Clinical trial NCT04381169: Aggressive Versus Non-aggressive Goal-directed Fluid Resuscitation in Acute Pancreatitis
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Acute Pancreatitis
Keywords: Acute pancreatitis; fluid resuscitation; therapy; outcomes; randomized controlled trial; Ringer lactate; Lactated Ringer's solution
Lead sponsor: Hospital General Universitario de Alicante
Sponsor class: OTHER
Collaborators: name: Instituto de Salud Carlos III
name: Asociación Española de Gastroenterología
name: Asociación Española de Pancreatología
First posted: 2020-05-08
Enrollment: 249
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


Eligibility 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

Primary outcomes:
measure: Moderate-to-severe acute pancreatitis
timeFrame: From admission to discharge, up to 24 weeks
Secondary outcomes:
measure: Death and/or persistent organ failure and/or infection of pancreatic necrosis
timeFrame: From admission to discharge, up to 24 weeks
measure: Fluid overload
timeFrame: From admission to discharge, up to 24 weeks
measure: Shock
timeFrame: From admission to discharge, up to 24 weeks
measure: Respiratory failure
timeFrame: From admission to discharge, up to 24 weeks
measure: Kidney failure
timeFrame: From admission to discharge, up to 24 weeks
measure: Local complications (acute peripancreatic fluid collections/ pancreatic necrosis/peripancreatic necrosis)
timeFrame: From admission to discharge, up to 24 weeks
measure: Length of hospital stay
timeFrame: From admission to discharge, up to 24 weeks
measure: Intensive care unit stay
timeFrame: From admission to discharge, up to 24 weeks
measure: Need for invasive treatment
timeFrame: From admission to discharge, up to 24 weeks
measure: Need for nutritional support
timeFrame: From admission to discharge, up to 24 weeks
measure: PAN-PROMISE scale
timeFrame: At 12, 24, 48 and 72 hours
measure: C-reactive protein
timeFrame: 48 and 72 hours
measure: Systemic inflammatory response syndrome (SIRS)
timeFrame: Baseline, 12, 24, 48 and 72 hours
Other outcomes:
Locations:
city: Alicante
country: Spain
facility: Alicante
city: Alicante
country: Spain
facility: Hospital General Universitario de Alicante
Study officials:
References:
citation: 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.
citation: 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.