Safety and Efficacy of Early, seQUential Oral dIuretic Nephron blockAde In Acute Heart Failure

NCT04062760 | Unknown Phase 4

• 1 other identifier: SEEQUOIA-AHF
• Study Type: interventional
• Target: 206
• Locations: 1 country
• Sites: 1

Brief Summary

The SEEQUOIA-AHF (Safety and Efficacy of Early, seQUential oral dIuretic nephron blockAde in Acute Heart Failure) trial is a multicenter, randomized, open-label, parallel-arm trial assessing the impact of early sequential nephron blockade (i.e. a regimen based on the combination of four oral diuretics with different sites of action along the nephron at low doses) compared to a conventional approach with a high-dose loop diuretic in the treatment of congestion in patients hospitalized with acute heart failure (AHF). In this study, after 24-72 hours of high-dose intravenous furosemide started at the time of hospital admission, patients admitted with AHF will be randomized to open-label oral treatment with either low-dose sequential nephron blockade or high-dose furosemide for 96 hours. The primary end-point will be the bivariate change in body weight and serum creatinine value at 96 hours since randomization. Secondary endpoints will include clinical (e.g., total change in body weight during hospitalization, change in dyspnea score at 96 hours since randomization, 30-day readmission rate) and laboratory (e.g., change in BNP or NT-proBNP at discharge vs randomization) parameters, and safety (e.g., change in serum creatinine value at discharge versus randomization and up to 30 days from discharge) issues.

Conditions

Acute Heart Failure

Keywords

Acute Heart Failure; Diuretics; Sequential nephron blockade; Fluid balance; Worsening kidney failure

Outcome Measures

Primary Outcomes (2)

• Body weight change at 96 hours since randomization

  Difference between body weight (in Kg) at 96 hours since randomization and the value at randomization

  96 hours since randomization

• Serum creatinine change at 96 hours since randomization

  Difference between the concentration of serum creatinine (in mg/dL) at 96 hours since randomization and the value at randomization

  96 hours since randomization

Secondary Outcomes (30)

• Efficacy: Total weight change during hospitalization

  Up to 30 days

• Efficacy: Percent change in body weight at discharge versus at randomization

  Up to 30 days

• Efficacy: Change in dyspnea score at 96 hours since randomization

  96 hours since patient randomization

• Efficacy: Total equivalent furosemide dose at 96 hours since randomization

  96 hours since patient randomization

• Efficacy: Proportion of patients requiring an increase in furosemide dose or switching to intravenous infusion within the first 96 hours since randomization

  96 hours since patient randomization

Study Arms (2)

Standard diuretic therapy (SDT)

ACTIVE COMPARATOR

Furosemide +/- spironolactone or potassium canrenoate

Drug: Standard diuretic therapy

Early sequential nephron blockade (ESNB)

EXPERIMENTAL

Furosemide + metolazone + acetazolamide +/- spironolactone or potassium canrenoate

Drug: Early sequential nephron blockade

Interventions

Standard diuretic therapy DRUG

The patients in this arm will be randomized to receiving oral furosemide in 2 daily divided doses at twice the intravenous dose administered during the past 24 hours. Unless serum potassium value is higher than 5 mmol/L, oral spironolactone or potassium canrenoate will be added; dose will be established based on serum creatinine value.

Standard diuretic therapy (SDT)

Early sequential nephron blockade DRUG

After 24-72 hours of an algorithm-based treatment with high-dose intravenous furosemide started at the time of hospital admission, the patients in this arm will be randomized to receiving: 1. oral furosemide in 2 daily divided doses at a dose equivalent to that administered intravenously during the past 24 hours 2. metolazone at a dose based on serum creatinine value 3. acetazolamide at a dose based on serum creatinine value 4. spironolactone or potassium canrenoate (unless serum potassium value is higher than 5 mmol/L); dose will be established based on serum creatinine value

Early sequential nephron blockade (ESNB)

Eligibility Criteria

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

You may qualify if:

• Male or non-pregnant female patient, 18 years or older
• Patients admitted to Cardiology or Internal Medicine units with a diagnosis of acute decompensated heart failure and congestion: NT-proBNP \> 1,000 pg/ml or BNP \>250 pg/ml, dyspnea and at least two of the following clinical signs: 2+ pitting edema, pulmonary edema/pleural effusions at chest x-ray or US body weight increase above usual \> 5% over the last 4 weeks
• Clinically stable patients that can be switched to oral diuretic therapy after 24-72 hours of an algorithm-based treatment with high-dose intravenous furosemide started at the time of hospital admission
• Patients capable to provide written informed consent

You may not qualify if:

• Serum creatinine levels \> 3.5 mg per deciliter at admission to the hospital or usual estimated glomerular filtration rate (eGFR) \< 20 ml/min/1.73 m2 by the MDRD or CKD-EPI formula
• Systolic blood pressure \< 90 mmHg at time of enrollment and/or hemodynamic instability severe enough to require intravenous inotropes, intravenous vasodilators, or both
• Severe arrhythmias with hemodynamic instability or DC shock occurred prior to randomization
• Ascertained acute coronary syndrome (ACS), or ACS occurred within the last 4 weeks
• Hematocrit \> 45%
• Use of iodinated radio contrast material occurred in the last 72 hours
• Current mechanical ventilator support
• Previous solid organ transplant
• Primary hypertrophic or infiltrative cardiomyopathy, active myocarditis, constrictive pericarditis or cardiac tamponade, severe valvular stenosis
• Complex congenital heart disease
• Liver disease (serum ALT or AST \> 4, and/or total serum bilirubin \> 3)
• Known bilateral renal artery stenosis
• Active sepsis or ongoing systemic infection
• Active gastrointestinal tract bleeding
• Enrollment in another clinical trial

Sponsors & Collaborators

• University of Parma: lead
• Azienda Ospedaliero-Universitaria di Parma: collaborator
• Azienda USL di Parma: collaborator
• Azienda USL Reggio Emilia - IRCCS: collaborator

Study Sites (1)

UO Nefrologia, Azienda Ospedaliero-Universitaria di Parma

Parma, PR, 43126, Italy

Location

Study Officials

• Enrico Fiaccadori, MD, PhD

  Universita degli Studi di Parma

  PRINCIPAL INVESTIGATOR

• Giuseppe Regolisti, MD

  UO Nefrologia, Azienda Ospedaliero-Universitaria di Parma

  STUDY DIRECTOR

Central Study Contacts

Giuseppe Regolisti, MD

CONTACT

+39 348 4450210; giuregolisti@gmail.com

Enrico Fiaccadori, MD, PhD

CONTACT

+39 0521 703336; enrico.fiaccadori@unipr.it

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: Associate Professor of Nephrology

Model Details: Multicenter, randomized, open-label, parallel-arm trial. Eligible patients will be randomized in a 1:1 proportion to treatment with either high-dose oral furosemide or sequential nephron blockade with different classes of diuretics at low doses. The primary endpoint will be the bivariate change in body weight and serum creatinine value at 96 hours since patient randomization.

Study Record Dates

• First Submitted: August 16, 2019
• First Posted: August 20, 2019
• Study Start: December 1, 2019
• Primary Completion: December 1, 2021
• Study Completion: December 1, 2024
• Last Updated: August 20, 2019

Record last verified: 2019-08

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)