Sequential Nephron Blockade in Acute Heart Failure
Primary Purpose
Acute Heart Failure
Status
Unknown status
Phase
Phase 3
Locations
Italy
Study Type
Interventional
Intervention
Metolazone
Loop Diuretics
Sponsored by
About this trial
This is an interventional treatment trial for Acute Heart Failure focused on measuring acute heart failure, decongestion, diuretics, outcomes
Eligibility Criteria
Inclusion Criteria:
- 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.
Assessed LVEF by any imaging technique; i.e. echocardiography, catheterization, nuclear scan or magnetic resonance imaging within 12 months of inclusion
Exclusion Criteria:
- 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
- Use of renal replacement therapy or ultrafiltration at any time before study inclusion
- 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
Sites / Locations
- Policlinico CasilinoRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Experimental
Arm Label
Standard therapy
SNB
Arm Description
intravenous loop diuretics as recommended by current guidelines plus placebo
loop diuretics plus oral metolazone at a dose of 5/10 mg once daily
Outcomes
Primary Outcome Measures
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).
Secondary Outcome Measures
global well-being assessment by a visual-analogue scale
Global well-being is assessed with the use of a visual-analogue scale that ranged from 0 to 100, with higher scores indicating greater well-being (Chest 1999;116:1208-17)
body weight assessment
total changes in body weight in kilograms
congestion
proportion of patients who were free from congestion (defined as jugular venous pressure of <8 cm, with no orthopnoea and with trace peripheral oedema or no oedema)
treatment failure
death, worsening/persistent HF, need for dialysis, crossover from standard pharmacologic care to sequential nephron blockade or the occurrence of a serious adverse event during the first 7 days from admission
Biomarkers
changes in NT-proBNP levels (in pg/mL) at 72 hours, day 7 or discharge
clinical end-point
composite of death, rehospitalization, or an emergency room visit within 60 days
hospitalization-death
composite of total number of days hospitalized or dead during the 60 days after randomization
Total net fluid loss
total urinary output (in milliliters) from randomization to 76 hours
dyspnea assessment by a visual-analogue scale
Dyspnea is assessed with the use of a visual-analogue scale that ranged from 0 to 100, with higher scores indicating less dyspnea (Chest 1999;116:1208-17)
Full Information
NCT ID
NCT04163588
First Posted
October 26, 2019
Last Updated
November 15, 2019
Sponsor
Policlinico Casilino ASL RMB
Collaborators
Umberto I Hospital, Nocera Inferiore, IRCCS San Raffaele
1. Study Identification
Unique Protocol Identification Number
NCT04163588
Brief Title
Sequential Nephron Blockade in Acute Heart Failure
Official Title
Early Sequential Nephron Blockade Versus Standard Diuretic Treatment in Acute Heart Failure
Study Type
Interventional
2. Study Status
Record Verification Date
November 2019
Overall Recruitment Status
Unknown status
Study Start Date
October 1, 2019 (Actual)
Primary Completion Date
October 31, 2020 (Anticipated)
Study Completion Date
December 31, 2020 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Policlinico Casilino ASL RMB
Collaborators
Umberto I Hospital, Nocera Inferiore, IRCCS San Raffaele
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Heart Failure
Keywords
acute heart failure, decongestion, diuretics, outcomes
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
Participant
Allocation
Randomized
Enrollment
310 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Standard therapy
Arm Type
Active Comparator
Arm Description
intravenous loop diuretics as recommended by current guidelines plus placebo
Arm Title
SNB
Arm Type
Experimental
Arm Description
loop diuretics plus oral metolazone at a dose of 5/10 mg once daily
Intervention Type
Drug
Intervention Name(s)
Metolazone
Intervention Description
Study participants receive loop diuretics plus oral metolazone at a dose of 5/10 mg once daily
Intervention Type
Drug
Intervention Name(s)
Loop Diuretics
Intervention Description
Study participants receive a standard diuretic strategy (intravenous loop diuretics as recommended by current guidelines plus placebo)
Primary Outcome Measure Information:
Title
change in the serum creatinine level and the change in weight, considered both as a bivariate response and with their single components
Description
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).
Time Frame
72 hours
Secondary Outcome Measure Information:
Title
global well-being assessment by a visual-analogue scale
Description
Global well-being is assessed with the use of a visual-analogue scale that ranged from 0 to 100, with higher scores indicating greater well-being (Chest 1999;116:1208-17)
Time Frame
72 hours
Title
body weight assessment
Description
total changes in body weight in kilograms
Time Frame
72 hours
Title
congestion
Description
proportion of patients who were free from congestion (defined as jugular venous pressure of <8 cm, with no orthopnoea and with trace peripheral oedema or no oedema)
Time Frame
72 hours
Title
treatment failure
Description
death, worsening/persistent HF, need for dialysis, crossover from standard pharmacologic care to sequential nephron blockade or the occurrence of a serious adverse event during the first 7 days from admission
Time Frame
7 days
Title
Biomarkers
Description
changes in NT-proBNP levels (in pg/mL) at 72 hours, day 7 or discharge
Time Frame
72 hours, 7 days or discharge
Title
clinical end-point
Description
composite of death, rehospitalization, or an emergency room visit within 60 days
Time Frame
60 days
Title
hospitalization-death
Description
composite of total number of days hospitalized or dead during the 60 days after randomization
Time Frame
60 days
Title
Total net fluid loss
Description
total urinary output (in milliliters) from randomization to 76 hours
Time Frame
76 hours
Title
dyspnea assessment by a visual-analogue scale
Description
Dyspnea is assessed with the use of a visual-analogue scale that ranged from 0 to 100, with higher scores indicating less dyspnea (Chest 1999;116:1208-17)
Time Frame
76 hours
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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.
Assessed LVEF by any imaging technique; i.e. echocardiography, catheterization, nuclear scan or magnetic resonance imaging within 12 months of inclusion
Exclusion Criteria:
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
Use of renal replacement therapy or ultrafiltration at any time before study inclusion
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Gennaro Cice, MD
Phone
0039330915294
Email
gennarocice@hotmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gennaro Cice, MD
Organizational Affiliation
Policlinico Casilino
Official's Role
Principal Investigator
Facility Information:
Facility Name
Policlinico Casilino
City
Rome
State/Province
Lazio
ZIP/Postal Code
00169
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gennaro Cice, MD
Phone
+39 0623188406
Email
gennarocice@hotmail.com
First Name & Middle Initial & Last Name & Degree
Gennaro Cice, MD
12. IPD Sharing Statement
Plan to Share IPD
Undecided
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Sequential Nephron Blockade in Acute Heart Failure
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