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

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ClinicalTrials.gov Identifier: NCT04381169
Recruitment Status : Terminated (Increased frequency of fluid overload on the aggressive fluid resuscitation arm of treatment)
First Posted : May 8, 2020
Last Update Posted : March 21, 2022
Sponsor:
Collaborators:
Instituto de Salud Carlos III
Asociación Española de Gastroenterología
Asociación Española de Pancreatología
Information provided by (Responsible Party):
Enrique de-Madaria, Hospital General Universitario de Alicante

Brief 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. 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


Condition or disease Intervention/treatment Phase
Acute Pancreatitis Drug: Lactated Ringer Solution Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 249 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 28, 2020
Actual Primary Completion Date : September 25, 2021
Actual Study Completion Date : September 25, 2021


Arm Intervention/treatment
Experimental: Aggressive fluid resuscitation

Lactated 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

Drug: Lactated Ringer Solution
Comparison of aggressive versus moderate Lactated Ringer-based fluid resuscitation
Other Names:
  • Aggressive fluid resuscitation
  • Moderate fluid resuscitation
  • Restrictive fluid resuscitation

Experimental: Moderate fluid resuscitation

At 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

Drug: Lactated Ringer Solution
Comparison of aggressive versus moderate Lactated Ringer-based fluid resuscitation
Other Names:
  • Aggressive fluid resuscitation
  • Moderate fluid resuscitation
  • Restrictive fluid resuscitation




Primary Outcome Measures :
  1. Moderate-to-severe acute pancreatitis [ Time Frame: From admission to discharge, up to 24 weeks ]
    Moderate or severe category of the Revised Atlanta Classification (Banks et al, Gut 2013)


Secondary Outcome Measures :
  1. Death and/or persistent organ failure and/or infection of pancreatic necrosis [ Time Frame: From admission to discharge, up to 24 weeks ]
    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

  2. Fluid overload [ Time Frame: From admission to discharge, up to 24 weeks ]

    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

  3. Shock [ Time Frame: From admission to discharge, up to 24 weeks ]
    Systolic blood pressure <90 mmHg after fluid resuscitation

  4. Respiratory failure [ Time Frame: From admission to discharge, up to 24 weeks ]
    PaO2/FIO2<300

  5. Kidney failure [ Time Frame: From admission to discharge, up to 24 weeks ]
    Creatinine >1.9 mg/dL

  6. Local complications (acute peripancreatic fluid collections/ pancreatic necrosis/peripancreatic necrosis) [ Time Frame: From admission to discharge, up to 24 weeks ]
    As described on the revised Atlanta classification, Banks et al, Gut 2013

  7. Length of hospital stay [ Time Frame: From admission to discharge, up to 24 weeks ]
  8. Intensive care unit stay [ Time Frame: From admission to discharge, up to 24 weeks ]
    Need for intensive care unit (ICU) admission, and days admitted in the ICU

  9. Need for invasive treatment [ Time Frame: From admission to discharge, up to 24 weeks ]
    Endoscopic, percutaneous or surgical treatment of acute pancreatitis complications

  10. Need for nutritional support [ Time Frame: From admission to discharge, up to 24 weeks ]
    Need for enteral/parenteral feeding

  11. PAN-PROMISE scale [ Time Frame: At 12, 24, 48 and 72 hours ]
    Score on an acute pancreatitis Patient-Reported Outcome Measurement

  12. C-reactive protein [ Time Frame: 48 and 72 hours ]
    Blood levels of C-reactive protein

  13. Systemic inflammatory response syndrome (SIRS) [ Time Frame: Baseline, 12, 24, 48 and 72 hours ]
    SIRS at the different checkpoints. Presence of persistent (>48h) SIRS



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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);
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04381169


Locations
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Spain
Alicante
Alicante, Spain, 03010
Hospital General Universitario de Alicante
Alicante, Spain, 03550
Sponsors and Collaborators
Enrique de-Madaria
Instituto de Salud Carlos III
Asociación Española de Gastroenterología
Asociación Española de Pancreatología
  Study Documents (Full-Text)

Documents provided by Enrique de-Madaria, Hospital General Universitario de Alicante:
Publications:
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Responsible Party: Enrique de-Madaria, Principal Investigator of the AUGH Clinical Pancreatology Research Group, Hospital General Universitario de Alicante
ClinicalTrials.gov Identifier: NCT04381169    
Other Study ID Numbers: CEIM HGUA 2019/003
PI19/01628 ( Other Grant/Funding Number: Instituto de Salud Carlos III )
2019-000788-26 ( EudraCT Number )
First Posted: May 8, 2020    Key Record Dates
Last Update Posted: March 21, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by Enrique de-Madaria, Hospital General Universitario de Alicante:
Acute pancreatitis; fluid resuscitation; therapy; outcomes; randomized controlled trial; Ringer lactate; Lactated Ringer's solution
Additional relevant MeSH terms:
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Pancreatitis
Pancreatic Diseases
Digestive System Diseases