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

Acute Pancreatitis Clinical Trial

— WATERFALL  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04381169
• Other study ID #: CEIM HGUA 2019/003
• Secondary ID: PI19/016282019-0
• Status: Terminated
• Phase: Phase 3
• Start date: May 28, 2020
• Est. completion date: September 25, 2021

Study information

• Verified date: March 2022
• Source: Hospital General Universitario de Alicante
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 249
• Est. completion date: September 25, 2021
• Est. primary completion date: September 25, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Pancreatitis
• Pancreatitis

Intervention

Drug:
• Lactated Ringer Solution
Comparison of aggressive versus moderate Lactated Ringer-based fluid resuscitation

Locations

Country	Name	City	State
Spain	Alicante	Alicante
Spain	Hospital General Universitario de Alicante	Alicante

Sponsors (4)

Lead Sponsor	Collaborator
Enrique de-Madaria	Asociación Española de Gastroenterología, Asociación Española de Pancreatología, Instituto de Salud Carlos III

Country where clinical trial is conducted

Spain, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Moderate-to-severe acute pancreatitis	Moderate or severe category of the Revised Atlanta Classification (Banks et al, Gut 2013)	From admission to discharge, up to 24 weeks
Secondary	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	From admission to discharge, up to 24 weeks
Secondary	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	From admission to discharge, up to 24 weeks
Secondary	Shock	Systolic blood pressure <90 mmHg after fluid resuscitation	From admission to discharge, up to 24 weeks
Secondary	Respiratory failure	PaO2/FIO2<300	From admission to discharge, up to 24 weeks
Secondary	Kidney failure	Creatinine >1.9 mg/dL	From admission to discharge, up to 24 weeks
Secondary	Local complications (acute peripancreatic fluid collections/ pancreatic necrosis/peripancreatic necrosis)	As described on the revised Atlanta classification, Banks et al, Gut 2013	From admission to discharge, up to 24 weeks
Secondary	Length of hospital stay		From admission to discharge, up to 24 weeks
Secondary	Intensive care unit stay	Need for intensive care unit (ICU) admission, and days admitted in the ICU	From admission to discharge, up to 24 weeks
Secondary	Need for invasive treatment	Endoscopic, percutaneous or surgical treatment of acute pancreatitis complications	From admission to discharge, up to 24 weeks
Secondary	Need for nutritional support	Need for enteral/parenteral feeding	From admission to discharge, up to 24 weeks
Secondary	PAN-PROMISE scale	Score on an acute pancreatitis Patient-Reported Outcome Measurement	At 12, 24, 48 and 72 hours
Secondary	C-reactive protein	Blood levels of C-reactive protein	48 and 72 hours
Secondary	Systemic inflammatory response syndrome (SIRS)	SIRS at the different checkpoints. Presence of persistent (>48h) SIRS	Baseline, 12, 24, 48 and 72 hours