PARAGON

Principal Investigator: John  Ryan
Keywords: Heart Failure , HFpEF , Structural Heart Disease Department: Cardiovascular Medicine
IRB Number: 00069054 Co Investigator: Nathan  Hatton
Specialty: Cardiology, Cardiology, Cardiology, Cardiology
Sub Specialties: General Cardiology, Heart Failure, Echocardiography
Recruitment Status: Completed

Contact Information

John Kirk
john.kirk@hsc.utah.edu
801-585-2944

Brief Summary

Study Objectives

Primary Objective

The primary objective of this 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 preserved EF (LVEF ≥45%).

Secondary Objectives

  • To compare LCZ696 to valsartan on changes in the clinical summary score for HF
    symptoms and physical limitations (as assessed by the Kansas City Cardiomyopathy
    Questionnaire [KCCQ]) at 8 months.
  • To compare LCZ696 to valsartan in improving NYHA functional classification at 8 months.
  • To compare LCZ696 to valsartan in delaying the time to first occurrence of a composite renal endpoint, defined as:
  1. renal death, or
  2. reaching end stage renal disease (ESRD), or
  3. ≥ 50% decline in estimated glomerular filtration rate (eGFR) relative to baseline
  • ​​To compare LCZ696 to valsartan in delaying the time to all-cause mortality.


Exploratory Objectives

  • To compare LCZ696 to valsartan in reducing the rate of the composite endpoint of CV death, total HF hospitalizations, total non-fatal strokes, and total non-fatal myocardial infarctions (MIs). Total is defined as the first and all recurrent events.
  • To compare LCZ696 to valsartan on changes in clinical composite assessment (assessedby NYHA, global patient assessment, and major adverse clinical events as defined by CV death and hospitalization for HF) at 8 months.
  • To compare LCZ696 to valsartan on patient global assessment at 8 months.
  • To compare LCZ696 to valsartan in reducing the rate of the composite endpoint of CV
    death, total non-fatal HF hospitalizations, total non-fatal strokes, and total non-fatal
    myocardial infarctions (MIs). Total is defined as the first and all recurrent events.
  • To compare LCZ696 to valsartan in delaying the time to new onset AF (NOAF).
  • To compare LCZ696 to valsartan on changes in the health related quality of life (assessed by total overall summary score, clinical summary score and individual scores of the sub-domains from the KCCQ [relative to treatment run-in epoch baseline scores and relative to randomized treatment epoch baseline scores] and total score of the EQ-5D for health status).
  • To compare LCZ696 to valsartan in reducing CV deaths and total worsening HF events. A subject will be defined as having a CV death or worsening HF event when the subject has:
  1. CV death or
  2. a hospitalization for HF or
  3. receives intravenous (IV) decongestive therapy (IV diuretics, IV neseritide or other natriuretic peptide, IV inotropes, and IV nitroglycerin [NTG]), and does not result in formal inpatient hospital admission, regardless of the setting (i.e. in an emergency room (ER) setting, in the physician’s office, an outpatient treatment facility, etc.).
  • To compare LCZ696 to valsartan on hospitalizations (all cause and cause specific).
  • To compare LCZ696 to valsartan on the number of days alive and out of hospital at 12 months.
  • To compare LCZ696 to valsartan in slowing the rate of decline in eGFR.
  • To compare LCZ696 to valsartan on delaying time to new onset diabetes mellitus (NODM).
  • To compare LCZ696 to valsartan on reducing healthcare resource utilization, e.g., number of days/ stays in intensive care unit (ICU), number of re-hospitalizations, and number of ER visits for HF.
  • To compare LCZ696 to valsartan on 30 day HF hospital readmissions and readmission rate after a prior HF hospitalization.
  • To compare LCZ696 to valsartan on the time between HF hospital readmissions.
  • To compare LCZ696 to valsartan on the profile of pre-specified biomarkers (e.g., cardiac, vascular,renal, collagen, metabolism, inflammatory, and/or other relevant biomarkers) from baseline to predefined time points in a subset of patients.
  • To characterize LCZ696 and valsartan pharmacokinetics (PK) at steady-state using population modeling and/or non-compartmental based methods in a subset of patients.
  • To compare LCZ696 to valsartan on the primary composite and secondary endpoints, andkey exploratory endpoints in ACEI-intolerant patients.
  • To compare LCZ696 to valsartan in evaluating the changes in cognitive function (assessed
    by the Mini-Mental State Examination [MMSE]) at 2 years.

Inclusion Criteria

Inclusion criteria

1. Written informed consent must be obtained before any assessment is performed.

2. ≥50 years of age, male or female.

3. LVEF >45% by echo during the screening epoch, or within 6 months prior to Visit 1 (any
local LVEF measurement made using echo only).

4. Symptom(s) of HF requiring treatment with diuretic(s) for at least 30 days prior to Visit 1.

5. Current symptom(s) of HF (NYHA class II-IV) at Visit 1.

6. Structural heart disease evidenced by at least one of the following echo findings (any local
measurement made during the screening epoch or within the 6 months prior to Visit 1):

a. left atrial (LA) enlargement defined by at least one of the following: LA width (diameter) ≥3.8
cm or LA length ≥5.0 cm or LA area ≥20 cm2 or LA volume ≥55 mL or LA volume
index ≥29 mL/m2

b. left ventricular hypertrophy (LVH) defined by septal thickness or posterior wall
thickness ≥1.1 cm

7. Patients with at least one of the following:

a. a HF hospitalization (defined as HF as the major reason for hospitalization within 9 months prior to Visit 1 and NT-proBNP > 200 pg/ml for patients not in AF for > 600 pg/ml for patients in AF on Visit 1 ECG

OR

b. NT-proBNP >300 pg/ml for patients not in AF or >900 pg/ml for
patients in AF on the Visit 1 ECG.

Exclusion Criteria

Exclusion criteria

1. Any prior echocardiographic measurement of LVEF <40%.

2. Acute coronary syndrome (including MI), cardiac surgery, other major CV surgery, or
urgent percutaneous coronary intervention (PCI) within the 3 months prior to Visit 1 or an
elective PCI within 30 days prior to Visit 1.

3. 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 ≥45%.

4. Current acute decompensated HF requiring augmented therapy with diuretics, vasodilators
and/or inotropic drugs.

5. Patients who require treatment with 2 or more of the following: an ACEI, an ARB or a
renin inhibitor.

6. History of hypersensitivity to any of the study drugs or to drugs of similar chemical
classes.

7. Patients with a known history of angioedema.

8. Probable alternative diagnoses that in the opinion of the investigator could account for the
patient’s HF symptoms (i.e., dyspnea, fatigue) such as significant pulmonary disease
(including primary pulmonary HTN), anemia or obesity. Specifically, patients with the
following are excluded:

a. severe pulmonary disease including chronic obstructive pulmonary disease (COPD)
(i.e., requiring home oxygen, chronic nebulizer therapy, chronic oral steroid therapy
or hospitalized for pulmonary decompensation within 12 months) or

b. hemoglobin (Hgb) <10 g/dl, or

c. body mass index (BMI) >40 kg/m2

9. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 halflives
of enrollment, whichever is longer.

10. Patients with any of the following:

a. systolic blood pressure (SBP) ≥180 mmHg at Visit 1, or

b. SBP >150 mmHg and < 180 mmHg at Visit 1 unless the patient is receiving 3 or more
antihypertensive drugs. Antihypertensive drugs include, but are not limited to, a
thiazide or other diuretic, mineralocorticoid (MRA), ACEI, ARB, beta blocker and
calcium channel blocker (CCB), or

c. SBP <110 mmHg at Visit 1, or

d. SBP <100 mmHg or symptomatic hypotension as determined by the investigator at
Visit 103 or Visit 199/201


11. Patients with history of any dilated cardiomyopathy, including peripartum cardiomyopathy,
chemotherapy induced cardiomyopathy, or viral myocarditis.

12. Evidence of right sided HF in the absence of left-sided structural heart disease.

13. Known pericardial constriction, genetic hypertrophic cardiomyopathy, or infiltrative
cardiomyopathy.

14. Clinically significant congenital heart disease that could be the cause of the patient’s
symptoms and signs of HF.

15. Presence of hemodynamically significant valvular heart disease in the opinion of the
investigator.

16. Stroke, transient ischemic attack, carotid surgery or carotid angioplasty within the 3
months prior to Visit 1.

17. Coronary or carotid artery disease or valvular heart disease likely to require surgical or
percutaneous intervention during the trial.

18. Life-threatening or uncontrolled dysrhythmia, including symptomatic or sustained
ventricular tachycardia and atrial fibrillation or flutter with a resting ventricular rate >110
beats per minute (bpm).

19. Patients with a cardiac resynchronization therapy (CRT) device.

20. Patients with prior major organ transplant or intent to transplant (i.e. on transplant list).

21. Any surgical or medical condition, which in the opinion of the investigator, may place the
patient at higher risk from his/her participation in the study, or is likely to prevent the
patient from complying with the requirements of the study or completing the study.

22. Any surgical or medical condition which might significantly alter the absorption,
distribution, metabolism, or excretion of study drugs, including but not limited to any of
the following:

• any history of pancreatic injury, pancreatitis or evidence of impaired pancreatic
function/injury within the last 5 years

23. Evidence of hepatic disease as determined by any one of the following: SGOT (AST) or
SGPT (ALT) values exceeding 3x the upper limit of normal (ULN), bilirubin >1.5 mg/dl
at Visit 1.

24. Patients with one of the following:

a. eGFR <30 mL/min/1.73m2 as calculated by the Modification in Diet in Renal Disease
(MDRD) formula at Visit 1 or

b. eGFR <25 mL/min/1.73m2 at Visit 103 or Visit 199/201, or

c. eGFR reduction ≥35% (compared to Visit 1) at Visit 103 or Visit 199/201

25. Presence of known functionally signficant bilateral renal artery stenosis

26. Patients with either of the following:

a. serum potassium >5.2 mmol/L (mEq/L) at Visit 1

b. serum potassium >5.4 mmol/L (mEq/L) at Visit 103 or Visit 199/201

27. History or presence of any other disease with a life expectancy of <3 years

28. History of non-compliance to medical regimens and patients who are considered potentially unreliable

29. History or evidence of drug or alcohol abuse within the last 12 months

30. Persons directly involved in the execution of this protocol

31. History of malignancy of any organ system (other than localized basal or squamous cell carcinoma of the skin or localized prostate cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.

32. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female
after conception and until the termination of gestation, confirmed by a positive human
chorionic gonadotropin (hCG) laboratory test.

33. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
during dosing and for 7 days off study drug. Highly effective contraception methods
include:

  • Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
  • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
  • Male sterilization (at least 6 months prior to Visit 1). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject
  • Combination of any two of the following (a+b or a+c, or b+c), according to country approvals and availability:

a. use of oral, injected or implanted hormonal methods of contraception or other
forms of hormonal contraception that have comparable efficacy (failure rate
<1%), for example hormone vaginal ring or transdermal hormone contraception.

b. placement of an intrauterine device (IUD) or intrauterine system (IUS)

c. barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository

  • In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
  • Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.