Pulmonary Artery Pressure Reduction With ENTresto (Sacubitril/Valsartan)

NCT02788656 | Terminated Phase 4 Results

• 1 other identifier: 2016P000831/MGH
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

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).

Conditions

Congestive Heart Failure

Keywords

heart failure; neprilysin; implantable hemodynamic monitor; angiotensin-receptor blocker; angiotensin-converting enzyme inhibitor

Outcome Measures

Primary Outcomes (2)

• Difference Between Mean Change in Mean Pulmonary Artery Pressure (PAPm) With Sacubitril/Valsartan Compared to the Mean Change in PAPm With Continued ACEi/ARB

  Change in mean PAP in group A versus group B

  Baseline, 6 weeks

• The Acute Change in PAPm After the First Administration of Sacubitril/Valsartan

  Change in PAPm at 3 hours

  Baseline, 3 hours (after first dose of sacubitril/valsartan)

Secondary Outcomes (4)

• Mean Change in PAPm in Both Groups on Sacubitril/Valsartan

  20 weeks (weeks 12 to 32 of the study)

• The Difference Between Mean Change in PAPm From Baseline on Sacubitril/Valsartan Compared to ACEI/ARB

  6 weeks (week 1-6 of the study for group A, weeks 7-12 for group B)

• Determine the Change in Distance Walked During a Standard 6 Minute Walk Test From Baseline

  Baseline, 6 weeks

• Change in NT-proBNP

  Baseline

Other Outcomes (2)

• The Relationship of Change in PAPm to Change in the Questions in the Kansas City Cardiomypathy Questionnaire (KCCQ) 3,7,8,9

  Baseline, 32 weeks (testing performed at intervals during study)

• Mean Change in Total Daily Diuretic Dose While on Sacubitril/Valsartan

  Baseline, 32 weeks (testing performed at intervals during study)

Study Arms (2)

Group A

EXPERIMENTAL

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; Drug: sacubitril/valsartan

Group B

ACTIVE COMPARATOR

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; Drug: Angiotensin-Converting Enzyme Inhibitor; Drug: Angiotensin II Type 1 Receptor Blocker; Drug: sacubitril/valsartan

Interventions

Implantable Hemodynamic Monitor DEVICE

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.

Also known as: CardioMEMS

Group A; Group B

Angiotensin-Converting Enzyme Inhibitor DRUG

Conventional, guideline-directed therapy for heart failure and reduced ejection fraction

Also known as: ACE inhibitor, ACEi

Group B

Angiotensin II Type 1 Receptor Blocker DRUG

Conventional, guideline-directed therapy for heart failure and reduced ejection fraction in ACE-inhibitor intolerant patients

Also known as: Angiotensin Receptor Blocker, ARB

Group B

sacubitril/valsartan DRUG

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

Also known as: Entresto

Group A; Group B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients able to provide written informed consent
• 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%.
• Systolic BP \> 95 mm Hg at most recent clinical assessment.
• 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
• CardioMEMS HF System implanted for NYHA Class III HF. Patient transmitting information regularly and system functioning appropriately.
• NT-proBNP \> 500 pg/ml within 90 days of CardioMEMS implantation.
• Average PAPm \>20mm Hg during the 7 days prior to enrollment, including at least 4 daily measurements.
• Women of childbearing age must be on highly effective method of contraception

You may not qualify if:

• Treatment with vasodilators (other than nitrates, hydralazine) and/or IV inotropic drugs.
• Entresto taken within the past 30 days.
• History of hypersensitivity, intolerance or angioedema to previous renin-angiotensin system (RAS) blocker, ACE inhibitor, ARB, or Entresto.
• eGFR \< 30 ml/min/1.73 m2 as measured by the simplified MDRD formula.
• Serum potassium \> 5.5 mmol/L.
• Acute coronary syndrome, stroke, transient ischemic attack, cardiovascular surgery, PCI, or carotid angioplasty within the preceding 3 months.
• Coronary or carotid artery disease likely to require surgical or percutaneous intervention within 3 months after trial entry.
• Non-cardiac condition(s) as the primary cause of dyspnea.
• 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.
• 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.
• Documented untreated ventricular arrhythmia with syncopal episodes within the prior 3 months.
• Symptomatic bradycardia or second or third degree heart block without a pacemaker.
• Hepatic dysfunction, as evidenced by total bilirubin \> 3 mg/dl.
• Pregnancy
• Women who are breastfeeding

Sponsors & Collaborators

• Brigham and Women's Hospital: lead
• Novartis: collaborator

Study Sites (1)

Brigham and Women's Hospita

Boston, Massachusetts, 02115, United States

Location

MeSH Terms

Conditions

Heart Failure

Interventions

Angiotensin-Converting Enzyme Inhibitors; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; sacubitril and valsartan sodium hydrate drug combination

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses

Limitations and Caveats

Study terminated after enrollment of 4 patients due to lack of enrollment. Limited number of participants limits meaningful generalization of study results.

Results Point of Contact

• Title: Akshay Desai
• Organization: Brigham and Women's Hospital

adesai@bwh.harvard.edu

617-732-7046

Study Officials

• Lauren G Gilstrap, MD

  Brigham & Womens' Hospital

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 23, 2016
• First Posted: June 2, 2016
• Study Start: September 1, 2016
• Primary Completion: November 9, 2018
• Study Completion: November 9, 2018
• Last Updated: February 17, 2020
• Results First Posted: February 17, 2020

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)