A multicenter study to evaluate safety and tolerability in patients with chronic heart failure and reduced ejection fraction from PARADIGM-HF receiving open label LCZ696

In Europe, the prevalence of HF is between 2 and 3%, and in the elderly is
estimated between 10 to 20%. Medical therapies targeted at improving outcomes
in HF with a low EF have been well studied over the past two decades, leading
to an improvement in survival as well as a decrease in morbidity, mostly in the
form of decreased re-hospitalization for HF. These medical therapies include
angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers
(ARBs), *-blockers and mineralocorticoid antagonists. However, despite advances
in therapies, the outlook remains poor. Overall, 50% of patients die within 4
years and 40% of patients admitted to the hospital with HF die or are
readmitted within 1 year. Thus, HF still represents a major cause of cardiac
mortality and morbidity with a clear need for better therapy.

LCZ696 is a first-in-class, angiotensin receptor neprilysin inhibitor (ARNI)
being developed for the treatment of heart failure.
The PARADIGM-HF study (protocol CLCZ696B2314) was a randomized, double-blind,
Phase III outcome trial that evaluated the efficacy and safety of LCZ696 versus
enalapril in 8,436 heart failure patients with reduced ejection fraction. The
primary endpoint was time to first occurrence of either cardiovascular (CV)
death or heart failure hospitalization, and the trial was also designed to be
able to detect a significant
difference in CV death alone.
On March 28, 2014 the Data Monitoring Committee (DMC) for PARADIGM-HF reviewed
efficacy and safety data for the third interim analysis with approximately
1,027 CV death events and concluded that LCZ696 was superior to enalapril in
delaying the time to first occurrence of the primary composite endpoint and
most importantly, in delaying the time to the CV death component as well. Based
on these results and an acceptable safety profile, the DMC unanimously
recommended early closure of the study, which was agreed by the study Executive
Committee and Sponsor of the trial.
In order to provide patients the opportunity to receive life-saving treatment
with LCZ696 and to collect safety data, this open-label, safety and
tolerability study will offer enrollment to all surviving, eligible patients
that had been randomized in PARADIGM-HF.

The primary objective of this study is to continue to evaluate the safety and
tolerability of LCZ696 in heart failure patients from PARADIGM-HF receiving
open-label investigational drug.
There are no secondary objectives for this study.

This trial is a multicenter, open-label follow-up to PARADIGMHF, which
evaluated the morbidity, mortality and safety of LCZ696 compared to enalapril
in patients with chronic heart failure and reduced ejection fraction. Prior to
enrollment in this trial, all patients will have been enrolled and treated with
double-blind study medication in the PARADIGM-HF study and most will have
transitioned to an ACEI or ARB. Investigators will be offered the option to
initiate open-label treatment with LCZ696 for any PARADIGM-HF patient that
meets the eligibility criteria. Consenting patients will undergo a washout
period, if necessary (36 hr for patients on ACEIs only), be up-titrated to the
maximally tolerated dose of LCZ696 and scheduled for visits to dispense study
drug and assess safety and tolerability at 6-month intervals until the
conclusion of the trial.

Treatment with LCZ696.

Burden and risks of participation is the chance of side effects from the study
medication and inconveniences of blood sampling.

The known most common side effects of the study medication include:
Dizziness, and postural dizziness (get dizzy when you stand up), vertigo,
syncope (transient loss of consciousness), headache, cough, diarrhea, and
nausea, worsening kidney function, fatigue, feeling of physical weakness,
hypersensitivity (such as skin rushes, urticaria, etc.), liver disorder,
hypokalemia and hyperkalemia (decreased and increased blood potassium levels,
respectively) hypotension, and orthostatic hypotension (lowering of blood
pressure when you stand up). Angioedema (localized swelling of the head, neck,
throat, tongue, genitalia and/or intestines) have also been reported.

Assessments:
Length: 1x (visit 1)
Weight: Every visit (max 9x).
Physical examination: Every visit (max 9x)
Blood pressure and pulse: Every visit (max 9x)
Urinalysis: 5x (in women, pregnancy)
Blood tests: Each visit (max 9x), including 2 x serum preganancy test in women.

During treatment with LCZ696 there is prohibited medication (such as ACE
inhibitors, ARBs and renin inhibitors).