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Acute PancreatitisPhase 3WATERFALLNCT04381169

Aggressive Versus Non-aggressive Goal-directed Fluid Resuscitation in Acute Pancreatitis

A Phase 3 study testing Lactated Ringer Solution in people with Acute Pancreatitis, run by Enrique de-Madaria at 2 sites in Spain.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

WATERFALL is an investigator-initiated international multicenter open-label randomized clinical trial comparing aggressive versus moderate fluid resuscitation in acute pancreatitis. The main outcome variable will be the proportion of patients with moderate-to-severe AP. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Acute Pancreatitis
What is being tested?
Lactated Ringer Solution
Could I receive a placebo?
No, everyone receives an active treatment
How many people
249 participants
Where
2 sitesSpain
Study dates
28 May 2020to 25 Sep 2021
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 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients age greater or equal to 18 presenting to one of the collaborating centers
  • Diagnosis of acute pancreatitis according to the revised Atlanta classification which requires 2 of the following 3 criteria: A) Typical abdominal pain; B) Increase in serum amylase or lipase levels higher than 3 times the upper limit of normality; and C) Signs of AP in imaging.

Who cannot join

  • Uncontrolled arterial hypertension (systolic blood pressure >180 and/or diastolic blood pressure 100 mmHg);
  • New York Heart Association Class II hear failure (slight limitation of physical activity; fatigue, palpitations or dyspnea with ordinal physical activity) or worse, or ejection fraction<50% in the last echocardiography;
  • Decompensated cirrhosis (Child's Class B or C);
  • Hyper or hyponatremia (<135 or >145 mEq/l);
  • Hyperkalemia (>5 mEq/l);
  • Hypercalcemia (albumin or protein-corrected calcium>10.5 mg/dl);
Show all 13Show fewer
  • Chronic kidney failure (basal glomerular filtration rate <60 mL/min/1.73m2);
  • Clinical signs or symptoms of volume overload or heart failure at recruitment (dyspnea, peripheral edema, pulmonary rales, or evident increased jugular ingurgitation at 45º);
  • Shock or respiratory failure according to the revised Atlanta classification at recruitment (non-fluid responding systolic blood pressure< 90 mmHg, PaO2/FIO2≤300 mmHg);
  • Time from pain onset to arrival to emergency room >24h;
  • Time from confirmation of pancreatitis to randomization >8h;
  • Severe comorbidity associated with an estimated life expectancy <1 year;
  • Confirmed chronic pancreatitis (in case of recurrent alcoholic pancreatitis a recent (<6 months) CT scan/MRI or endoscopic ultrasound is needed to rule out chronic pancreatitis

Trial locations and contacts

2 sites in 1 country.

Spain2 sites

  • Alicante

    Alicante, 03010

  • Hospital General Universitario de Alicante

    Alicante, 03550

Other trials in Spain

About this study

Official title: Effect of Early Weight-based Aggressive Versus Non-aggressive Goal-directed Fluid Resuscitation in the Early Phase of Acute Pancreatitis: an Open-label Multicenter Randomized-controlled Trial

WATERFALL is an investigator-initiated international multicenter open-label randomized clinical trial comparing aggressive versus moderate fluid resuscitation in acute pancreatitis. The main outcome variable will be the proportion of patients with moderate-to-severe AP. Aggressive fluid resuscitation will consist in Lactated Ringer Solution (LR) 20 ml/kg bolus (administered over 2 hours) followed by LR 3 ml/kg/h and moderate a LR bolus 10 ml/kg in case of hypovolemia or no bolus in patients with normal volemia, followed by LR 1.5 ml/kg/h. The patients will be assessed at 3 (±1), 12 (±4), 24 (±4), 48 (±4) and 72 (±4) hours from recruitment, and fluid resuscitation will be adjusted to the patient´s clinical and analytical status according to a protocol. Subgroup analysis will include patients with systemic inflammatory response syndrome (SIRS) at admission, with persistent (>48h) SIRS and with hypovolemia at admission.

Based on available data (Sternby et al, Ann Surg 2019) we expect a 35% incidence of moderate to severe AP in the moderate arm. Sample sizes of 372 per arm of treatment (744 patients) achieve 80% power to detect a difference of 10% between the treatment arms at a significance level (alpha) of 0.05 using a two-sided z-testNA, assuming a 10% dropout. These results assume that 3 sequential tests are made using the O'Brien-Fleming spending function to determine the test boundaries.

All analyses will be performed on an intention-to-treat basis. The trial could be stop early for efficacy (primary end-point) if the observed two-sided P value is <0.0002 at the first interim analysis (after 1/3 of patients have been enrolled) or is <0.012 at second interim analysis (after 2/3 of patients have been enrolled), favoring aggressive fluid resuscitation. At final analysis, the hypothesis that the incidence of moderate-to-severe pancreatitis is similar in the two treatment arms will be rejected if p<0.046

Being tested
Lactated Ringer Solution
Keywords
Acute pancreatitis; fluid resuscitation; therapy; outcomes; randomized controlled trial; Ringer lactate; Lactated Ringer's solution
Medical subject headings
Pancreatitis

What participants receive

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

  • Lactated Ringer SolutionDrug

    Also called Aggressive fluid resuscitation, Moderate fluid resuscitation, Restrictive fluid resuscitation

    Comparison of aggressive versus moderate Lactated Ringer-based fluid resuscitation

Study groups in NCT04381169
Study groupRoleWhat they receive
Aggressive fluid resuscitationExperimentalLactated Ringer Solution 20 ml/kg bolus (administered over 2 hours) followed by an infusion of 3 ml/kg/h. At 12(±4) hours: A) Hypovolemia: same bolus and infusion B) No hypovolemia: infusion of lactated Ringer Solution 1.5 ml/kg/h C) Fluid overload: infusion rate of lactated Ringer Solution will be decreased or stopped Similar adjustments are repeated at 24(±4), 48(±4) and 72(±4) hours Fluid resuscitation is maintained at least 48h, and then it can be stopped in case of tolerating oral feeding for at least 8 hours
Receives: Drug: Lactated Ringer Solution
Moderate fluid resuscitationExperimentalAt recruitment: A) Hypovolemia: Lactated Ringer Solution 10 ml/kg bolus (administered over 2 hours) followed by an infusion of 1.5 ml/kg/h. B) No hypovolemia: infusion of lactated Ringer Solution of 1.5 ml/kg/h (no bolus). At 12(±4) hours: A) Hypovolemia: same bolus and infusion B) No hypovolemia: infusion of lactated Ringer Solution 1.5 ml/kg/h C) Fluid overload: infusion rate of lactated Ringer Solution will be decreased or stopped Similar adjustments are repeated at 24(±4), 48(±4) and 72(±4) hours Fluid resuscitation can be stopped before the first 48h in case of tolerating oral feeding for at least 8 hours
Receives: Drug: Lactated Ringer Solution

What is being measured

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

  1. Moderate-to-severe acute pancreatitis

    Moderate or severe category of the Revised Atlanta Classification (Banks et al, Gut 2013)

    Measured: From admission to discharge, up to 24 weeks

Secondary outcomes (13)

  1. Death and/or persistent organ failure and/or infection of pancreatic necrosis

    Analyzed as a composite endpoint and each of its components, includes in-hospital mortality, persistent organ failure (according to the revised Atlanta classification, Banks et al, Gut 2013) or infection of pancreatic necrosis

    Measured: From admission to discharge, up to 24 weeks

  2. Fluid overload

    Fluid overload is defined by the absence of Acute Respiratory Distress Syndrome and at least 2 of the following 3 criteria (based on Sharma et al, Lancet Diabetes Endocrinol 2016, with modifications):

    Criteria 1. Hemodynamic-imaging evidence (≥1):

    • Non-invasive diagnostic evidence of heart failure (i.e., echocardiographic, cardiac MRI)
    • Radiographic evidence of pulmonary congestion
    • Invasive cardiac catheterization suggesting evidence of heart failure (i.e., pulmonary capillary wedge pressure [or left ventricular end-diastolic pressure] >18 mm Hg, right arterial pressure [or central venous pressure] >12 mm Hg, or cardiac index < 2·2 L/min per m2)

    Criteria 2. Heart failure symptoms (1):

    • Dyspnea

    Criteria 3. Heart failure signs (≥1):

    • Peripheral edema
    • Pulmonary rales or crackles, or crepitation
    • Increased jugular venous pressure, hepatojugular reflux, or both

    Measured: From admission to discharge, up to 24 weeks

  3. Shock

    Systolic blood pressure <90 mmHg after fluid resuscitation

    Measured: From admission to discharge, up to 24 weeks

  4. Respiratory failure

    PaO2/FIO2<300

    Measured: From admission to discharge, up to 24 weeks

  5. Kidney failure

    Creatinine >1.9 mg/dL

    Measured: From admission to discharge, up to 24 weeks

  6. Local complications (acute peripancreatic fluid collections/ pancreatic necrosis/peripancreatic necrosis)

    As described on the revised Atlanta classification, Banks et al, Gut 2013

    Measured: From admission to discharge, up to 24 weeks

  7. Length of hospital stay

    Measured: From admission to discharge, up to 24 weeks

  8. Intensive care unit stay

    Need for intensive care unit (ICU) admission, and days admitted in the ICU

    Measured: From admission to discharge, up to 24 weeks

  9. Need for invasive treatment

    Endoscopic, percutaneous or surgical treatment of acute pancreatitis complications

    Measured: From admission to discharge, up to 24 weeks

  10. Need for nutritional support

    Need for enteral/parenteral feeding

    Measured: From admission to discharge, up to 24 weeks

  11. PAN-PROMISE scale

    Score on an acute pancreatitis Patient-Reported Outcome Measurement

    Measured: At 12, 24, 48 and 72 hours

  12. C-reactive protein

    Blood levels of C-reactive protein

    Measured: 48 and 72 hours

  13. Systemic inflammatory response syndrome (SIRS)

    SIRS at the different checkpoints. Presence of persistent (>48h) SIRS

    Measured: Baseline, 12, 24, 48 and 72 hours

Timeline

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

  1. First posted8 May 2020
  2. Study start28 May 2020
  3. Primary completion25 Sep 2021
  4. Study completion25 Sep 2021

Why it stopped: Increased frequency of fluid overload on the aggressive fluid resuscitation arm of treatment

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 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
249 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04381169
Sponsor's protocol ID
CEIM HGUA 2019/003
Other IDs
PI19/01628, 2019-000788-26, 2019
Acronym
WATERFALL
Status last verified
Mar 2022
First submitted
2 May 2020
Last updated
21 Mar 2022
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, Tsiotos GG, Vege SS; Acute Pancreatitis Classification Working Group. Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013 Jan;62(1):102-11. doi: 10.1136/gutjnl-2012-302779. Epub 2012 Oct 25.

    PubMed 23100216

  • de-Madaria E, Buxbaum JL, Maisonneuve P, Garcia Garcia de Paredes A, Zapater P, Guilabert L, Vaillo-Rocamora A, Rodriguez-Gandia MA, Donate-Ortega J, Lozada-Hernandez EE, Collazo Moreno AJR, Lira-Aguilar A, Llovet LP, Mehta R, Tandel R, Navarro P, Sanchez-Pardo AM, Sanchez-Marin C, Cobreros M, Fernandez-Cabrera I, Casals-Seoane F, Casas Deza D, Lauret-Brana E, Marti-Marques E, Camacho-Montano LM, Ubieto V, Ganuza M, Bolado F; ERICA Consortium. Aggressive or Moderate Fluid Resuscitation in Acute Pancreatitis. N Engl J Med. 2022 Sep 15;387(11):989-1000. doi: 10.1056/NEJMoa2202884.

    PubMed 36103415

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Lactated Ringer Solution in people with Acute Pancreatitis, run by Enrique de-Madaria at 2 sites in Spain.

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 2 inclusion and 13 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: stopped early, as of the sponsor's last update on 21 Mar 2022. 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 Spain. 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?

The study was stopped early (reason given: Increased frequency of fluid overload on the aggressive fluid resuscitation arm of treatment). Results are not available in the source record.

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?

Moderate-to-severe acute pancreatitis (time frame: From admission to discharge, up to 24 weeks). 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 NCT04381169, which also lists 2 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 Mar 2022.

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