Acute Heart FailurePhase 3NCT04163588
Sequential Nephron Blockade in Acute Heart Failure
A Phase 3 study testing Metolazone and Loop Diuretics in people with Acute Heart Failure, run by Policlinico Casilino ASL RMB at 1 site in Italy.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 99 years
- Conditions the study is for
- Acute Heart Failure
- What is being tested?
- Metolazone and Loop Diuretics
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 310 participants
- Where
- 1 siteItaly
- Study dates
- 1 Oct 2019to 31 Dec 2020
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 99 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
1 site in 1 country.
Italy1 site, 1 recruiting
- Recruiting
Policlinico Casilino
Rome, Lazio, 00169
Gennaro Cice, MD, +39 0623188406, gennarocice@hotmail.com
Gennaro Cice, MD
About this study
Official title: Early Sequential Nephron Blockade Versus Standard Diuretic Treatment in Acute Heart Failure
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
- Being tested
- Metolazone, Loop Diuretics
- Keywords
- acute heart failure, decongestion, diuretics, outcomes
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MetolazoneDrug
Study participants receive loop diuretics plus oral metolazone at a dose of 5/10 mg once daily
Loop DiureticsDrug
Study participants receive a standard diuretic strategy (intravenous loop diuretics as recommended by current guidelines plus placebo)
| Study group | Role | What they receive |
|---|---|---|
| Standard therapy | Active comparator | intravenous loop diuretics as recommended by current guidelines plus placebo Receives: Drug: Loop Diuretics |
| SNB | Experimental | loop diuretics plus oral metolazone at a dose of 5/10 mg once daily Receives: Drug: Metolazone; Drug: Loop Diuretics |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 72 hours
Secondary outcomes (9)
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)
Measured: 72 hours
body weight assessment
total changes in body weight in kilograms
Measured: 72 hours
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)
Measured: 72 hours
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
Measured: 7 days
Biomarkers
changes in NT-proBNP levels (in pg/mL) at 72 hours, day 7 or discharge
Measured: 72 hours, 7 days or discharge
clinical end-point
composite of death, rehospitalization, or an emergency room visit within 60 days
Measured: 60 days
hospitalization-death
composite of total number of days hospitalized or dead during the 60 days after randomization
Measured: 60 days
Total net fluid loss
total urinary output (in milliliters) from randomization to 76 hours
Measured: 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)
Measured: 76 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Nov 2019
- Study start1 Oct 2019
- Primary completion31 Oct 2020 (estimated)
- Study completion31 Dec 2020 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Acute Heart FailureStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 310 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Policlinico Casilino ASL RMB
- Sponsor type
- University, hospital or other
- Collaborators
- Umberto I Hospital, Nocera Inferiore, IRCCS San Raffaele
- Responsible party
- Principal investigator, Leonardo Calò, MD, Policlinico Casilino ASL RMB
- Investigators
- Gennaro Cice, MD, Principal investigator, Policlinico Casilino
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04163588
- Sponsor's protocol ID
- SNB01
- Status last verified
- Nov 2019
- First submitted
- 26 Oct 2019
- Last updated
- 19 Nov 2019
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 19 Nov 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Early Sequential Nephron Blockade Versus Standard Diuretic Treatment in Acute Heart Failure
- ClinicalTrials.gov ID
- NCT04163588
- Acronym / sponsor ID
- SNB01
- Conditions
- Acute Heart Failure
- Keywords
- acute heart failure, decongestion, diuretics, outcomes
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 310 participants (estimated)
- Lead sponsor
- Policlinico Casilino ASL RMBUniversity, hospital or other
- Collaborators
- Umberto I Hospital, Nocera Inferiore, IRCCS San Raffaele
- Study start
- 1 Oct 2019 (actual)
- Primary completion
- 31 Oct 2020 (estimated)
- Study completion
- 31 Dec 2020 (estimated)
- First posted
- 15 Nov 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (participant)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Standard therapy | Active comparator | Drug: Loop Diureticsintravenous loop diuretics as recommended by current guidelines plus placebo |
| SNB | Experimental | Drug: Metolazone, Drug: Loop Diureticsloop diuretics plus oral metolazone at a dose of 5/10 mg once daily |
Who may qualify
- Ages
- 18 to 99 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (11 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MetolazoneStudy participants receive loop diuretics plus oral metolazone at a dose of 5/10 mg once daily | Drug | SNB |
| Loop DiureticsStudy participants receive a standard diuretic strategy (intravenous loop diuretics as recommended by current guidelines plus placebo) | Drug | SNB, Standard therapy |
Primary outcome
change in the serum creatinine level and the change in weight, considered both as a bivariate response and with their single components
Time frame: 72 hours
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).
9 secondary outcomes
global well-being assessment by a visual-analogue scale
Time frame: 72 hours
body weight assessment
Time frame: 72 hours
congestion
Time frame: 72 hours
treatment failure
Time frame: 7 days
Biomarkers
Time frame: 72 hours, 7 days or discharge
clinical end-point
Time frame: 60 days
hospitalization-death
Time frame: 60 days
Total net fluid loss
Time frame: 76 hours
dyspnea assessment by a visual-analogue scale
Time frame: 76 hours
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Nov 2019.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Gennaro Cice, MD principal investigator
Policlinico Casilino
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Metolazone and Loop Diuretics in people with Acute Heart Failure, run by Policlinico Casilino ASL RMB at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 19 Nov 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Gennaro Cice, MD (0039330915294, gennarocice@hotmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
change in the serum creatinine level and the change in weight, considered both as a bivariate response and with their single components (time frame: 72 hours). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Nov 2019.