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Pulmonary Artery Pressure Reduction With ENTresto (Sacubitril/Valsartan) (PARENT)

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ClinicalTrials.gov Identifier: NCT02788656
Recruitment Status : Recruiting
First Posted : June 2, 2016
Last Update Posted : January 18, 2018
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
Akshay Desai, MD, Brigham and Women's Hospital

Brief Summary:
This pilot study will assess the impact of sacubitril/valsartan (trade name Entresto) on the elevated pulmonary artery pressures in patients with heart failure with reduced ejection fraction, measured using a previously implanted hemodynamic monitoring device (CardioMEMS).

Condition or disease Intervention/treatment Phase
Congestive Heart Failure Device: Implantable Hemodynamic Monitor Drug: Angiotensin-Converting Enzyme Inhibitor Drug: Angiotensin II Type 1 Receptor Blocker Drug: sacubitril/valsartan Not Applicable

Detailed Description:

Angiotensin-converting enzyme inhibitors (ACEi) have been a cornerstone treatment for patients with heart failure and reduced ejection fraction (HFrEF) for over 25 years. They are included in every major set of guidelines for HFrEF management. Angiotensin receptor blockers (ARB's, such as valsartan) have similarly been shown to decrease the mortality rate of patients with HFrEF for patients who are unable to tolerate ACEi therapy.

The newest neurohormonal therapy approved for heart failure (August 2015) is sacubitril/valsartan (trade name Entresto). This medication is the first of a new family of agents (ARNI = angiotensin receptor antagonist with neprilysin inhibitor), combining the approved angiotensin receptor blocker valsartan with sacubitril, an inhibitor of neprilysin, which is a neutral endopeptidase that degrades endogenous vasoactive peptides. Treatment with sacubitril increases circulating levels of natriuretic peptides, which have been shown to facilitate natriuresis and vasodilation. Although the precise mechanisms responsible for benefit in heart failure remain unclear, sacubitril/valsartan may reduce the fluid retention and vasoconstriction that contribute to heart failure symptoms, and may also decrease apoptosis and remodeling that lead to disease progression. There is limited data about the incremental acute and long-term hemodynamic effects of composite neprilysin/angiotensin-receptor inhibitors over enalapril, and these data may provide important mechanistic insights.

Progress in HF management outside the hospital has included validation of a strategy of ongoing monitoring of pulmonary artery pressures every day from home via a monitor implanted in a distal pulmonary artery, the CardioMEMS device. The information is transmitted to a website where it is reviewed by the HF team, who can intervene to adjust diuretics and other medications by phone to avert decompensation and re-hospitalization. The device received FDA approval in mid 2014, and is now being implanted in many cardiac catheterization laboratories, including at Brigham and Women's Hospital. The pressure information is reviewed regularly by the HF management team who are in regular contact with the patient to aid in management decisions.

In summary, this pilot study will assess the impact of sacubitril/valsartan, an approved drug for heart failure with reduced ejection fraction (HFrEF) on the elevated pulmonary artery pressures measured using an implanted monitoring device that is also approved for such patients. Both the medication and the device will be used according to approved indications.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: PARENT Trial Pilot Pulmonary Artery Pressure Reduction With ENTresto (Sacubitril/Valsartan)
Study Start Date : September 2016
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : March 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure
Drug Information available for: Valsartan

Arm Intervention/treatment
Experimental: Group A
Group A will receive sacubitril/valsartan + placebo for weeks 1-12. and then sacubitril/valsartan only for weeks 13-32. All subjects in Group A will also receive longitudinal pulmonary artery pressure monitoring using a previously placed implantable hemodynamic monitor (CardioMEMS device).
Device: Implantable Hemodynamic Monitor
The CardioMEMS device is an implantable pulmonary artery pressure monitor that is FDA-approved for use in patients with symptomatic heart failure and previous heart failure hospitalization. Patients eligible for this study are those with an already implanted CardioMEMS device.
Other Name: CardioMEMS

Drug: sacubitril/valsartan
Angiotensin-neprilysin inhibitor that is now FDA-approved and guideline-directed therapy for patients with symptomatic heart failure and reduced ejection fraction despite treatment with an ACE-inhibitor/Angiotensin-Receptor Blocker
Other Name: Entresto

Active Comparator: Group B

Group B will receive an Angiotensin-Converting Enzyme Inhibitor (ACEi) or Angiotensin II Type 1 Receptor Blocker (ARB) + placebo for weeks 1-6 (depending on previous background therapy) and then switch to sacubitril/valsartan + placebo for weeks 7-12.

Group B will then receive sacubitril/valsartan only for weeks 13-32. All subjects in Group B will also receive longitudinal pulmonary artery pressure monitoring using a previously placed implantable hemodynamic monitor (CardioMEMS device).

Device: Implantable Hemodynamic Monitor
The CardioMEMS device is an implantable pulmonary artery pressure monitor that is FDA-approved for use in patients with symptomatic heart failure and previous heart failure hospitalization. Patients eligible for this study are those with an already implanted CardioMEMS device.
Other Name: CardioMEMS

Drug: Angiotensin-Converting Enzyme Inhibitor
Conventional, guideline-directed therapy for heart failure and reduced ejection fraction
Other Name: ACE inhibitor, ACEi

Drug: Angiotensin II Type 1 Receptor Blocker
Conventional, guideline-directed therapy for heart failure and reduced ejection fraction in ACE-inhibitor intolerant patients
Other Name: Angiotensin Receptor Blocker, ARB

Drug: sacubitril/valsartan
Angiotensin-neprilysin inhibitor that is now FDA-approved and guideline-directed therapy for patients with symptomatic heart failure and reduced ejection fraction despite treatment with an ACE-inhibitor/Angiotensin-Receptor Blocker
Other Name: Entresto




Primary Outcome Measures :
  1. Difference between mean change in mean pulmonary artery pressure (PAPm) with sacubitril/valsartan compared to the mean change in PAPm with continued ACEi/ARB [ Time Frame: Baseline, 6 weeks ]
  2. The acute change in PAPm after the first administration of sacubitril/valsartan [ Time Frame: Baseline, 3 hours (after first dose of sacubitril/valsartan) ]

Secondary Outcome Measures :
  1. Mean change in PAPm in both groups on sacubitril/valsartan [ Time Frame: 20 weeks (weeks 12 to 32 of the study) ]
  2. The difference between mean change in PAPm from baseline on sacubitril/valsartan compared to ACEI/ARB [ Time Frame: 6 weeks (week 1-6 of the study for group A, weeks 7-12 for group B) ]
  3. Determine the change in distance walked during a standard 6 minute walk test from baseline [ Time Frame: Baseline, 6 weeks, 12 weeks and 32 weeks ]

    There will be 3 comparisons:

    1. 6 weeks of Entresto vs 6 weeks of continued ACEI/ARB (Group A compared to B at 6 weeks)
    2. Baseline on ACEI/ARB compared to 6 weeks on Entresto (Groups A and B combined)
    3. 12 weeks on Entresto compared to 32 weeks on Entresto in longitudinal study (all pts)

  4. Determine the change in NT-proBNP and the BNP/NT-proBNP ratio [ Time Frame: Baseline, 6 weeks, 12 weeks and 32 weeks ]

    There will be 3 comparisons:

    1. 6 weeks of Entresto vs 6 weeks of continued ACEI/ARB (Group A compared to B at 6 weeks)
    2. Baseline on ACEI/ARB compared to 6 weeks on Entresto (Groups A and B combined)
    3. 12 weeks on Entresto compared to 32 weeks on Entresto in longitudinal study (all pts)


Other Outcome Measures:
  1. The relationship of change in PAPm to change in the questions in the Kansas City Cardiomypathy Questionnaire (KCCQ) 3,7,8,9 [ Time Frame: Baseline, 32 weeks (testing performed at intervals during study) ]
  2. Mean change in total daily diuretic dose while on sacubitril/valsartan [ Time Frame: Baseline, 32 weeks (testing performed at intervals during study) ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients able to provide written informed consent
  2. Patients ≥18 years of age, male or female, in NYHA Class II- III HF, previously hospitalized for HFrEF with LVEF < 35% (measured within the past year), and who have no subsequent LVEF>35%.
  3. Systolic BP > 95 mm Hg at most recent clinical assessment.
  4. Stable, ambulatory patients without the need for change in diuretics and other HF drugs (RAS blockers, beta blockers or mineralocorticoid receptor blockers) during the past 5 days
  5. CardioMEMS HF System implanted for NYHA Class III HF. Patient transmitting information regularly and system functioning appropriately.
  6. NT-proBNP > 500 pg/ml within 90 days of CardioMEMS implantation.
  7. Average PAPm >20mm Hg during the 7 days prior to enrollment, including at least 4 daily measurements.
  8. Women of childbearing age must be on highly effective method of contraception

Exclusion Criteria:

  1. Treatment with vasodilators (other than nitrates, hydralazine) and/or IV inotropic drugs.
  2. Entresto taken within the past 30 days.
  3. History of hypersensitivity, intolerance or angioedema to previous renin-angiotensin system (RAS) blocker, ACE inhibitor, ARB, or Entresto.
  4. eGFR < 30 ml/min/1.73 m2 as measured by the simplified MDRD formula.
  5. Serum potassium > 5.5 mmol/L.
  6. Acute coronary syndrome, stroke, transient ischemic attack, cardiovascular surgery, PCI, or carotid angioplasty within the preceding 3 months.
  7. Coronary or carotid artery disease likely to require surgical or percutaneous intervention within 3 months after trial entry.
  8. Non-cardiac condition(s) as the primary cause of dyspnea.
  9. Implantation of a cardiac resynchronization therapy device (CRT/D) within the pr preceding 3 months or intent to implant a CRT/D, which may alter the pressures during the course of the study.
  10. History of heart transplantation, placement of an LVAD, listing for Status IA for cardiac transplantation or planned placement of an LVAD within 3 months following randomization.
  11. Documented untreated ventricular arrhythmia with syncopal episodes within the prior 3 months.
  12. Symptomatic bradycardia or second or third degree heart block without a pacemaker.
  13. Hepatic dysfunction, as evidenced by total bilirubin > 3 mg/dl.
  14. Pregnancy
  15. Women who are breastfeeding
  16. Chronic lithium use

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02788656


Contacts
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Contact: Lynne W Stevenson, MD 617-732-7406 lstevenson@partners.org
Contact: Akshay S Desai, MD 617-732-7406 adesai@partners.org

Locations
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United States, Massachusetts
Brigham and Women's Hospita Recruiting
Boston, Massachusetts, United States, 02115
Contact: Lynne Stevenson, MD    617-732-5500    lstevenson@partners.org   
Contact: Akshay Desai, MD    917-732-5500    adesai@partners.org   
Sponsors and Collaborators
Brigham and Women's Hospital
Novartis
Investigators
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Study Director: Lauren G Gilstrap, MD Brigham & Womens' Hospital

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Responsible Party: Akshay Desai, MD, Principal Investigator (Interim), Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT02788656     History of Changes
Other Study ID Numbers: 2016P000831/MGH
First Posted: June 2, 2016    Key Record Dates
Last Update Posted: January 18, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Akshay Desai, MD, Brigham and Women's Hospital:
heart failure
neprilysin
implantable hemodynamic monitor
angiotensin-receptor blocker
angiotensin-converting enzyme inhibitor

Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases
Valsartan
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
LCZ 696
Enzyme Inhibitors
Angiotensinogen
Angiotensin-Converting Enzyme Inhibitors
Angiotensin II
Giapreza
Antihypertensive Agents
Molecular Mechanisms of Pharmacological Action
Protease Inhibitors
Vasoconstrictor Agents
Serine Proteinase Inhibitors