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

NCT04381169 | Terminated Phase 3 DMC

• 3 other identifiers: CEIM HGUA 2019/003PI19/016282019-000788-26
• Study Type: interventional
• Target: 249
• Locations: 1 country
• Sites: 2

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

Conditions

Acute Pancreatitis

Keywords

Acute pancreatitis; fluid resuscitation; therapy; outcomes; randomized controlled trial; Ringer lactate; Lactated Ringer's solution

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (13)

• Death and/or persistent organ failure and/or infection of pancreatic necrosis

  From admission to discharge, up to 24 weeks

• Fluid overload

  From admission to discharge, up to 24 weeks

• Shock

  From admission to discharge, up to 24 weeks

• Respiratory failure

  From admission to discharge, up to 24 weeks

• Kidney failure

  From admission to discharge, up to 24 weeks

Study Arms (2)

Aggressive fluid resuscitation

EXPERIMENTAL

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

Moderate fluid resuscitation

EXPERIMENTAL

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

Interventions

Lactated Ringer Solution DRUG

Comparison of aggressive versus moderate Lactated Ringer-based fluid resuscitation

Also known as: Aggressive fluid resuscitation, Moderate fluid resuscitation, Restrictive fluid resuscitation

Aggressive fluid resuscitation; Moderate fluid resuscitation

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Enrique de-Madaria: lead
• Instituto de Salud Carlos III: collaborator
• Asociación Española de Gastroenterología: collaborator
• Asociación Española de Pancreatología: collaborator

Study Sites (2)

Alicante

Alicante, 03010, Spain

Location

Hospital General Universitario de Alicante

Alicante, 03550, Spain

Location

Related Publications (2)

• 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.

  PMID: 23100216 BACKGROUND

• 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.

  PMID: 36103415 DERIVED

MeSH Terms

Conditions

Pancreatitis

Interventions

Ringer's Lactate

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator of the AUGH Clinical Pancreatology Research Group

Study Record Dates

• First Submitted: May 2, 2020
• First Posted: May 8, 2020
• Study Start: May 28, 2020
• Primary Completion: September 25, 2021
• Study Completion: September 25, 2021
• Last Updated: March 21, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will not share

Locations

ES (2)