A multicenter, randomized, double-blind, parallel group, active-controlled study to evaluate the efficacy and safety of LCZ696 compared to valsartan, on morbidity and mortality in heart failure patients (NYHA Class II-IV) with preserved ejection fraction (CLCZ696D2301)

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%, with 45% being the most common cut-off. 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
(CAD). 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 CAD.
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 objective of the current study is to compare LCZ696 to valsartan in
reducing the rate of the composite endpoint of CV death and total (first and
recurrent) HF hospitalizations, in HF patients (NYHA Class II-IV) with EF *45%.

The primary objective:
To compare LCZ696 to valsartan in reducing the rate of the composite endpoint
of cardiovascular death and
total (first and recurrent) heart failure (HF) hospitalizations, in HF patients
(NYHA Class II-IV) with preserved EF (LVEF *45%). The
treatment arm with the lower rate of events will be deemed as having a
successful response.

The secondary objectives:
- Evaluation of the changes in the clinical summary score for HF symptoms and
physical limitations (as assessed by Kansas
City Cardiomyopathy Questionnaire [KCCQ]) at 8 months.
- Evaluation of change from baseline to Month 8 in NYHA functional class.
- Evaluation of the time to onset of first composite renal endpoint.
- Evaluation of the time to all cause death.

Multi-center, randomized, double-blind, parallel group phase III study with
active comparator.
Screening period of up to 2 weeks. Single-blind, run-in period 3-8 weeks
(treatment with LCZ696 and valsartan separately).
Thereafter randomization (1:1) to:
1. LCZ696 200 mg bid,
2. Valsartan 160 mg bid.
Back-titration if dose is not tolerated.
Continuation of regular treatment against heart failure (except ACE-,
angiotensin - and renin inhibitors)
Event-driven study.
Total study duration estimated at 24-57 months (depending on time point of
study start).
Approx 4.600 patients.

Treatment with LCZ696 or valsartan.

Risk:
Adverse effects of study medication. Change of HF medication.

Burden:
Up to treatment month 1 (5-7 visits):
- physical examination 3x
- vital signs: 3-5x
- blood draw (5-10 ml): 5x
- urine test: 3x
- pregnancy test: 4-6x
- ECG: 3x
- Echocardiogram:1x
- 2 questionnaires: 1 and 2x
- MMSE: 1x

After treatment month 1 (visit every 16 weeks (1st year) to 24 weeks (after 1st
year):
- physical examination each visit
- vital signs: each visit
- blood draw (5-10 ml): each visit
- urine test: annually
- pregnancy test: first year 4x, bi-annually thereafter
- ECG: annually
- 2 questionnaires: first year 3x, annually thereafter
- MMSE: annually and at final visit

Optional Biomarker Substudy: Blood- and urine tests, 5x (30 ml in total)
combined with other blood draws.

Optional Pharmacogenetic and Pharmacogenomic substudy:
Farmacogenetic: blood test 1x (10 ml)
Farmacogenomic: blood test 2x (13 ml)