Sequential Nephron Blockade in Acute Heart Failure

NCT04163588 | Unknown Phase 3

• 1 other identifier: SNB01
• Study Type: interventional
• Target: 310
• Locations: 1 country
• Sites: 1

Brief Summary

Background - Volume overload is an important clinical target in acute heart failure management (AHF), typically addressed using loop diuretics. An important and challenging subset of heart failure patients exhibit fluid overload despite significant doses of loop diuretics. One approach to overcome loop diuretic resistance is the addition of a thiazide-type diuretic to produce diuretic synergy via "sequential nephron blockade". Although potentially able to induce diuresis in patients otherwise resistant to high doses of loop diuretics, this strategy has not been subjected to large-scale clinical trials to establish safety and clinical efficacy. Methods - Our trial is a multicentric, double blind, randomized clinical study, aiming to recruit 310 patients with AHF and clinically evident volume overload. Study participants are randomized to receive a standard diuretic therapy (intravenous loop diuretics as recommended by current guidelines plus placebo) or SNB therapy (loop diuretics plus oral metolazone at the dose of 5/10 mg once daily) on top of standard medical therapy. Mineralocorticoid antagonists will be used in association with the two regimens according to blood potassium level and kidney function at the discretion of the treating physician. The primary endpoint is defined as the change in the serum creatinine level and the change in weight, considered both as a bivariate response and with their single components, between the time of randomization and 72 hours after randomization. Secondary endpoints include global well-being and dyspnoea assessed by a visual-analogue scale, changes in body weight and net fluid loss, proportion of patients free from congestion, treatment failure, changes in biomarker levels and the composite of death, rehospitalization, or an emergency room visit within 60 days, as well as the composite of total number of days hospitalized or death during the 60 days after randomization.

Conditions

Acute Heart Failure

Keywords

acute heart failure; decongestion; diuretics; outcomes

Outcome Measures

Primary Outcomes (1)

• change in the serum creatinine level and the change in weight, considered both as a bivariate response and with their single components

  The bivariate response will be displayed on a two-dimensional grid with individual data points for each patient representing paired changes in both creatinine (inmg/dL) and weight (in kilograms) 76 hours after randomization. A confidence region for the average difference between treatment arms in this bivariate response can be described as an ellipse, and the 2 treatment arms will be compared statistically with the use of the Hotelling T- square, which is a multivariate analog of the 2-sample t test used with a single continuous variable (Ann Math Stat. 1931; 2:360-78). Evaluating these 2 important responses to treatment as a bivariate end point reflects clinically important responses to therapy and avoids the requirement of making adjustments in sample size to prevent a type 1 error that would be necessary if the end points were considered separately (Eur J Heart Fail. 2003; 5:717-23).

  72 hours

Secondary Outcomes (9)

• global well-being assessment by a visual-analogue scale

  72 hours

• body weight assessment

  72 hours

• congestion

  72 hours

• treatment failure

  7 days

• Biomarkers

  72 hours, 7 days or discharge

Study Arms (2)

Standard therapy

ACTIVE COMPARATOR

intravenous loop diuretics as recommended by current guidelines plus placebo

Drug: Loop Diuretics

SNB

EXPERIMENTAL

loop diuretics plus oral metolazone at a dose of 5/10 mg once daily

Drug: Metolazone; Drug: Loop Diuretics

Interventions

Metolazone DRUG

Study participants receive loop diuretics plus oral metolazone at a dose of 5/10 mg once daily

SNB

Loop Diuretics DRUG

Study participants receive a standard diuretic strategy (intravenous loop diuretics as recommended by current guidelines plus placebo)

SNB; Standard therapy

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed written informed consent must be obtained before any study assessment is performed
• Male or female patients 18 years of age or older
• An elective or emergency hospital admission with clinical diagnosis of decompensated HF with at least one clinical sign of volume overload (e.g. oedema (score 2 or more), ascites confirmed by echography or pleural effusion confirmed by chest X-ray or echography) Plasma NT-proBNP levels \>1000 ng/mL or BNP levels \>250 ng/mL at the time of screening.

You may not qualify if:

• Concurrent diagnosis of an acute coronary syndrome defined as typical chest pain in addition to a troponin rise above the 99th percentile and/or electrocardiographic changes suggestive of cardiac ischemia
• History of congenital heart disease requiring surgical correction
• History of a cardiac transplantation and/or ventricular assist device
• Systolic blood pressure \<90 mmHg or mean arterial pressure \<65 mmHg at the moment of admission
• Estimated glomerular filtration rate \<20 mL/min/1.73m² at screening
• Treatment with metolazone during the index hospitalization and prior to randomization
• Exposure to nephrotoxic agents (i.e. contrast dye) anticipated within the next 3 days
• Use of any non-protocol defined diuretic agent with the exception of mineralocorticoid receptor antagonists.
• Current use of sodium-glucose transporter-2 inhibitors
• Subjects who are pregnant or breastfeeding

Sponsors & Collaborators

• Policlinico Casilino ASL RMB: lead
• Umberto I Hospital, Nocera Inferiore: collaborator
• IRCCS San Raffaele: collaborator

Study Sites (1)

Policlinico Casilino

Rome, Lazio, 00169, Italy

RECRUITING

MeSH Terms

Interventions

Metolazone; Sodium Potassium Chloride Symporter Inhibitors

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Quinazolinones; Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Diuretics; Natriuretic Agents; Physiological Effects of Drugs

Study Officials

• Gennaro Cice, MD

  Policlinico Casilino

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Gennaro Cice, MD

CONTACT

0039330915294; gennarocice@hotmail.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: October 26, 2019
• First Posted: November 15, 2019
• Study Start: October 1, 2019
• Primary Completion: October 31, 2020
• Study Completion: December 31, 2020
• Last Updated: November 19, 2019

Record last verified: 2019-11

Locations

IT (1)