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

A Multicenter, Randomized, Double-blind, Active-controlled Study to Evaluate the Effects of LCZ696 Compared to Valsartan on Cognitive Function in Patients With Chronic Heart Failure and Preserved Ejection Fraction

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).

Study Overview

• Status: Completed
• Conditions: Chronic Heart Failure (CHF)
• Intervention / Treatment: Drug: LCZ696; Drug: Placebo of Valsartan; Drug: Valsartan; Drug: Placebo of LCZ696

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.

• Study Type: Interventional
• Enrollment (Actual): 592
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • ARG
    • Buenos Aires, ARG, Argentina, C1405BCK
      • Novartis Investigative Site
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, 1407
      • Novartis Investigative Site
    • Ciudad Autonoma de Bs As, Buenos Aires, Argentina, C1119ACN
      • Novartis Investigative Site
    • Ramos Mejia, Buenos Aires, Argentina, B1704ETD
      • Novartis Investigative Site
  • Capital Federal
    • Caba, Capital Federal, Argentina, C1179AAB
      • Novartis Investigative Site
• Australia
  • Queensland
    • Chemside, Queensland, Australia, 4032
      • Novartis Investigative Site
    • Milton, Queensland, Australia, 4064
      • Novartis Investigative Site
  • South Australia
    • Bedford Park, South Australia, Australia, 5042
      • Novartis Investigative Site
  • Victoria
    • Geelong, Victoria, Australia, 3220
      • Novartis Investigative Site
• Belgium
  • Aalst, Belgium, 9300
    • Novartis Investigative Site
• Bulgaria
  • Sofia, Bulgaria, 1431
    • Novartis Investigative Site
  • BGR
    • Sofia, BGR, Bulgaria, 1407
      • Novartis Investigative Site
• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8L 2X2
      • Novartis Investigative Site
  • Quebec
    • Greenfield Park, Quebec, Canada, J4V 2G8
      • Novartis Investigative Site
• Croatia
  • Rijeka, Croatia, 51000
    • Novartis Investigative Site
  • Zagreb, Croatia, 10000
    • Novartis Investigative Site
• France
  • Paris, France, 75013
    • Novartis Investigative Site
  • Tourcoing, France, 59208
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 10367
    • Novartis Investigative Site
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Berlin Buch, Germany, 13125
    • Novartis Investigative Site
  • Bielefeld, Germany, 33604
    • Novartis Investigative Site
  • Bitburg, Germany, 54634
    • Novartis Investigative Site
  • Dessau-Roßlau, Germany, 06846
    • Novartis Investigative Site
  • Dresden, Germany, 01277
    • Novartis Investigative Site
  • Elsterwerda, Germany, 04910
    • Novartis Investigative Site
  • Frankfurt, Germany, 60594
    • Novartis Investigative Site
  • Koeln, Germany, 50937
    • Novartis Investigative Site
  • Koeln, Germany, 51065
    • Novartis Investigative Site
  • Ulm, Germany, 89077
    • Novartis Investigative Site
  • Wuerzburg, Germany, 97080
    • Novartis Investigative Site
  • Wuppertal, Germany, 42109
    • Novartis Investigative Site
  • Bavaria
    • Regensburg, Bavaria, Germany, 93053
      • Novartis Investigative Site
  • Sachsen
    • Dresden, Sachsen, Germany, 01099
      • Novartis Investigative Site
• Italy
  • AN
    • Ancona, AN, Italy, 60128
      • Novartis Investigative Site
  • BG
    • Bergamo, BG, Italy, 24127
      • Novartis Investigative Site
  • FE
    • Cona, FE, Italy, 44100
      • Novartis Investigative Site
  • FI
    • Firenze, FI, Italy, 50134
      • Novartis Investigative Site
  • IS
    • Pozzilli, IS, Italy, 86077
      • Novartis Investigative Site
  • MI
    • Rozzano, MI, Italy, 20089
      • Novartis Investigative Site
  • MO
    • Modena, MO, Italy, 41100
      • Novartis Investigative Site
  • PI
    • Pisa, PI, Italy, 56124
      • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
  • Gangwon-Do
    • Wonju, Gangwon-Do, Korea, Republic of, 26426
      • Novartis Investigative Site
  • Gyeonggi Do
    • Seongnam Si, Gyeonggi Do, Korea, Republic of, 13620
      • Novartis Investigative Site
• Lithuania
  • Vilnius, Lithuania, LT-08661
    • Novartis Investigative Site
  • LTU
    • Kaunas, LTU, Lithuania, LT 50161
      • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Novartis Investigative Site
  • Den Bosch, Netherlands, 5223 GZ
    • Novartis Investigative Site
• Poland
  • Bialystok, Poland, 15 276
    • Novartis Investigative Site
  • Katowice, Poland, 40-645
    • Novartis Investigative Site
  • Krakow, Poland, 31 202
    • Novartis Investigative Site
  • Warszawa, Poland, 02-097
    • Novartis Investigative Site
  • Lodzkie
    • Lodz, Lodzkie, Poland, 90 549
      • Novartis Investigative Site
  • Malopolskie
    • Tarnow, Malopolskie, Poland, 33-100
      • Novartis Investigative Site
  • Maloposkie
    • Krakow, Maloposkie, Poland, 31271
      • Novartis Investigative Site
• Russian Federation
  • Moscow, Russian Federation, 127644
    • Novartis Investigative Site
  • Saint Petersburg, Russian Federation, 197022
    • Novartis Investigative Site
  • Saint Petersburg, Russian Federation, 199106
    • Novartis Investigative Site
  • Saratov, Russian Federation, 410012
    • Novartis Investigative Site
  • St Petersburg, Russian Federation, 196601
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28041
    • Novartis Investigative Site
  • Madrid, Spain, 28034
    • Novartis Investigative Site
  • Madrid, Spain, 28040
    • Novartis Investigative Site
  • Valencia, Spain, 46026
    • Novartis Investigative Site
  • Zaragoza, Spain, 50009
    • Novartis Investigative Site
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46010
      • Novartis Investigative Site
  • Madrid
    • San Sebastian de los Reyes, Madrid, Spain, 28702
      • Novartis Investigative Site
• Switzerland
  • Basel, Switzerland, 4031
    • Novartis Investigative Site
• Taiwan
  • Tainan, Taiwan, 70403
    • Novartis Investigative Site
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
  • Taipei, Taiwan, 11217
    • Novartis Investigative Site
• Turkey
  • Sivas, Turkey, 58140
    • Novartis Investigative Site
  • Eskisehir
    • Meselik, Eskisehir, Turkey, 26480
      • Novartis Investigative Site
• United Kingdom
  • Birmingham, United Kingdom, B16 8QQ
    • Novartis Investigative Site
  • Bournemouth, United Kingdom, BH7 7DW
    • Novartis Investigative Site
  • East Yorkshire, United Kingdom, HU16 5JQ
    • Novartis Investigative Site
  • Harrow, United Kingdom, HA1 3UJ
    • Novartis Investigative Site
  • Liverpool, United Kingdom, L9 7AL
    • Novartis Investigative Site
  • Newport, United Kingdom, NP20 2UB
    • Novartis Investigative Site
  • Stevenage, United Kingdom, SG1 4AB
    • Novartis Investigative Site
  • Somerset
    • Axbridge, Somerset, United Kingdom, BS26 2BJ
      • Novartis Investigative Site
  • Wales
    • Cardiff, Wales, United Kingdom, CF5 4AD
      • Novartis Investigative Site
• United States
  • Alabama
    • Andalusia, Alabama, United States, 36420
      • Novartis Investigative Site
  • Arizona
    • Glendale, Arizona, United States, 85306
      • Novartis Investigative Site
    • Mesa, Arizona, United States, 85206
      • Novartis Investigative Site
    • Phoenix, Arizona, United States, 85004
      • Novartis Investigative Site
    • Sun City West, Arizona, United States, 85375
      • Novartis Investigative Site
    • Tucson, Arizona, United States, 85723
      • Novartis Investigative Site
  • California
    • Beverly Hills, California, United States, 90211
      • Novartis Investigative Site
    • Fresno, California, United States, 93720
      • Novartis Investigative Site
    • Loma Linda, California, United States, 92357
      • Novartis Investigative Site
    • Long Beach, California, United States, 90806
      • Novartis Investigative Site
    • Newport Beach, California, United States, 92663
      • Novartis Investigative Site
    • Santa Ana, California, United States, 92704
      • Novartis Investigative Site
    • Santa Ana, California, United States, 92705
      • Novartis Investigative Site
    • Torrance, California, United States, 90503
      • Novartis Investigative Site
  • Connecticut
    • Danbury, Connecticut, United States, 06810
      • Novartis Investigative Site
  • Florida
    • Clearwater, Florida, United States, 33756
      • Novartis Investigative Site
    • Edgewater, Florida, United States, 32132
      • Novartis Investigative Site
    • Hollywood, Florida, United States, 33312
      • Novartis Investigative Site
    • Homestead, Florida, United States, 33030
      • Novartis Investigative Site
    • Inverness, Florida, United States, 34452
      • Novartis Investigative Site
    • Jacksonville Beach, Florida, United States, 32050
      • Novartis Investigative Site
    • Miami, Florida, United States, 33133
      • Novartis Investigative Site
    • Miami, Florida, United States, 33144
      • Novartis Investigative Site
    • Miami, Florida, United States, 33176
      • Novartis Investigative Site
    • Naples, Florida, United States, 34102
      • Novartis Investigative Site
    • Port Orange, Florida, United States, 32127
      • Novartis Investigative Site
    • Tampa, Florida, United States, 33612
      • Novartis Investigative Site
  • Illinois
    • Lombard, Illinois, United States, 60148
      • Novartis Investigative Site
    • Springfield, Illinois, United States, 62701
      • Novartis Investigative Site
  • Kansas
    • Topeka, Kansas, United States, 66606
      • Novartis Investigative Site
  • Louisiana
    • Eunice, Louisiana, United States, 70535
      • Novartis Investigative Site
  • Maryland
    • Baltimore, Maryland, United States, 21229
      • Novartis Investigative Site
  • Michigan
    • Saginaw, Michigan, United States, 48601
      • Novartis Investigative Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Novartis Investigative Site
  • Montana
    • Kalispell, Montana, United States, 59901 3158
      • Novartis Investigative Site
  • Nevada
    • Reno, Nevada, United States, 89502
      • Novartis Investigative Site
  • New Jersey
    • Elmer, New Jersey, United States, 08318
      • Novartis Investigative Site
  • New York
    • Buffalo, New York, United States, 14215
      • Novartis Investigative Site
  • North Carolina
    • Gastonia, North Carolina, United States, 28054
      • Novartis Investigative Site
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Novartis Investigative Site
  • Oregon
    • Oregon City, Oregon, United States, 97045
      • Novartis Investigative Site
    • Springfield, Oregon, United States, 97477
      • Novartis Investigative Site
  • South Carolina
    • Fort Mill, South Carolina, United States, 29707
      • Novartis Investigative Site
    • Rock Hill, South Carolina, United States, 29732
      • Novartis Investigative Site
    • Summerville, South Carolina, United States, 29485
      • Novartis Investigative Site
  • Texas
    • Dallas, Texas, United States, 75235
      • Novartis Investigative Site
    • Dallas, Texas, United States, 75226
      • Novartis Investigative Site
    • Gonzales, Texas, United States, 78629
      • Novartis Investigative Site
    • Houston, Texas, United States, 77030
      • Novartis Investigative Site
    • Lufkin, Texas, United States, 75904
      • Novartis Investigative Site
    • San Antonio, Texas, United States, 78229
      • Novartis Investigative Site
  • Washington
    • Tacoma, Washington, United States, 98405
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key 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

Key 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).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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	Drug: LCZ696; LCZ696 50, 100, and 200 mg tablets taken orally twice daily with matching placebo for valsartan; Drug: Placebo of Valsartan; Placebo to match valsartan 40 mg, 80 mg, and 160 mg tablets
Active Comparator: 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.	Drug: Valsartan; Valsartan 40, 80, and 160 mg tablets taken orally twice daily with matching placebo for LCZ696; Drug: Placebo of LCZ696; Placebo to match LCZ696 50 mg, 100 mg, and 200 mg tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Cortical Composite Standardized Uptake Value Ratio (SUVr)	The effects of LCZ696 compared to valsartan on Aβ deposition in the brain over 3 years were evaluated in a subset of patients using amyloid positron emission tomography (PET) imaging by assessing the change from baseline in cortical composite SUVr. PET imaging was performed at selected PET-capable centers on all eligible patients participating in the substudy. Sites with patients performing the PET scan were a subset of the overall patient population and overall sites for the study. Change from baseline to 3 years was analyzed based on an ANCOVA model with treatment, age, MMSE, amyloid status (+ve/-ve) stratification factors, region, APOE4 status and cerebrovascular disease burden as fixed effects, with baseline SUVr and treatment-by-baseline SUVr interaction as covariates for each of these imputed datasets. Results were obtained by applying Rubin's rules on the estimates from the imputed datasets.	Baseline, month 36
Change From Baseline in Individual Cognitive Domains	The effects of LCZ696 compared to valsartan on the individual cognitive domains (memory, executive function, and attention) over 3 years were evaluated by assessing the individual components of the CogState cognitive battery. Composite scores for the 3 individual cognitive domains were generated by combining the standardized z-scores of selected tests from the CogState cognitive battery. Each composite score was the average of the non-missing individual test z-scores. A higher score indicated better cognitive function.	Baseline, month 36
Change From Baseline in the Summary Score of the Instrumental Activities of Daily Living (IADL)	The effects of LCZ696 compared to valsartan on the changes in IADL over 3 years were evaluated by as assessing the Functional activities questionnaire (FAQ) summary scores. The FAQ is a 30-point questionnaire that is made up of 10 questions that reflect a patient's ability to perform activities of daily living and to function independently. A score of 0 represents no impairment and a score of 30 represents severe impairment.	Baseline, month 36

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): November 23, 2016
• Primary Completion (Actual): May 16, 2022
• Study Completion (Actual): May 16, 2022

Study Registration Dates

• First Submitted: August 25, 2016
• First Submitted That Met QC Criteria: August 25, 2016
• First Posted (Estimated): August 30, 2016

Study Record Updates

• Last Update Posted (Actual): August 6, 2024
• Last Update Submitted That Met QC Criteria: July 15, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: magnetic resonance imaging; cognition; heart failure; positron emission tomography; CHF; LCZ696; valsartan; Chronic heart failure
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Valsartan; Sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: CLCZ696B2320; 2016-001254-17 (EudraCT Number)

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.