NATriuretic Response to Expansion and dIUretics in huMans With Heart Failure

NCT04235062 | Completed

• 1 other identifier: CHF201901
• Study Type: interventional
• Target: 229
• Locations: 3 countries
• Sites: 13

Brief Summary

NATRIUM-HF is a multicenter, non-randomized, pre-post intervention study designed to assess renal response to intravascular fluid expansion and diuretics after sacubitril/valsartan (Entresto®) in euvolemic heart failure patients with reduced ejection fraction. Approximately 230 eligible patients will attend one visit prior to and visits 2 and 3 months after starting Entresto®. At each visit, the patient's responses to extravascular fluid expansion with Ringer's solution and to a loop diuretic bolus will be measured. Biomarkers measured in blood and urine samples will include natriuretic peptides (NP) B-type NP (BNP) and N-terminal proBNP (NT-proBNP), NP fragments, neprilysin activity and concentration, and other biomarkers related to heart failure.

Conditions

Heart Failure

Outcome Measures

Primary Outcomes (2)

• Natriuretic response to intravascular volume expansion

  The average change in natriuretic response to intravascular volume expansion from before to 2 and 3 months after initiation of sacubitril/valsartan therapy. Natriuretic response is defined as the cumulative sodium excretion over the 3 hours of intravascular volume expansion and follow up.

  2 and 3 months

• Natriuretic response to IV diuretic administration

  The average change in cumulative natriuresis during the first 3 h following the bolus IV furosemide administration from before to 2 and 3 months after initiation of sacubitril/valsartan therapy.

  2 and 3 months

Secondary Outcomes (4)

• Natriuretic peptide (NP) response to intravascular volume expansion

  2 and 3 months

• Natriuretic peptide response to IV diuretic administration

  2 and 3 months

• Diuretic response

  2 and 3 months

• 4. Changes in dyspnea as measured by a 1-10 scale in response to intravascular fluid expansion, and diuretic administration

  2 and 3 months

Study Arms (1)

Fluid Expansion and Diuretic Challenge

EXPERIMENTAL

Subject receive intravenous infusion of Ringer's (8.6 g/L sodium chloride, 0.33 g/L calcium chloride, 0.3 g/L potassium chloride) solution, followed by diuretic challenge with 40mg Furosemide intravenous bolus.

Drug: Ringer's (8.6 g/L sodium chloride, 0.33 g/L calcium chloride, 0.3 g/L potassium chloride) Solution; Drug: Intravenous Bolus Furosemide

Interventions

Ringer's (8.6 g/L sodium chloride, 0.33 g/L calcium chloride, 0.3 g/L potassium chloride) Solution DRUG

A 2-hour of infusion of Ringer's (8.6 g/L sodium chloride, 0.33 g/L calcium chloride, 0.3 g/L potassium chloride) solution will be given following completion of the first 3-hour urine collection period: 0.5 liter infused over 10 min followed by 0.5 liter infused over 1 hour 50 minutes.

Also known as: Intravascular fluid expansion

Fluid Expansion and Diuretic Challenge

Intravenous Bolus Furosemide DRUG

Following completion of the second 3-hour urine collection period and after the second set of blood and urine samples are obtained, 40 mg of furosemide will be given as an IV bolus.

Also known as: Loop diuretic administration

Fluid Expansion and Diuretic Challenge

Eligibility Criteria

• Age: 18 Years - 79 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female patients ≥ 18 and \< 80 years of age.
• Ambulatory patients with a diagnosis of stable NYHA class II heart failure with left ventricular ejection fraction \<40 %, for whom sacubitril/valsartan (Entresto®) is indicated as recommended by ESC guidelines and are about to be switched to Entresto® therapy.
• Stable oral doses of ACEi or ARB, beta-blocker, mineralocorticoid antagonist (MRA), and loop diuretic (up to 120 mg daily furosemide or equivalent\*) for \> 3 months prior to Screening, except where intolerance or contraindication documented.
• Stable HF without any recent exacerbation of symptoms and/or signs of HF, admission for HF, unplanned clinic visit or emergency service visit for HF or need for significant up titration or new administration of oral or IV diuretics, renin-angiotensin system (RAAS) blockers (including ACEi, ARB, and/or MRA) and/or beta blockers for \> 3 months.
• Euvolemia as defined by no signs of congestion (pulmonary rales or \>1+ peripheral edema) by physical examination.
• Written informed consent to participate in the study.
• Ability to comply with all study requirements, without major morbidities compromising the patient's ability to participate and understand the study for 90 days.

You may not qualify if:

• Significant pulmonary disease contributing substantially to the patients' dyspnea such as FEV1\< 1 liter or need for chronic steroid therapy.
• Myocardial infarction, unstable angina, ICD or CRT implantation, or cardiac surgery, including percutaneous transluminal coronary intervention, within past 3 months.
• History of heart transplant or on a transplant list, or using or planned to be implanted with a ventricular assist device.
• Sustained ventricular arrhythmia with syncopal episodes within past 3 months that is untreated.
• Presence of any hemodynamically significant valvular stenosis or regurgitation, except mitral or tricuspid regurgitation secondary to left ventricular dilatation. Presence of hemodynamically significant obstructive lesions of left ventricular outflow tract.
• Stroke or TIA within the past 3 months
• Primary liver disease considered to be life threatening.
• Any episode of symptomatic hypotension within 3 months prior to screening.
• Known history of angioedema with ACEi or ARB use, or history of hereditary or idiopathic angioedema.
• Coagulation or bleeding disorder.
• Systolic blood pressure \< 100 mmHg.
• Serum sodium \> 146 mEq/L (146 mmol/L).
• Serum potassium \> 5.2 mEq/L (5.2 mmol/L) or \< 3.5 mEq/L (3.5 mmol/L).
• Renal disease or eGFR \< 30 ml/min/1.73m2 (as measured by the simplified MDRD formula).
• Ultrafiltration or dialysis within 3 months prior to Screening.

Sponsors & Collaborators

• Momentum Research, Inc.: lead
• Saint-Louis-Lariboisière University Hospitals: collaborator
• Abbott: collaborator

Study Sites (13)

Erebouni Medical Center CJSC

Yerevan, Armenia

Location

Institute of Cardiology named after L.A. Hovhannisyan

Yerevan, Armenia

Location

Nairi Medical Center

Yerevan, Armenia

Location

Yerevan State Medical University

Yerevan, Armenia

Location

University Clinical Center Republic of Srpska, Banja Luka Department of Cardiology

Banja Luka, Bosnia and Herzegovina

Location

University Clinical Center Mostar

Mostar, Bosnia and Herzegovina

Location

Regional budget Healthcare Institution "Cardiological dispensary"

Ivanovo, Russia

Location

Moscow State Budgetary Institution of Healthcare of Moscow "City Clinical Hospital named after V.V. Vinogradov of the Department of Healthcare of Moscow"

Moscow, Russia

Location

State Budgetary Healthcare Institution of Moscow "City clinical hospital #51 of the Department of Healthcare of Moscow"

Moscow, Russia

Location

State Budgetary Healthcare Institution of Moscow "City Clinical Hospital named after V.V. Veresaev of the Department of Healthcare of Moscow"

Moscow, Russia

Location

State Budgetary Healthcare Institution of Moscow "Moscow City Clinical Hospital named after V.M. Buyanov" of the Department of Healthcare of Moscow"

Moscow, Russia

Location

MedFort LLC

Saint Petersburg, Russia

Location

State Budgetary Healthcare Institution of Vladimir region "Vladimir City Hospital # 4"

Vladimir, Russia

Location

Related Publications (4)

• 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

• Nijst P, Verbrugge FH, Martens P, Dupont M, Tang WHW, Mullens W. Renal response to intravascular volume expansion in euvolemic heart failure patients with reduced ejection fraction: Mechanistic insights and clinical implications. Int J Cardiol. 2017 Sep 15;243:318-325. doi: 10.1016/j.ijcard.2017.05.041. Epub 2017 May 14.

  PMID: 28545850 BACKGROUND

• Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P; Authors/Task Force Members; Document Reviewers. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016 Aug;18(8):891-975. doi: 10.1002/ejhf.592. Epub 2016 May 20. No abstract available.

  PMID: 27207191 BACKGROUND

• Tuttolomondo A, Pinto A, Di Raimondo D, Corrao S, Di Sciacca R, Scaglione R, Caruso C, Licata G. Changes in natriuretic peptide and cytokine plasma levels in patients with heart failure, after treatment with high dose of furosemide plus hypertonic saline solution (HSS) and after a saline loading. Nutr Metab Cardiovasc Dis. 2011 May;21(5):372-9. doi: 10.1016/j.numecd.2009.10.014. Epub 2010 Mar 25.

  PMID: 20346637 BACKGROUND

MeSH Terms

Conditions

Heart Failure

Interventions

Sodium Chloride; Calcium Chloride; Potassium Chloride; Solutions

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Calcium Compounds; Potassium Compounds; Pharmaceutical Preparations

Study Officials

• Alexandre Mebazaa, MD PhD FESC

  Hôpitaux Universitaires Saint-Louis-Lariboisière

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 15, 2020
• First Posted: January 21, 2020
• Study Start: April 1, 2020
• Primary Completion: April 26, 2021
• Study Completion: April 26, 2021
• Last Updated: April 18, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will not share

Locations

BO (2); AR (4); RU (7)