Clinical trial NCT02884206: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Heart Failure (CHF)
Keywords: heart failure
cognition
positron emission tomography
magnetic resonance imaging
LCZ696
valsartan
Chronic heart failure
CHF
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2016-08-30
Enrollment: 592
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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).

Primary outcomes:
measure: Change From Baseline in the CogState Global Cognitive Composite Score (GCCS)
timeFrame: Baseline, month 36
Secondary outcomes:
measure: Change From Baseline in Cortical Composite Standardized Uptake Value Ratio (SUVr)
timeFrame: Baseline, month 36
measure: Change From Baseline in Individual Cognitive Domains
timeFrame: Baseline, month 36
measure: Change From Baseline in the Summary Score of the Instrumental Activities of Daily Living (IADL)
timeFrame: Baseline, month 36
Other outcomes:
Locations:
city: Andalusia
country: United States
facility: Novartis Investigative Site
state: Alabama
city: Glendale
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Mesa
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Phoenix
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Sun City West
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Tucson
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Beverly Hills
country: United States
facility: Novartis Investigative Site
state: California
city: Fresno
country: United States
facility: Novartis Investigative Site
state: California
city: Loma Linda
country: United States
facility: Novartis Investigative Site
state: California
city: Long Beach
country: United States
facility: Novartis Investigative Site
state: California
city: Newport Beach
country: United States
facility: Novartis Investigative Site
state: California
city: Santa Ana
country: United States
facility: Novartis Investigative Site
state: California
city: Santa Ana
country: United States
facility: Novartis Investigative Site
state: California
city: Torrance
country: United States
facility: Novartis Investigative Site
state: California
city: Danbury
country: United States
facility: Novartis Investigative Site
state: Connecticut
city: Clearwater
country: United States
facility: Novartis Investigative Site
state: Florida
city: Edgewater
country: United States
facility: Novartis Investigative Site
state: Florida
city: Hollywood
country: United States
facility: Novartis Investigative Site
state: Florida
city: Homestead
country: United States
facility: Novartis Investigative Site
state: Florida
city: Inverness
country: United States
facility: Novartis Investigative Site
state: Florida
city: Jacksonville Beach
country: United States
facility: Novartis Investigative Site
state: Florida
city: Miami
country: United States
facility: Novartis Investigative Site
state: Florida
city: Miami
country: United States
facility: Novartis Investigative Site
state: Florida
city: Miami
country: United States
facility: Novartis Investigative Site
state: Florida
city: Naples
country: United States
facility: Novartis Investigative Site
state: Florida
city: Port Orange
country: United States
facility: Novartis Investigative Site
state: Florida
city: Tampa
country: United States
facility: Novartis Investigative Site
state: Florida
city: Lombard
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Springfield
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Topeka
country: United States
facility: Novartis Investigative Site
state: Kansas
city: Eunice
country: United States
facility: Novartis Investigative Site
state: Louisiana
city: Baltimore
country: United States
facility: Novartis Investigative Site
state: Maryland
city: Saginaw
country: United States
facility: Novartis Investigative Site
state: Michigan
city: Saint Louis
country: United States
facility: Novartis Investigative Site
state: Missouri
city: Kalispell
country: United States
facility: Novartis Investigative Site
state: Montana
city: Reno
country: United States
facility: Novartis Investigative Site
state: Nevada
city: Elmer
country: United States
facility: Novartis Investigative Site
state: New Jersey
city: Buffalo
country: United States
facility: Novartis Investigative Site
state: New York
city: Gastonia
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Cincinnati
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Oregon City
country: United States
facility: Novartis Investigative Site
state: Oregon
city: Springfield
country: United States
facility: Novartis Investigative Site
state: Oregon
city: Fort Mill
country: United States
facility: Novartis Investigative Site
state: South Carolina
city: Rock Hill
country: United States
facility: Novartis Investigative Site
state: South Carolina
city: Summerville
country: United States
facility: Novartis Investigative Site
state: South Carolina
city: Dallas
country: United States
facility: Novartis Investigative Site
state: Texas
city: Dallas
country: United States
facility: Novartis Investigative Site
state: Texas
city: Gonzales
country: United States
facility: Novartis Investigative Site
state: Texas
city: Houston
country: United States
facility: Novartis Investigative Site
state: Texas
city: Lufkin
country: United States
facility: Novartis Investigative Site
state: Texas
city: San Antonio
country: United States
facility: Novartis Investigative Site
state: Texas
city: Tacoma
country: United States
facility: Novartis Investigative Site
state: Washington
city: Buenos Aires
country: Argentina
facility: Novartis Investigative Site
state: ARG
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Ciudad Autonoma de Bs As
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Ramos Mejia
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Capital Federal
city: Chemside
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: Milton
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: Bedford Park
country: Australia
facility: Novartis Investigative Site
state: South Australia
city: Geelong
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Aalst
country: Belgium
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
state: BGR
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Hamilton
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Greenfield Park
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Rijeka
country: Croatia
facility: Novartis Investigative Site
city: Zagreb
country: Croatia
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Tourcoing
country: France
facility: Novartis Investigative Site
city: Regensburg
country: Germany
facility: Novartis Investigative Site
state: Bavaria
city: Dresden
country: Germany
facility: Novartis Investigative Site
state: Sachsen
city: Berlin Buch
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Bielefeld
country: Germany
facility: Novartis Investigative Site
city: Bitburg
country: Germany
facility: Novartis Investigative Site
city: Dessau-Roßlau
country: Germany
facility: Novartis Investigative Site
city: Dresden
country: Germany
facility: Novartis Investigative Site
city: Elsterwerda
country: Germany
facility: Novartis Investigative Site
city: Frankfurt
country: Germany
facility: Novartis Investigative Site
city: Koeln
country: Germany
facility: Novartis Investigative Site
city: Koeln
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Wuerzburg
country: Germany
facility: Novartis Investigative Site
city: Wuppertal
country: Germany
facility: Novartis Investigative Site
city: Ancona
country: Italy
facility: Novartis Investigative Site
state: AN
city: Bergamo
country: Italy
facility: Novartis Investigative Site
state: BG
city: Cona
country: Italy
facility: Novartis Investigative Site
state: FE
city: Firenze
country: Italy
facility: Novartis Investigative Site
state: FI
city: Pozzilli
country: Italy
facility: Novartis Investigative Site
state: IS
city: Rozzano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Modena
country: Italy
facility: Novartis Investigative Site
state: MO
city: Pisa
country: Italy
facility: Novartis Investigative Site
state: PI
city: Wonju
country: Korea, Republic of
facility: Novartis Investigative Site
state: Gangwon-Do
city: Seongnam Si
country: Korea, Republic of
facility: Novartis Investigative Site
state: Gyeonggi Do
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Kaunas
country: Lithuania
facility: Novartis Investigative Site
state: LTU
city: Vilnius
country: Lithuania
facility: Novartis Investigative Site
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Den Bosch
country: Netherlands
facility: Novartis Investigative Site
city: Lodz
country: Poland
facility: Novartis Investigative Site
state: Lodzkie
city: Tarnow
country: Poland
facility: Novartis Investigative Site
state: Malopolskie
city: Krakow
country: Poland
facility: Novartis Investigative Site
state: Maloposkie
city: Bialystok
country: Poland
facility: Novartis Investigative Site
city: Katowice
country: Poland
facility: Novartis Investigative Site
city: Krakow
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Saratov
country: Russian Federation
facility: Novartis Investigative Site
city: St Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: San Sebastian de los Reyes
country: Spain
facility: Novartis Investigative Site
state: Madrid
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Valencia
country: Spain
facility: Novartis Investigative Site
city: Zaragoza
country: Spain
facility: Novartis Investigative Site
city: Basel
country: Switzerland
facility: Novartis Investigative Site
city: Tainan
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Meselik
country: Turkey
facility: Novartis Investigative Site
state: Eskisehir
city: Sivas
country: Turkey
facility: Novartis Investigative Site
city: Axbridge
country: United Kingdom
facility: Novartis Investigative Site
state: Somerset
city: Cardiff
country: United Kingdom
facility: Novartis Investigative Site
state: Wales
city: Birmingham
country: United Kingdom
facility: Novartis Investigative Site
city: Bournemouth
country: United Kingdom
facility: Novartis Investigative Site
city: East Yorkshire
country: United Kingdom
facility: Novartis Investigative Site
city: Harrow
country: United Kingdom
facility: Novartis Investigative Site
city: Liverpool
country: United Kingdom
facility: Novartis Investigative Site
city: Newport
country: United Kingdom
facility: Novartis Investigative Site
city: Stevenage
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: