Study to evaluate the effect of LCZ696 compared to individualized medical therapy for comorbidities in Heart Failure with preserved Ejection Fraction (HFpEF) patients

• Register: EUCTR
• Last refreshed on: 16 December 2019
• Main ID: EUCTR2016-003410-28-ES
• Date of registration: 07/04/2017
• Prospective Registration: Yes
• Primary sponsor: Novartis Farmacética S.A.
• Public title: Study to evaluate the effect of LCZ696 compared to individualized medical therapy for comorbidities in Heart Failure with preserved Ejection Fraction (HFpEF) patients
• Scientific title: A 24-week, randomized, double-blind, multi-center, parallel group, active controlled study to evaluate the effect of LCZ696 on NT-proBNP, symptoms, exercise function and safety compared to individualized medical management of comorbidities in patients with heart failure and preserved ejection fraction
• Date of first enrolment: 22/05/2017
• Target sample size: 2200
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-003410-28
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Austria, Belgium, Brazil, Bulgaria, Canada, Colombia, Czech Republic, Denmark, Estonia, France, Germany, Guatemala, Hungary, India, Ireland, Israel, Italy, Latvia, Lithuania, Mexico, Netherlands, Peru, Portugal, Romania, Russian Federation, Serbia, Slovakia, Spain, Thailand, Turkey, United Kingdom, United States

Contacts

• Name: Departamento Médico (ICRO)
• Affiliation: Novartis Farmacéutica, S.A.

• Name: Departamento Médico (ICRO)
• Affiliation: Novartis Farmacéutica, S.A.

Key inclusion & exclusion criteria

Inclusion criteria:
- Left ventricular ejection fraction (LVEF) =45% by echo within 6 months prior to study entry or during the screening epoch
- Symptom(s) of heart failure (HF) requiring treatment with diuretics (including loop, or thiazide diuretics, or mineralocorticoid antagonist [MRAs]) for at least 30 days prior to study entry
- NYHA class II-IV
- Structural heart disease (left atrial enlargement or left ventricular hypertrophy) documented by echocardiogram.
- NT-proBNP > 220 pg/mL for patients with no atrial fibrillation/atrial flutter (AF) or >600 pg/mL for patients with AF
- KCCQ clinical summary score < 75
- Patients on ACEi or ARB therapy must have a history of HTN
Other protocol-defined inclusion criteria may apply.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 440
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 1760

Exclusion criteria:
- Any prior measurement of LVEF < 40%
- Acute coronary syndrome (including MI), cardiac surgery, other major CV surgery within 3 months , or urgent percutaneous coronary intervention (PCI) within 3 months or an elective PCI within 30 days prior to study entry
- Any clinical event within the 6 months prior to Visit 1 that could have reduced the LVEF (e.g. MI, coronary artery bypass graft [CABG]), unless an echo measurement was performed after the event confirming the LVEF to be = 40% and EF = 45% by the time of screening
- Current acute decompensated HF requiring therapy.
- Current use of renin inhibitor(s)
- History of hypersensitivity to LCZ696 or its components
- Patients with a known history of angioedema
- Walking distance primarily limited by non-cardiac comorbid conditions
- Alternative reason for shortness of breath such as: significant pulmonary disease or severe COPD, hemoglobin (Hgb) <10 g/dL males and < 9.5 g/dL
females, or body mass index (BMI) > 40 kg/m2.
- Systolic blood pressure (SBP) = 180 mmHg at study entry, or SBP >150 mmHg and <180 mmHg at study entry unless the patient is receiving 3 or more
antihypertensive drugs, or SBP < 110 mmHg at study entry.
- Patients with HbA1c > 7.5% not treated for diabetes
- Patients with prior major organ transplant or intent to transplant (ie on transplant list)
- eGFR < 30 ml/min/1.73 m2 as measured by MDRD at screening
- Serum potassium > 5.2 mmol /L at study entry
- History or presence of any other disease with a life expectancy of < 3 years
- Pregnant or nursing women or women of childbearing potential unless they are using highly effective methods of contraception.
Other protocol-defined exclusion criteria may apply.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Heart Failure with preserved Ejection Fraction (HFpEF)
MedDRA version: 19.1 Level: LLT Classification code 10019279 Term: Heart failure System Organ Class: 100000004849

Intervention(s)

Trade Name: Entresto
Product Name: LCZ696 50 mg
Product Code: LCZ696
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: sacubitril/valsartan
Other descriptive name: SACUBITRIL VALSARTAN
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Entresto
Product Name: LCZ696 100 mg
Product Code: LCZ696
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: sacubitril/valsartan
Other descriptive name: SACUBITRIL VALSARTAN
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Entresto
Product Name: LCZ696 200 mg
Product Code: LCZ696
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: sacubitril/valsartan
Other descriptive name: SACUBITRIL VALSARTAN
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Diovan
Product Name: Diovan 80 mg
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: VALSARTAN
CAS Number: 137862-53-4
Concentration unit: mg milligram(s)
Concentrati

Primary Outcome(s)

Primary end point(s): Change from baseline in N-terminal pro-brain natriuretic peptide (NTproBNP) after 12 weeks

Main Objective: To demonstrate that LCZ696 is superior to individualized medical therapy for comorbidities in reducing NTproBNP from baseline after 12 weeks of treatment in patients with HFpEF

Secondary Objective: - To compare LCZ696 to individualized medical therapy for comorbidities on mean change of KCCQ clinical summary score (CSS) at Week 24
- To compare LCZ696 to individualized medical therapy for comorbidities on proportion of patients with = 5-points change in KCCQ CSS at Week 24 (= 5-points deterioration and separate analyses for = 5-points improvement)
- To compare LCZ696 to individualized medical therapy for comorbidities in improving functional capacity as assessed by the 6-minute walk test (6 MWT) at Week 24
- To compare LCZ696 to individualized medical therapy for comorbidities in improving NYHA functional class at Week 24
- To compare LCZ696 to individualized medical therapy for comorbidities in improving symptoms as assessed by The Short Form (36) Health Survey (SF-36) physical component summary (PCS) score at Week 24

Timepoint(s) of evaluation of this end point: baseline, week 12

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: baseline, week 24

Secondary end point(s): - Mean change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS)
- Percentage of patients with = 5-points deterioration in KCCQ CSS at Week 24
- Percentage of patients with = 5-points improvement in KCCQ CSS at Week 24
- Change from baseline in the 6-minute walk test (6MWT) to week 24
- Change in NYHA functional class from baseline to week 24
- Change from baseline in SF- 36 physical component summary (PCS) score score to week 24

Secondary ID(s)

CLCZ696D2302

2016-003410-28-PT

Source(s) of Monetary Support

Novartis Pharma AG

Ethics review

Status: Approved
Approval date:
Contact: