A Randomized, Double-blind Controlled Study Comparing LCZ696 to Medical Therapy for Comorbidities in HFpEF Patients

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to demonstrate the superiority of LCZ696 over individualized medical therapy for comorbidities in reducing N-terminal pro-brain natriuretic peptide (NT-proBNP) and improving exercise capacity and HF symptoms in patients with heart failure with preserved ejection fraction (HFpEF).

Detailed Description
-----------------
This study was a 24-week, randomized, double-blind, multi-center, parallel group, active controlled study to evaluate sacubitril/valsartan compared to individualized medical therapy on NT proBNP, exercise capacity, symptoms and QoL in patients with heart failure and preserved left ventricular ejection (HFpEF) fraction (LVEF > 40%). Patients were initially stratified into one of three strata according to prior treatment for comorbidities: Angiotensin converting enzyme inhibitor (ACEi), angiotensin receptor blocker (ARB) or no prior renin angiotensin system inhibitors (RASi). Patients in each stratum were randomized in a 1:1 ratio and received either sacubitril/valsartan or comparator (i.e. enalapril for patients in ACEi strata, valsartan for patients in the ARB strata and placebo for patients in the No RASi strata). There was no designated proportion of patients planned in each stratum; the strata were populated based upon the patient's prior treatment regimen. The study consisted of a screening epoch of up to 2 weeks and a randomized treatment epoch of 24 weeks, which included a 1 to 4 week study drug up-titration epoch followed by a 20 to 23 week maintenance epoch. Uptitration to target doses was recommended to occur within the first four weeks of the study, and was performed by Investigator's discretion based on the patient's clinical status.

Official Title
-----------------
A 24-week, Randomized, Double-blind, Multi-center, Parallel LCZ696 on NT-proBNP, Exercise Capacity, Symptoms and Safety Compared to Individualized Medical Management of Comorbidities in Patients With Heart Failure and Preserved Ejection Fraction

Conditions
-----------------
Heart Failure With Preserved Ejection Fraction

Intervention / Treatment
-----------------
* Drug: sacubitril/valsartan
* Drug: Enalapril
* Drug: Valsartan
* Drug: Placebo to match sacubitril/valsartan
* Drug: Placebo to match enalapril
* Drug: Placebo to match valsartan


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Left ventricular ejection fraction (LVEF) >40% 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 Exclusion Criteria: Any prior measurement of LVEF ≤ 40%, under stable conditions 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 (eg MI, coronary artery bypass graft [CABG]), unless an echo measurement was performed after the event confirming the LVEF to be >40% Current (within 30 days from Visit 1) acute decompensated HF requiring therapy. Current (within 30 days from Visit 1) use of renin inhibitor(s), dual RAS blockade or LCZ696 History of hypersensitivity to LCZ696 or its components Patients with a known history of angioedema Walk distance primarily limited by non-cardiac comorbid conditions at study entry 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/m^2. 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 m^2 as measured by MDRD at screening Serum potassium > 5.2 mmol /L (or equivalent plasma potassium value) at study entry History or presence of any other disease with a life expectancy of < 3 years Pregnant or nursing women or women of child-bearing potential unless they are using highly effective methods of contraception Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
-----------------
Minimum Age: 45 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: sacubitril/valsartan (LCZ696)<br>All patients who fulfill the inclusion/exclusion criteria will be stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi. Patients in the ACEi strata will receive LCZ696 or enalapril. Patients in the ARB strata will receive LCZ696 or valsartan. Patients in the no RASi strata will receive LCZ696 or matching placebo. Patients in the ACEi and ARB strata will take two pills twice daily for each dose: one tablet from the LCZ696 pack and one tablet from the comparator pack. Patients in the no RASi strata will take only one tablet twice daily (LCZ696 or matching placebo). In the LCZ696 arm, patients will receive active LCZ696 in titrated doses from level 1 up to level 3 (50 mg, 100 mg and 200 mg twice daily orally). | Drug: sacubitril/valsartan<br>* Sacubitril/valsartan is available as 24 mg/26 mg, 49 mg/51 mg, 97 mg/103 mg, respectively in tablet form to be taken orally<br>Drug: Placebo to match enalapril<br>* Placebo to match enalapril 2.5 mg, 5 mg, 10 mg tablet form to be taken orally<br>Drug: Placebo to match valsartan<br>* Placebo to match valsartan 40 mg, 80 mg, 160 mg tablet form to be taken orally<br>|
| Active Comparator: Comparator<br>Patients randomized to the comparator arm will receive either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum). Patients in the ACE stratum randomized to comparator, will receive enalapril in titrated doses from level 1 up to level 3 (2.5 mg, 5 mg and 10 mg twice daily). Patients in the ARB stratum randomized to comparator will receive valsartan in titrated doses from level 1 up to level 3 (40 mg , 80 mg and 160 mg twice daily). Patients in the no RASi stratum randomized to comparator will receive LCZ696 matching placebo. | Drug: Enalapril<br>* Enalapril is available as 2.5 mg, 5 mg, and 10 mg tablet form to be taken orally<br>Drug: Valsartan<br>* Valsartan is available as 40 mg, 80 mg, 160 mg tablet form to be taken orally<br>Drug: Placebo to match sacubitril/valsartan<br>* Placebo to match LCZ696 50 mg, 100 mg, 200 mg tablet form to be taken orally<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) at Week 12 | To demonstrate that LCZ696 is superior to individualized medical therapy for comorbidities in reducing NT-proBNP from baseline at Week 12 in patients with HFpEF | Baseline, week 12 | 
| Change From Baseline in 6 Minute Walk Distance (6MWD) at Week 24 | Change from baseline in 6-minute walk distance (6MWD) will be reported at Week 24. The 6 MWT will be performed in accordance with the guidelines of the American Thoracic Society 2002. | Baseline, week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) at Week 24 | The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The CSS is a combined score based upon the clinical symptoms and physical function domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status. | Baseline, Week 24 | 
| Percentage of Patients With ≥ 5-points Deterioration in KCCQ Clinical Symptom Score(CSS) at Week 24 | Percentage of patients with KCCQ CSS deterioration ≥ 5-points will be reported at Week 24. The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The CSS is a combined score based upon the clinical symptoms and physical function domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status. | Baseline, Week 24 | 
| Percentage of Patients With ≥ 5-points Improvement in KCCQ Clinical Symptom Score(CSS) at Week 24 | Percentage of patients with KCCQ CSS improvement ≥ 5-points will be reported at Week 24. The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The CSS is a combined score based upon the clinical symptoms and physical function domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status. | Baseline, Week 24 | 
| Change From Baseline in NYHA Functional Class at Week 24 | NYHA classification is a subjective physician's assessment of patient's functional capacity and symptomatic status and can change frequently over time. Class I - No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF Class II - Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms of HF Class III - Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms of HF Class IV - Unable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest The NYHA class change will be analyzed as a three category ordinal variable with levels: improved, unchanged, and worsened, defined by at least one class improvement, no change, at least one class worsening, in NYHA class, respectively. | Baseline, week 24 | 
| Change From Baseline in The Short Form 36 Health Survey (SF-36) Physical Component Summary (PCS) Score at Week 24 | The SF-36 PCS score reflects the measure of quality of life based on the 36 questions which evaluate the person's physical, emotional, and mental status, including general health. Specifically, the SF-36 PCS score focuses on assessing the person's physical status. The score ranges from 0 to 100 with a higher score indicating a better status of physical wellbeing (range = 0 worst-100 best). | Baseline, Week 24 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Cardiovascular Diseases, Heart Failure, Heart failure with Preserved Ejection Fraction, NT-proBNP, 6 MWT, KCCQ, SF-36, NYHA Class, LCZ696, Renin Angiotensin System Inhibitors (RASi), Enalapril, Valsartan, Angiotensin-Converting Enzyme Inhibitors (ACEi), Angiotensin II Type 1 Receptor Blockers (ARB)