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

Study Overview
=================
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.

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

Conditions
-----------------
Chronic Heart Failure (CHF)

Intervention / Treatment
-----------------
* Drug: LCZ696
* Drug: Valsartan
* Drug: Placebo of LCZ696
* Drug: Placebo of Valsartan


Participation Criteria
=================
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: 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 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).

Ages Eligible for Study
-----------------
Minimum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

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) | 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. | Baseline, week 156 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in cortical composite standardized uptake value ratio (SUVr) | 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. | Baseline, week 156 | 
| Change from baseline in individual cognitive domains (memory, executive function, and attention) | Specific cognitive domains to be assessed include memory, executive function, and attention. A negative change from baseline will indicate worsening performance. | Baseline, week 156 | 
| Change from baseline in the summary score of the instrumental activities of daily living (IADL) | 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. | Baseline, week 156 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
heart failure, cognition, positron emission tomography, magnetic resonance imaging, LCZ696, valsartan, Chronic heart failure, CHF