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Heart FailurePhase 2ESCALATENCT04481919

Randomized Controlled Trial of urinE chemiStry Guided aCute heArt faiLure treATmEnt (ESCALATE)

A Phase 2 study testing Protocolized diuretic therapy in people with Heart Failure and Acute Heart Failure, run by Vanderbilt University Medical Center at 2 sites in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial summary

This is a randomized trial of protocolized diuretic therapy guided by urinary sodium compared to structured usual care in ED patients with AHF. Participants will be recruited following an initial standard evaluation in the ED and randomized in a 1:1 fashion to structured usual care or protocolized diuretic therapy… Read more about this study

Who is it for?
Ages 19 years and older
Conditions the study is for
Heart Failure, Acute Heart Failure
What is being tested?
Protocolized diuretic therapy
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
474 participants
Where
2 sitesUnited States
Study dates
1 May 2022to 28 Feb 2027
Phase
Phase 2
Are there results?
Not yet: the study is under way

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 19 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Age > 18
  • Emergency Department diagnosis of Acute Heart Failure (AHF)
  • Any one of the following:
  • Chest radiograph or lung ultrasound consistent with AHF ii. Jugular venous distension iii. Pulmonary rales on auscultation iv. Lower extremity edema v. S3 gallop
  • > 10 pounds of volume overload physician estimate or historical dry weight
  • IV diuretic ordered or planned to be during first 24 hours of ED or inpatient stay

Who cannot join

  • End Stage Renal Disease (ESRD) requiring dialysis
  • Need for immediate intubation
  • Acute Coronary Syndrome - presentation consistent with myocardial ischemia AND new ST-Segment elevation/depression
  • Temperature > 100.5ºF
  • End Stage Heart Failure: transplant list or ventricular assist device
  • Concurrent use of ototoxic medications including intravenous aminoglycosides and cisplatin
Show all 11Show fewer
  • Systolic Blood Pressure < 90 mmHg at time of consent
  • LV outflow obstruction, severe uncorrected stenotic valvular disease or severe restrictive cardiomyopathy
  • Greater than 2 doses of IV diuretic administered at the time of screening from the time of the hospital presentation leading to this admission (outside hospital time is included)
  • Severe, uncorrected serum electrolyte abnormalities at the time of consent (serum potassium <3.0 mEq/L, magnesium <1.0 mEq/L or sodium <125 or >150 mEq/l)
  • Lack of informed consent

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • VA Tennessee Valley Health Service

    Nashville, Tennessee, 37232

  • Vanderbilt University Medical Center

    Nashville, Tennessee, 37232

Other trials in United States

About this study

Official title: A Randomized Trial of Protocolized Diuretic Therapy Compared to Standard Care in Emergency Department Patients With Acute Heart Failure

This is a randomized trial of protocolized diuretic therapy guided by urinary sodium compared to structured usual care in ED patients with AHF. Participants will be recruited following an initial standard evaluation in the ED and randomized in a 1:1 fashion to structured usual care or protocolized diuretic therapy guided by urinary sodium.

Read the detailed description

A standardized protocol driven treatment pathway for hospitalized patients started in the first few hours of ED evaluation and utilizing objective measures of diuretic response is needed. The investigators believe this would maximize diuretic efficiency, facilitate quicker resolution of congestion, avoid WHF and prolonged LOS, and reduce AHF readmissions. Propr data suggests low urine sodium predicts length of stay and outcomes after initial diuretic dosing in the outpatient and inpatient setting. Further, use of our pathway using spot urine sodium to titrate subsequent loop diuretic doses and maximize response in inpatients with AHF has shown compelling improvements in congestion and weight loss. However, a randomized trial is necessary to determine if initiating this protocol ,started in the ED, will improve AHF outcomes relative to structured usual care. Specifically, the investigators hypothesize use of spot urine sodium guided diuretic therapy will result in significant improvement in days of benefit over the 14 days after randomization. Days of benefit combines patient symptoms captured by global clinical status with clinical state quantifying the need for hospitalization and IV diuresis.

Being tested
Protocolized diuretic therapy
Keywords
Diuretic Therapy, Emergency Department
Medical subject headings
Heart Failure, Emergencies

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Protocolized diuretic therapyDrug

    The urine sodium, urine creatinine and serum creatinine results will be input into the diuretic calculator and the diuretic dose will be chosen based on daily goals for urine output and net negative fluid balance.

Study groups in NCT04481919
Study groupRoleWhat they receive
Protocolized spot urine sodium guided diuretic therapyActive comparatorPatients will have a spot urine sodium and urine creatinine obtained. The urine and creatinine results will be input into the diuretic calculator and the diuretic dose will be chosen based on daily goals for urine output and net negative fluid balance. Performed 3 times per day, diuretic dosing will be individualized based on the proportion of 24-hour diuresis achieved since the prior IV diuretic dose. Every 24 hours new goals for urine output and net negative fluid balance are established based on the study and treatment team's assessment of residual congestion until protocol completion.
Receives: Drug: Protocolized diuretic therapy
Guideline-based careNo interventionPatients will be placed on guideline-based diuretic dosing consistent with usual practice. The initial dose will be two times their home dose and will be subsequently adjusted by the treating team based on renal function and symptom severity. The treating team can increase or decrease the frequency and dose of diuretic based on urine output and clinical assessment. Patients in this arm also have urine collected 3 times per day by the bedside nurse to mirror the intervention arm.

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Clinical Status Score

    Daily composite of the clinical state and global clinical status (GCS), expressed as an integer ranging in value from 0 (deceased) to 15 (outpatient; best possible GCS).

    Measured: From the time of randomization through day 14

Secondary outcomes (11)

  1. Inpatient clinical congestion

    Daily orthodema score

    Measured: from the time of randomization through the end of protocolized IV diuretics, approximately 14 days

  2. Cardiorenal Death and AHF Readmission

    Cardiorenal death and Acute Heart Failure Readmission

    Measured: within 30 days of hospital discharge

  3. Global clinical status (GCS)

    measured daily using a continuous scale of 1-100

    Measured: from the time of randomization through 14 days after randomization

  4. Change in natriuretic peptides

    Blood measurement

    Measured: from the time of randomization through the end of protocolized IV diuretics, approximately 14 days

  5. Net fluid loss

    difference between fluid input and urine output in ml

    Measured: from the time of randomization through the end of protocolized IV diuretics, approximately 14 days

  6. Total urine output

    cumulative urine output in ml

    Measured: from the time of randomization through the end of protocolized IV diuretics, approximately 14 days

  7. Weight Loss

    cumulative weight loss in pounds

    Measured: from the time of randomization through the end of protocolized IV diuretics, approximately 14 days

  8. Home days

    Those days not in the hospital, rehab or a skilled nursing facility from the time of randomization through day 30

    Measured: within 30 days from randomization

  9. Subclinical ototoxicity

    As measured by shoebox audiometry with a significant change in hearing threshold (dB) across frequencies from 250-8000 Hz

    Measured: at two time points: 1) the day of randomization and 2) the next calendar day after protocolized IV diuretics are stopped

  10. Cumulative natriuresis

    cumulative sodium excretion estimated using the NRPE (based on spot urine creatinine and sodium)

    Measured: from the time of randomization through the end of protocolized diuretics, approximately 14 days

  11. Average daily natriuresis

    mean daily sodium excretion estimated using the NRPE (based on spot urine creatinine and sodium)

    Measured: from the time of randomization through the end of protocolized diuretics, approximately 14 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted22 Jul 2020
  2. Study start1 May 2022
  3. Primary completion22 Nov 2025
  4. Study completion28 Feb 2027 (estimated)

Resources

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 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Two-arm comparison of structured usual care vs urinary sodium guided diuresis
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
474 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04481919
Sponsor's protocol ID
190690
Acronym
ESCALATE
Status last verified
Sep 2026
First submitted
19 Jul 2020
Last updated
21 Sep 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: The Publication Committee will authorize access to study data. Investigators must submit a proposal requesting approval to access our trial data. Our trial will participate in the NHLBI Central Repository for study data and specimens. All data access will follow guidelines described in the NHLBI Limited Access Data Policy.

Publications

  • Cox ZL, Rao VS, Ivey-Miranda JB, Myers S, Manning K, Imhoff B, Jenkins CA, Shotwell MS, Miller KF, Storrow AB, Watson P, Rivera-Sanchez A, Wilson FP, Yamamoto Y, Siddiqi H, Schlendorf KH, Stevenson LW, Lindenfeld J, Rybak LP, Collins SP, Testani JM. Assessment of Ototoxicity in Patients With Heart Failure Receiving High-Dose IV Loop Diuretics. JAMA Cardiol. 2026 Oct 30:e264913. doi: 10.1001/jamacardio.2026.4913. Online ahead of print.

    PubMed 42961411

  • Mullens W, Martens P. Contemporary Diuretic Therapies for Acute Heart Failure: Time for a Desalination-Guided Approach? J Card Fail. 2024 May;30(5):737-738. doi: 10.1016/j.cardfail.2024.01.013. Epub 2024 Mar 4. No abstract available.

    PubMed 38447632

  • Cox ZL, Siddiqi HK, Stevenson LW, Bales B, Han JH, Hart K, Imhoff B, Ivey-Miranda JB, Jenkins CA, Lindenfeld J, Shotwell MS, Miller KF, Ooi H, Rao VS, Schlendorf K, Self WH, Siew ED, Storrow A, Walsh R, Wrenn JO, Testani JM, Collins SP. Randomized controlled trial of urinE chemiStry guided aCute heArt faiLure treATmEnt (ESCALATE): Rationale and design. Am Heart J. 2023 Nov;265:121-131. doi: 10.1016/j.ahj.2023.07.014. Epub 2023 Aug 6.

    PubMed 37544492

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Protocolized diuretic therapy in people with Heart Failure and Acute Heart Failure, run by Vanderbilt University Medical Center at 2 sites in United States.

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 6 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: under way, not looking for participants, as of the sponsor's last update on 21 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Clinical Status Score (time frame: From the time of randomization through day 14). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04481919, which also lists 3 linked publications.

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 21 Sep 2026.

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