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

• ClinicalTrials.gov Identifier: NCT02884206
• Recruitment Status: Completed
• First Posted: August 30, 2016
• Last Update Posted: November 3, 2022
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: August 25, 2016
• First Posted Date: August 30, 2016
• Last Update Posted Date: November 3, 2022
• Actual Study Start Date: November 23, 2016
• Actual Primary Completion Date: May 16, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 11, 2021)

Change from baseline in the CogState Global Cognitive Composite Score (GCCS) [ Time Frame: Baseline, week 156 ]

Change in cognition is assessed as a change in a Global Cognitive Composite Z score. The cognitive composite comprises cognitive domains including attention, memory, and executive function. A negative change from baseline will indicate worsening performance.

Original Primary Outcome Measures (submitted: August 25, 2016)

Change from baseline in the CogState Global Cognitive Composite Score (GCCS) [ Time Frame: baseline, week 156 ]

Change in cognition is assessed as a change in a Global Cognitive Composite Z score. The cognitive composite comprises cognitive domains including attention, memory, and executive function. A negative change from baseline will indicate worsening performance.

Current Secondary Outcome Measures (submitted: October 31, 2017)

• Change from baseline in cortical composite standardized uptake value ratio (SUVr) [ Time Frame: Baseline, week 156 ]
  Changes in amyloid plaque deposition over time will be assessed using florbetapir-18F. The longitudinal change in the standardized uptake value ratio will be determined.
• Change from baseline in individual cognitive domains (memory, executive function, and attention) [ Time Frame: Baseline, week 156 ]
  Specific cognitive domains to be assessed include memory, executive function, and attention. A negative change from baseline will indicate worsening performance.
• Change from baseline in the summary score of the instrumental activities of daily living (IADL) [ Time Frame: Baseline, week 156 ]
  Instrumental activities of daily living will be assessed using the functional activities questionnaire. The functional activities questionnaire will be used as a standardized assessment of activities of daily living. This questionnaire is typically used to distinguish normal subjects from subjects with mild to moderate cognitive impairment. The test is made up of 10 questions that reflect a subject's ability to perform activities of daily living and to function independently. Test scores range from 0 to 30, a score of 0 is completely normal where as a higher score denotes impairment. Each of 10 questions is scored from 0, representing normal to 3, dependent on someone else to perform the activity. A negative change from baseline denotes improvement.

Original Secondary Outcome Measures (submitted: August 25, 2016)

• Change from baseline in a cortical composite standardized uptake value ratio (SUVr) [ Time Frame: Baseline, week 156 ]
  Changes in amyloid plaque deposition over time will be assessed using florbetapir-18F. The longitudinal change in the standardized uptake value ratio will be determined.
• Change from baseline in individual cognitive domains (memory, executive function, and attention) [ Time Frame: Baseline, week 156 ]
  Specific cognitive domains to be assessed include memory, executive function, and attention. A negative change from baseline will indicate worsening performance.
• Change from baseline in the summary score of the instrumental activities of daily living (IADL) [ Time Frame: Baseline, week 156 ]
  Instrumental activities of daily living will be assessed using the functional activities questionnaire. The functional activities questionnaire will be used as a standardized assessment of activities of daily living. This questionnaire is typically used to distinguish normal subjects from subjects with mild to moderate cognitive impairment. The test is made up of 10 questions that reflect a subject's ability to perform activities of daily living and to function independently. Test scores range from 0 to 30, a score of 0 is completely normal where as a higher score denotes impairment. Each of 10 questions is scored from 0, representing normal to 3, dependent on someone else to perform the activity. A negative change from baseline denotes improvement.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy and Safety of LCZ696 Compared to Valsartan on Cognitive Function in Patients With Chronic Heart Failure and Preserved Ejection Fraction
• Official Title: 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
• Brief Summary: The purpose of this study is to evaluate the effect of LCZ696 compared to valsartan on cognitive function in patients with chronic heart failure and preserved ejection fraction. Cognitive function will be assessed using a comprehensive battery of tests with an evaluation of longitudinal change of cognitive domains including memory, executive function, and attention.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Chronic Heart Failure (CHF)

Intervention

• Drug: LCZ696
  LCZ696 50, 100, and 200 mg tablets taken orally twice daily with matching placebo for valsartan
• 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
• Drug: Placebo of Valsartan
  Placebo to match valsartan 40 mg, 80 mg, and 160 mg tablets

Study Arms

• Experimental: LCZ696
  Patients will receive LCZ696 at 100 mg twice daily during a single-blind treatment run-in period to ensure patients tolerate this medication before they are randomized. Down-titration is not allowed during this period. Patients who are able to tolerate LCZ696 100 mg twice daily are eligible to enter the randomized treatment period. Patients randomized to receive LCZ696 will be given LCZ696 at 200 mg twice daily. Patients will receive randomized study drug for three years.
  Interventions:

  • Drug: LCZ696
  • Drug: Placebo of Valsartan
• Active Comparator: Valsartan
  Patients will receive valsartan at 40mg and/or 80mg twice daily during a single-blind treatment run-in period. Following the run-in period, patients randomized to receive valsartan will be given valsartan at 160 mg twice daily for three years.
  Interventions:

  • Drug: Valsartan
  • Drug: Placebo of LCZ696

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 3, 2020): 592
• Original Estimated Enrollment (submitted: August 25, 2016): 520
• Actual Study Completion Date: May 16, 2022
• Actual Primary Completion Date: May 16, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 60 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Belgium, Bulgaria, Canada, Croatia, France, Germany, Italy, Korea, Republic of, Lithuania, Netherlands, Poland, Russian Federation, Spain, Switzerland, Taiwan, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT02884206
• Other Study ID Numbers: CLCZ696B2320; 2016-001254-17 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes

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.

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: November 2022