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

• ClinicalTrials.gov Identifier: NCT04381169
• Recruitment Status: Terminated
• First Posted: May 8, 2020
• Last Update Posted: March 21, 2022
• Sponsor: Enrique de-Madaria
• 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

Study Description

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

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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

Eligibility Criteria

• 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

Contacts and Locations

Locations

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:

Study Protocol and Statistical Analysis Plan  [PDF] May 5, 2020

More Information

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.

• 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
• Last Update Posted: March 21, 2022
• Last Verified: March 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

Pancreatitis; Pancreatic Diseases; Digestive System Diseases