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
Overview
- Phase
- Phase 3
- Intervention
- LCZ696
- Conditions
- Chronic Heart Failure (CHF)
- Sponsor
- Novartis Pharmaceuticals
- Enrollment
- 592
- Locations
- 1
- Primary Endpoint
- Change From Baseline in the CogState Global Cognitive Composite Score (GCCS)
- Status
- Completed
- Last Updated
- last year
Overview
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.
Investigators
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:
- •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
Arms & Interventions
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
Intervention: LCZ696
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
Intervention: Placebo of Valsartan
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.
Intervention: Valsartan
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.
Intervention: Placebo of LCZ696
Outcomes
Primary Outcomes
Change From Baseline in the CogState Global Cognitive Composite Score (GCCS)
Time Frame: Baseline, month 36
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.
Secondary Outcomes
- 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)