Early Sequential Nephron Blockade in Acute Heart Failure Patients: A Randomised, Controlled Study (NEB-HF)

Furosemide With Early Sequential Nephron Blockade Versus Furosemide Alone in Acute Heart Failure Patients With Furosemide-guided Diuretic Resistance: A Double-blinded, Randomized, Placebo-controlled Study

This study aims to demonstrate the efficacy of sequential nephron blockade by adding hydrochlorothiazide or spironolactone on intravenous furosemide compared to intravenous furosemide alone in the treatments of volume overload in patients with acute heart failure who have diuretic resistance from furosemide stress test.

Study Overview

• Status: Unknown
• Conditions: Acute Kidney Injury; Acute Heart Failure
• Intervention / Treatment: Drug: Spironolactone or hydrochlorothiazide; Drug: Placebo

Detailed Description

This study is a randomised, double-blinded, double-dummy, placebo-controlled study to demonstrate the efficacy of oral hydrochlorothiazide or spironolactone in combination with intravenous furosemide compared to intravenous furosemide in combination with placebo. Dosage of intravenous furosemide will be adjusted according to pre-defined protocol. The primary outcome is urine volume during 72 hours after randomisation.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 3

Contacts and Locations

Study Locations

• Thailand
  • Chiang Mai, Thailand, 50200
    • Recruiting
    • Chiang Mai University Hospital, Faculty of Medicine, Chiang Mai University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥18 years
• Diagnosis of acute heart failure which is defined by 2 of the 3 following features: ≥2+ leg edema, jugular venous pressure >10 cm from physical examination or central venous pressure >10 mmHg, and bilateral pulmonary edema or bilateral pleural effusion from chest radiography
• Patients consent to participate into the study

Exclusion Criteria:

• Patients who receive furosemide ≥500 mg/day or hydrochlorothiazide ≥100 mg/day or spironolactone ≥100 mg/day or tolvaptan of any doses
• Patients who have systolic blood pressure <100 mmHg or who need vasoactive drugs inotropic agents (except dobutamine)
• Patients with intravascular volume depletion from clinical evaluation
• Patients with chronic kidney disease stage 5 (estimated glomerular filtration rate <15 ml/min/1.73 m2) or patients who receive maintenance dialysis
• Patients who require renal replacement therapy at the time of admission
• Patients whom diagnosed hypertrophic obstructive cardiomyopathy, severe valvular stenosis or complex congenital heart disease
• Patients with sepsis or systemic infection
• Pregnant women
• Patients who have history of furosemide, spironolactone or hydrochlorothiazide allergy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Furosemide with spironolactone or hydrochlorothiazide; IV furosemide dosage will be adjusted according to the protocol as follows. Level 1: previous oral furosemide dose ≤80 mg/day; furosemide 80 mg IV bolus every 6 hours Level 2: previous oral furosemide dose 81-160 mg/day; furosemide 160 mg IV bolus every 6 hours Level 3: previous oral furosemide dose >160 mg/day; furosemide 250 mg IV bolus every 6 hours Furosemide dosage will be adjusted to keep urine output between 3,000 and 5,000 ml/day and >600 ml during 6 hours after furosemide administration. If the urine output <3,000 ml/day or <600 ml per 6 hours, furosemide dosage will be increase 1-level up per protocol above. If the urine output >5,000 ml/day, furosemide dosage will be reduced 1-level down per protocol above. Patients will be received spironolactone or hydrochlorothiazide in combination with intravenous furosemide according to patients' serum potassium levels.	Drug: Spironolactone or hydrochlorothiazide; Patients will be received spironolactone or hydrochlorothiazide in combination with intravenous furosemide according to patients' serum potassium levels. If serum potassium levels ≤4 mEq/L, patients will be received spironolactone 100 mg every 12 hour for 72 hours. If serum potassium levels >4 mEq/L, patients will be received hydrochlorothiazide 50 mg every 12 hour for 72 hours.; Other Names: Aldactone; HCTZ; Thiazide
ACTIVE_COMPARATOR: Furosemide with placebo; IV furosemide dosage will be adjusted according to the pre-defined protocol as shown in the experimental group. Patients will be received spironolactone placebo or hydrochlorothiazide placebo in combination with intravenous furosemide according to patients' serum potassium levels.	Drug: Placebo; Patients will be received spironolactone placebo or hydrochlorothiazide placebo in combination with intravenous furosemide according to patients' serum potassium levels. If serum potassium levels ≤4 mEq/L, patients will be received spironolactone placebo every 12 hour for 72 hours. If serum potassium levels >4 mEq/L, patients will be received hydrochlorothiazide placebo every 12 hour for 72 hours.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urine volume	Total urine volume after randomisation	72 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urine volume	Total urine volume after randomization	24 and 48 hours
Body weight	Changes of patient's body weight	72 hours after randomisation
Length of hospital admission	Number of days that patients need to stay in the hospital	During hospital admission period
Furosemide dose	Total dosage of intravenous furosemide	72 hours after randomisation
Levels of B-type atrial natriuretic peptide (BNP)	levels of pro-BNP	72 hours and 7 days after randomisation
Number of participants with adverse events	All adverse events during hospital admission	During hospital admission
Dyspnea score assessed by visual analogue scale	The scale is between 0 and 100. The higher scale represents lower level of dyspnea	At randomization, and 6, 12, 24, 48 and 72 hours after randomization

Collaborators and Investigators

• Sponsor: Chiang Mai University

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 13, 2020
• Primary Completion (ANTICIPATED): July 31, 2022
• Study Completion (ANTICIPATED): December 31, 2022

Study Registration Dates

• First Submitted: July 6, 2020
• First Submitted That Met QC Criteria: July 6, 2020
• First Posted (ACTUAL): July 9, 2020

Study Record Updates

• Last Update Posted (ACTUAL): August 18, 2020
• Last Update Submitted That Met QC Criteria: August 16, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: Acute heart failure; Sequential nephron blockade; Diuretic resistance; Diuretic combination
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Kidney Diseases; Urologic Diseases; Renal Insufficiency; Heart Failure; Acute Kidney Injury; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Sodium Chloride Symporter Inhibitors; Spironolactone; Hydrochlorothiazide
• Other Study ID Numbers: MED-2563-07080 (2)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Request for individual participant data (IPD) has to be submitted to the Institutional Review Board (IRB) of Faculty of Medicine, Chiang Mai University, Chiang Mai, THAILAND.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No