Clinical trial NCT03928158: LCZ696 in Advanced LV Hypertrophy and HFpEF
Official title: Sacubitril/Valsartan (LCZ696) in Patients With Advanced Hypertensive Left Ventricular Hypertrophy and Heart Failure With Preserved Ejection Fraction: Clinical, Haemodynamic and Neurohumoral Effects (a Phase 2, Randomized, Single-center, Parallel Group Study)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Heart Failure
Essential Hypertension
Keywords: left ventricular hypertrophy
diastolic dysfunction
LCZ696
HFpEF
HF
LV filling pressures
Lead sponsor: National Medical Research Center for Cardiology, Ministry of Health of Russian Federation
Sponsor class: OTHER_GOV
First posted: 2019-04-26
Enrollment: 61
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Patients with advanced LVH and HFpEF will be randomly assigned in open-label fashion to receive LCZ696 titrated to 200 mg twice daily or valsartan titrated to 160 mg twice daily, and will be treated for 24 weeks.

Detailed description: Heart failure with preserved ejection fraction (HFpEF) has a signiﬁcant morbidity and mortality, and therapies that have proven effective in HF with reduced EF have not been shown to improve long-term prognosis in HFpEF. Inhibition of circulating neprilysin could augment deficient NP-receptor GC signaling and therefore be beneficial in HFpEF, as suggested by the decrease in NP following administration of valsartan/sacubitril in the phase 2 (PARAMOUNT study). Use of valsartan/sacubitril is currently being tested in the multicenter PARAGON-HF trial with HFpEF patients. The investigators suppose the best candidates for LCZ696 therapy will be patients with HFpEF and advanced concentric LV hypertrophy and obesity, i.e. having the lowest BNP bioavailability.

Eligibility criteria: Inclusion Criteria:

1. Moderate/severe hypertensive left ventricular (LV) hypertrophy (LVMi ≥109 g/m² in women and ≥132 g/m² in men);
2. New York Heart Association (NYHA) class II-III heart failure;
3. Left ventricular ejection fraction \> 50%;
4. Increased LV filling pressures assessed at rest or at peak exercise by echocardiography
5. Body mass index (BMI) \> 30 kg/m²
6. Signed and data informed consent

Exclusion Criteria:

1. Age ≤ 18 years;
2. Evidence of myocardial ischemia during stress echocardiography;
3. Chronic atrial flutter or atrial fibrillation;
4. Alternative cause of left ventricular hypertrophy and impaired diastolic function (hypertrophic/restictive cardiomyopathy, aortic stenosis, constrictive pericarditis and etc.);
5. NYHA classification I or decompensated heart failure at screening;
6. Systolic blood pressure \< 110 mmHg or \> 180 mmHg;
7. Diastolic blood pressure \< 40 mmHg or \> 100 mmHg;
8. Anemia (Hb \< 100 g/l);
9. Significant left sided structural valve disease;
10. Secondary hypertension;
11. Dyspnea due to non-cardiac causes such as pulmonary disease, anemia, severe obesity, primary valvular, or myocardial diseases;
12. Myocardial infarction or myocardial revascularization within the last 3 months of screening;
13. Stroke or TIA within the last 3 months of screening;
14. Autoimmunic and oncological diseases;
15. Impaired renal function, defined as eGFR \< 30 ml/min/1.73 m²;
16. Impaired liver function;
17. Potassium concentration \>5.2 mmol/L.

Primary outcomes:
measure: Change in 6-minute walking distance (6MWD)
timeFrame: 24 weeks
Secondary outcomes:
measure: Change in exercise time during diastolic stress-test (DST)
timeFrame: 24 weeks
measure: Change in left atrial volume index (LAVI)
timeFrame: 24 weeks
measure: Change in average E/e' ratio
timeFrame: 24 weeks
measure: Change estimated pulmonary artery systolic pressure (PASP)
timeFrame: 24 weeks
measure: Change in left ventricular mass index (LVMI)
timeFrame: 24 weeks
measure: Change of New York Heart Association (NYHA) functional classification
timeFrame: 24 weeks
measure: Change in Minnesota Living With Heart Failure Questionnaire (MLHFQ) score
timeFrame: 24 weeks
measure: Change in N-terminal pro b-type natriuretic peptide (NT-proBNP)
timeFrame: 24 weeks
measure: Change in high-sensitivity C-reactive protein (hsCRP)
timeFrame: 24 weeks
measure: Change in carboxyterminal propeptide of type I collagen (PICP)
timeFrame: 24 weeks
measure: Change in carboxyterminal telopeptide of type I collagen (CITP)
timeFrame: 24 weeks
measure: Change in N-Propeptide Of Type III Procollagen (PIIINP)
timeFrame: 24 weeks
measure: Change in Growth/differentiation factor 15 (GDF-15)
timeFrame: 24 weeks
measure: Change in sST2
timeFrame: 24 weeks
measure: Change in Galectin-3
timeFrame: 24 weeks
measure: Change in monocyte chemoattractant-1 (MCP-1)
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Moscow
country: Russian Federation
facility: National Medical Research Center for Cardiology
Study officials:
References: