36

• Change From Baseline in the Summary Score of the Instrumental Activities of Daily Living (IADL)

  Baseline, month 36

Study Arms (2)

LCZ696 200 mg bid

EXPERIMENTAL

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

Drug: LCZ696; Drug: Placebo of Valsartan

Valsartan 160 mg bid

ACTIVE COMPARATOR

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.

Drug: Valsartan; Drug: Placebo of LCZ696

Interventions

LCZ696 DRUG

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

LCZ696 200 mg bid

Valsartan DRUG

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

Valsartan 160 mg bid

Placebo of LCZ696 DRUG

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

Valsartan 160 mg bid

Placebo of Valsartan DRUG

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

LCZ696 200 mg bid

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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:
• Patients with serum potassium \>5.2 mmol/L (mEq/L) at Screening visit
• Patients with serum potassium \>5.4 mmol/L (mEq/L) at any visit during run-in treatment period or at randomization visit
• Systolic blood pressure (SBP) ≥180 mmHg at Screening visit, or
• SBP \<110 mmHg at Screening visit, or
• SBP \<100 mmHg or symptomatic hypotension as determined by the investigator at Visit 103 or at randomization visit
• Body mass index (BMI) \>45 kg/m\^2
• Patients with
• known pericardial constriction, genetic hypertrophic cardiomyopathy, infiltrative cardiomyopathy
• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (135)

Novartis Investigative Site

Andalusia, Alabama, 36420, United States

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Glendale, Arizona, 85306, United States

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Mesa, Arizona, 85206, United States

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Phoenix, Arizona, 85004, United States

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Sun City West, Arizona, 85375, United States

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Tucson, Arizona, 85723, United States

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Beverly Hills, California, 90211, United States

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Fresno, California, 93720, United States

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Loma Linda, California, 92357, United States

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Long Beach, California, 90806, United States

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Newport Beach, California, 92663, United States

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Santa Ana, California, 92704, United States

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Santa Ana, California, 92705, United States

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Torrance, California, 90503, United States

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Danbury, Connecticut, 06810, United States

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Clearwater, Florida, 33756, United States

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Edgewater, Florida, 32132, United States

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Hollywood, Florida, 33312, United States

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Homestead, Florida, 33030, United States

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Inverness, Florida, 34452, United States

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Jacksonville Beach, Florida, 32050, United States

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Miami, Florida, 33133, United States

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Miami, Florida, 33144, United States

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Miami, Florida, 33176, United States

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Naples, Florida, 34102, United States

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Port Orange, Florida, 32127, United States

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Tampa, Florida, 33612, United States

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Lombard, Illinois, 60148, United States

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Springfield, Illinois, 62701, United States

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Topeka, Kansas, 66606, United States

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Eunice, Louisiana, 70535, United States

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Baltimore, Maryland, 21229, United States

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Saginaw, Michigan, 48601, United States

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St Louis, Missouri, 63110, United States

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Kalispell, Montana, 59901 3158, United States

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Reno, Nevada, 89502, United States

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Elmer, New Jersey, 08318, United States

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Buffalo, New York, 14215, United States

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Gastonia, North Carolina, 28054, United States

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Cincinnati, Ohio, 45219, United States

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Oregon City, Oregon, 97045, United States

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Springfield, Oregon, 97477, United States

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Fort Mill, South Carolina, 29707, United States

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Rock Hill, South Carolina, 29732, United States

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Summerville, South Carolina, 29485, United States

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Dallas, Texas, 75226, United States

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Dallas, Texas, 75235, United States

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Gonzales, Texas, 78629, United States

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Houston, Texas, 77030, United States

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Lufkin, Texas, 75904, United States

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San Antonio, Texas, 78229, United States

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Tacoma, Washington, 98405, United States

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Buenos Aires, ARG, C1405BCK, Argentina

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CABA, Buenos Aires, 1407, Argentina

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Ciudad Autonoma de Bs As, Buenos Aires, C1119ACN, Argentina

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Ramos Mejía, Buenos Aires, B1704ETD, Argentina

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CABA, Buenos Aires F.D., C1179AAB, Argentina

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Chemside, Queensland, 4032, Australia

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Milton, Queensland, 4064, Australia

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Bedford Park, South Australia, 5042, Australia

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Geelong, Victoria, 3220, Australia

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Aalst, 9300, Belgium

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Sofia, BGR, 1407, Bulgaria

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Sofia, 1431, Bulgaria

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Hamilton, Ontario, L8L 2X2, Canada

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Greenfield Park, Quebec, J4V 2G8, Canada

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Rijeka, 51000, Croatia

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Zagreb, 10000, Croatia

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Paris, 75013, France

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Tourcoing, 59208, France

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Regensburg, Bavaria, 93053, Germany

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Dresden, Saxony, 01099, Germany

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Berlin, 10367, Germany

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Berlin, 13353, Germany

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Bielefeld, 33604, Germany

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Bitburg, 54634, Germany

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Buch, 13125, Germany

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Cologne, 50937, Germany

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Cologne, 51065, Germany

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Dessau, 06846, Germany

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Dresden, 01277, Germany

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Elsterwerda, 04910, Germany

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Frankfurt, 60594, Germany

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Ulm, 89077, Germany

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Wuppertal, 42109, Germany

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Würzburg, 97080, Germany

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Ancona, AN, 60128, Italy

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Bergamo, BG, 24127, Italy

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Cona, FE, 44100, Italy

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Florence, FI, 50134, Italy

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Pozzilli, IS, 86077, Italy

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Rozzano, MI, 20089, Italy

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Modena, MO, 41100, Italy

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Pisa, PI, 56124, Italy

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Kaunas, LTU, LT 50161, Lithuania

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Vilnius, LT-08661, Lithuania

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's-Hertogenbosch, 5223 GZ, Netherlands

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Amsterdam, 1081 HV, Netherlands

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Tarnów, Lesser Poland Voivodeship, 33-100, Poland

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Krakow, Maloposkie, 31271, Poland

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Bialystok, 15 276, Poland

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Katowice, 40-645, Poland

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Krakow, 31 202, Poland

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Warsaw, 02-097, Poland

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Lodz, Łódź Voivodeship, 90 549, Poland

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Moscow, 127644, Russia

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Saint Petersburg, 196601, Russia

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Saint Petersburg, 197022, Russia

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Saint Petersburg, 199106, Russia

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Saratov, 410012, Russia

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Wŏnju, Gangwon-do, 26426, South Korea

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Seongnam-si, Gyeonggi-do, 13620, South Korea

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Seoul, 03080, South Korea

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San Sebastián de los Reyes, Madrid, 28702, Spain

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Valencia, Valencia, 46010, Spain

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Madrid, 28034, Spain

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Madrid, 28040, Spain

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Madrid, 28041, Spain

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Valencia, 46026, Spain

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Zaragoza, 50009, Spain

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Basel, 4031, Switzerland

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Tainan, 70403, Taiwan

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Taipei, 10002, Taiwan

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Taipei, 11217, Taiwan

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Meselik, Eskişehir, 26480, Turkey (Türkiye)

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Sivas, 58140, Turkey (Türkiye)

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Axbridge, Somerset, BS26 2BJ, United Kingdom

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Cardiff, Wales, CF5 4AD, United Kingdom

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Birmingham, B16 8QQ, United Kingdom

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Bournemouth, BH7 7DW, United Kingdom

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East Yorkshire, HU16 5JQ, United Kingdom

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Harrow, HA1 3UJ, United Kingdom

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Liverpool, L9 7AL, United Kingdom

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Newport, NP20 2UB, United Kingdom

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Stevenage, SG1 4AB, United Kingdom

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MeSH Terms

Conditions

Heart Failure

Interventions

sacubitril and valsartan sodium hydrate drug combination; Valsartan

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Valine; Amino Acids, Branched-Chain; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Essential

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@Novartis.com

+ 1 862 778 8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 25, 2016
• First Posted: August 30, 2016
• Study Start: November 23, 2016
• Primary Completion: May 16, 2022
• Study Completion: May 16, 2022
• Last Updated: August 6, 2024
• Results First Posted: August 6, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will share

Locations

KR (3); LI (2); US (52); TW (3); AR (5); IT (8); TU (2); AU (4); PL (7); BU (2); CA (2); NL (2); ES (7); BE (1); RU (5); GB (9); FR (2); DE (16); CR (2); CH (1)