Safety and Efficacy of ARNI After LVAD ImplanT (SEAL-IT) Study

NCT04191681 | Recruiting Phase 4 FDA Drug

• 1 other identifier: 19-1132
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of the study is to evaluate how well tolerated and effective an angiotensin receptor-neprilysin inhibitor (sacubitril-valsartan) is in patients with contemporary durable continuous flow left ventricular assist device (CF-LVAD) implantation compared to usual care oral vasodilator therapy.

Conditions

Stage D Heart Failure

Keywords

continuous flow left ventricular assist device; sacubitril-valsartan; oral vasodilator; Heart failure

Outcome Measures

Primary Outcomes (2)

• Incidence of drug discontinuation from drug-related adverse events due to sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 3 months

  Incidence of drug discontinuation from drug-related adverse events due to sacubitril-valsartan versus standard-of-care oral vasodilator therapy evaluated at 3 months. Incidence of drug discontinuation is defined as the number of patients exposed to the drug with an adverse event over the total number of patients exposed to the drug. An adverse event is defined as any one of the following: acute kidney injury with eGFR decline \> 25% from baseline, hyperkalemia with potassium \> 5.5 mM, hypotension with mean arterial pressure (MAP) \< 60 mm Hg, angioedema, dizziness, and/or cough.

  3 months

• Time-averaged proportional change in NT-proBNP concentration (pg/mL) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 3 months

  Time-averaged proportional change in NT-proBNP concentration (pg/mL) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy evaluated at 3 months.

  3 months

Secondary Outcomes (17)

• Time-averaged proportional change in NT-proBNP concentration (pg/mL) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 6 and 12 months

  6 and 12 months

• Proportion of patients (%) with effective MAP control (65 to 85 mm Hg) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 3, 6 and 12 months

  3, 6 and 12 months

• Proportion of patients (%) on other cardiac medications with sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 3, 6 and 12 months relative to baseline

  3, 6 and 12 months

• Proportion of patients (%) in each New York Heart Association (NYHA) classification with sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 3, 6 and 12 months relative to baseline

  3, 6 and 12 months

• Proportion of patients (%) with heart failure readmissions with sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 6 and 12 months

  6 and 12 months

Study Arms (2)

Sacubitril-valsartan study arm

EXPERIMENTAL

1. Start medication-naïve patients on low-dose sacubitril-valsartan (24/26 mg PO BID) without a washout period per guideline and label recommendations. 2. Switch patients to equivalent dose sacubitril-valsartan if on prior ACE inhibitor (after a 36 hour washout period) or ARB therapy (after discontinuing one day prior). 3. If therapeutic range MAP (65 to 85 mm Hg), discontinue other oral vasodilator (e.g., hydralazine, isordil) or non-rate limiting dihydropyridine calcium channel blocker (non-DHP CCB, e.g., amlodipine) therapy on the day prior to sacubitril-valsartan initiation. If MAP \> 85 mm Hg, low-dose sacubitril-valsartan will be added with or without discontinuation of other oral vasodilator or non-DHP CCB per physician's discretion based on drug tolerability and maintenance of therapeutic range MAP. 4. Sacubitril-valsartan can be up-titrated every 2-4 weeks per standard practice guidelines per physician's discretion as above.

Drug: Sacubitril-Valsartan

Usual care (standard-of-care) arm

ACTIVE COMPARATOR

1\. Continue current regimen of patients on oral vasodilator therapy (e.g., ACE inhibitor, ARB, hydralazine, isordil), allowing for up-titration of the drug every 2-4 weeks per standard practice guidelines in keeping with physician's discretion as above. 2\. Start medication-naïve patients de novo on one of the oral vasodilators as below per guideline and label recommendations, allowing for up-titration of the drug every 2-4 weeks per standard practice guidelines in keeping with physician's discretion as above: i. ACE inhibitor: Enalapril 2.5 mg PO BID or Lisinopril 5 mg PO daily; ii. ARB: Valsartan 20 mg PO BID or Losartan 25 mg PO daily; iii. Other: Hydralazine 10 mg PO TID or Isordil 5 mg PO TID.

Drug: Usual care (standard-of-care) arm

Interventions

Sacubitril-Valsartan DRUG

Sacubitril-valsartan at low or equivalent dose to be initiated or added to patients randomized to this arm, and titrated up every 2-4 weeks, per standard practice guidelines and label recommendations per physician's discretion.

Also known as: Entresto

Sacubitril-valsartan study arm

Usual care (standard-of-care) arm DRUG

Other oral vasodilator therapy to be continued or initiated to patients randomized to this arm, and titrated up every 2-4 weeks, per standard practice guidelines and label recommendations per physician's discretion.

Also known as: Oral Vasodilator

Usual care (standard-of-care) arm

Eligibility Criteria

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

You may qualify if:

• Adults (age ≥ 18 years)
• Durable CF-LVAD for any indication
• NYHA II to IV classification
• LVEF \< 40%
• Written informed consent

You may not qualify if:

• Inability to comply with the conditions of the protocol
• Any patient with durable CF-LVAD who has any one of the following:
• i. symptomatic hypotension or MAP \< 60 mm Hg at randomization,
• ii. eGFR \< 30 mL/min/1.73 m2 at randomization,
• iii. potassium \> 5.4 mM at randomization,
• iv. history of angioedema at randomization,
• v. history of unacceptable side effects with ACE inhibitor, ARB, or sacubitril-valsartan therapy at randomization,
• vi. use of vasoactive agents (e.g., dobutamine, dopamine, epinephrine, norepinephrine, phenylephrine, vasopressin, nitroglycerin, nitroprusside, epoprostenol) or parenteral diuretics in 24 hours preceding randomization.

Sponsors & Collaborators

• The Cleveland Clinic: lead

Study Sites (1)

Cleveland Clinic

Cleveland, Ohio, 44195, United States

RECRUITING

Related Publications (4)

• Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Chang AR, Cheng S, Das SR, Delling FN, Djousse L, Elkind MSV, Ferguson JF, Fornage M, Jordan LC, Khan SS, Kissela BM, Knutson KL, Kwan TW, Lackland DT, Lewis TT, Lichtman JH, Longenecker CT, Loop MS, Lutsey PL, Martin SS, Matsushita K, Moran AE, Mussolino ME, O'Flaherty M, Pandey A, Perak AM, Rosamond WD, Roth GA, Sampson UKA, Satou GM, Schroeder EB, Shah SH, Spartano NL, Stokes A, Tirschwell DL, Tsao CW, Turakhia MP, VanWagner LB, Wilkins JT, Wong SS, Virani SS; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2019 Update: A Report From the American Heart Association. Circulation. 2019 Mar 5;139(10):e56-e528. doi: 10.1161/CIR.0000000000000659. No abstract available.

  PMID: 30700139 BACKGROUND

• McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004. doi: 10.1056/NEJMoa1409077. Epub 2014 Aug 30.

  PMID: 25176015 BACKGROUND

• Velazquez EJ, Morrow DA, DeVore AD, Duffy CI, Ambrosy AP, McCague K, Rocha R, Braunwald E; PIONEER-HF Investigators. Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure. N Engl J Med. 2019 Feb 7;380(6):539-548. doi: 10.1056/NEJMoa1812851. Epub 2018 Nov 11.

  PMID: 30415601 BACKGROUND

• Wachter R, Senni M, Belohlavek J, Straburzynska-Migaj E, Witte KK, Kobalava Z, Fonseca C, Goncalvesova E, Cavusoglu Y, Fernandez A, Chaaban S, Bohmer E, Pouleur AC, Mueller C, Tribouilloy C, Lonn E, A L Buraiki J, Gniot J, Mozheiko M, Lelonek M, Noe A, Schwende H, Bao W, Butylin D, Pascual-Figal D; TRANSITION Investigators. Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study. Eur J Heart Fail. 2019 Aug;21(8):998-1007. doi: 10.1002/ejhf.1498. Epub 2019 May 27.

  PMID: 31134724 BACKGROUND

MeSH Terms

Conditions

Heart Failure

Interventions

sacubitril and valsartan sodium hydrate drug combination; Standard of Care; Vasodilator Agents

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation; Cardiovascular Agents; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses

Study Officials

• Jerry D Estep, MD

  The Cleveland Clinic

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jerry D Estep, MD

CONTACT

216-444-7646; estepj@ccf.org

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: November 18, 2019
• First Posted: December 10, 2019
• Study Start: November 8, 2019
• Primary Completion: March 1, 2022
• Study Completion: December 1, 2022
• Last Updated: June 7, 2021

Record last verified: 2021-06

Locations

US (1)