A 24-week, randomized, double-blind, multi-center, parallel group, active controlled study to evaluate the effect of 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

Heart failure (HF) prevalence in Europe ranges between 2 and 3% and between 10
and 20% in the elderly.
Studies in HF with normal ejection fraction (EF) have defined preserved EF
(pEF) with a cut-off of 40-50%. HFpEF accounts for approximately half of HF
cases and is associated with substantial morbidity and mortality. Compared with
HFrEF (HF with reduced EF), patients with HFpEF are older, predominantly
female, more likely to have hypertension and atrial fibrillation (AF), and less
likely to have coronary artery disease (CAO). Mechanisms implicated in HFpEF
include abnormal diastolic function with resultant increase in ventricular
filling pressures, increased vascular stiffness, and abnormal systolic function
despite preserved EF. Recently, these individuals have also been shown to have
an impaired natriuretic and renal endocrine response to acute volume expansion
early in the development.
Unlike HFrEF, no pharmacologic therapies have shown benefit in HFpEF. Current
guidelines focus on treating co-morbid conditions, such as diabetes mellitus,
hypertension, renal insufficiency, AF and CAO.
LCZ696 is a first-in-class, angiotensin receptor neprilysin inhibitor.
Following ingestion, LCZ696 provides systemic exposure to AHU377 ,a neprilysin
(NEP) inhibitor and valsartan, an angiotensin receptor blocker. Prior research
had suggested that the potential clinical benefits from NEP inhibition can only
be leveraged if the RAS system is inhibited concomitantly . It is anticipated
that LCZ696 may provide clinical benefits to patients with CV disease,
including HF and hypertension, in which vasoconstriction, volume expansion and
target organ damage play a key role in pathophysiology.

The primary objectives of this study are:
- To demonstrate that LCZ696 is superior to individualized medical therapy for
comorbidities in reducing NT proBNP from baseline after 12 weeks of treatment
in patients with HFpEF.
- To demonstrate that LCZ696 is superior to individualized medical therapy for
comorbidities in improving exercise capacity as assessed by the six-minute walk
test (6MWT) at Week 24 in a subset of patients

Secundary:
To compare LCZ696 to individualized medical therpay for comorbidities for:
- Mean change from baseline in Kansas City Cardiomyophathy Questionnaire (KCCQ)
clinical summary score (CSS) at week 24
- proportion of patients with equal or larger than 5 points change in KCCQ CSS
at week 24
- improvement in NYHA functional class at week 24
- Improvement in symptoms as assessed by the SF-36 physical component summary
(PCS) score at week 24.

Multi-center ,randomized, double-blind, parallel group phase Ill study with
active comparator.
Screening period of up to 2 weeks.
Randomisation is determined by the treatment, which the patient receives before
start of the study:
When previously treated with ACE, randomisation will be between
enalapril/LCZ696.
When previously treated with valsartan/ARB, then valsartan/LCZ696
When no previous treatment with ACE or ARB has been given, it will be between
LCZ/placebo.
Blinding will be maintained because all parties involved will not know whether
LCZ or comparator will be provided.

Treatment will be twice daily:
LCZ696: 200 mg
Valsartan: 160 mg
Enalapril: 10 mg
Matching Placebo

Back-titration if dose is not tolerated.
Continuation of reguiar treatment against heart failure (except ACE-,
angiotensin - and renin inhibitors)
Total study duration estimated at 26 weeks
Approx 2500 patients.

No added risk will be applicable for subjects in the Placebogroup, since
regular therapy will be continued. When subjects will be placed in the
placebogroup, no risk of undertreatment is applicable, since their treatment
will be continued. When the subjects are placed in the LCZ696 group, a
treatment will be added.
At this timepoint, no study has proven ACE/ARB to be of additional value for
HF-pEF. ACE/ARB is routinely prescribed for other reasons (mainly
hypertension). When this is not applicable, a more conservative treatment with
diuretics etc is chosen.

Treatment with LCZ696, enalapril, valsartan or placebo.

Adverse effects of study medication and study procedures.
Change of HF medication.

- Physical examination 9x
- Vital signs: 9x
- Blood draw (10-12 ml}:9x
- Pregnancy test, if applicable (in urine/plasma): 9x
- ECG: 3x
- Echocardiogram:1x
- Completion of questionnaires: 6x
- 6MWT: 4x