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| Name | Class |
|---|---|
| Instituto de Salud Carlos III | OTHER_GOV |
| Universidad Miguel Hernandez de Elche | OTHER |
| Hospital del Mar | OTHER |
| Hospital Clinico Universitario de Santiago |
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Background: Some evidence suggests that fluid resuscitation with lactated Ringer's solution (LR) may have an anti-inflammatory effect on acute pancreatitis (AP) when compared to normal saline (NS), and may be associated with a decrease in severity, but existing single center randomized controlled trials showed conflicting results. The WATERLAND trial aims to investigate the efficacy and safety of fluid resuscitation using LR compared to NS in patients with AP.
Methods: The WATERLAND trial is an international multicenter, open-label, parallel-group, randomized, controlled, superiority trial. Patients will be randomly assigned in a 1:1 ratio to receive LR versus NS-based fluid resuscitation for at least 48 hours. The primary outcome will be moderately severe or severe AP, according to the revision of the Atlanta classification. The secondary objectives of the WATERLAND trial are to determine the effect of LR versus NS fluid resuscitation on several efficacy and safety outcomes in patients with AP.
A total sample of 720 patients, 360 in the LR group and 360 in the NS group, will achieve 90% power to detect a difference between the group proportions of 10%, assuming that the frequency of moderately severe or severe AP in the LR group will be 17%. A loss to follow-up of 10% of patients is expected, so the total sample size will be 396 patients in each treatment arm (792 patients overall). The test statistic used is the two-sided Z test with pooled variance set at a 0.05 significance level.
Discussion: The WATERLAND study aims to improve the early management of AP. Fluid resuscitation is an inexpensive treatment available in any hospital center worldwide. If a better evolution of pancreatitis is demonstrated in one of the treatment arms, it would have important repercussions in the management of this frequent disease.
The entire protocol is published in open-access format, including the Statistical Analysis plan, in the journal Trials: https://doi.org/10.1186/s13063-024-08539-2
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Lactated Ringer solution (LR) | Experimental | LR: Lactated Ringer solution. Patients in the LR treatment arm will receive fluid therapy based on lactated Ringer's solution for a minimum of 48 hours. |
|
| Normal saline (NS) | Active Comparator | NS: Normal Saline. Patients in the NS treatment arm will receive fluid therapy based on normal saline for a minimum of 48 hours. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Lactated Ringer Solution | Drug | Patients in the LR (Lactated Ringer solution) treatment arm will receive fluid therapy based on lactated Ringer's solution for a minimum of 48 hours. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants with moderately severe or severe acute pancreatitis | Presence of local complications, exacerbation of previous comorbidity or organ failure, according to the definitions of these complications provided by the revised Atlanta Classification (https://doi.org/10.1136/gutjnl-2012-302779) | From date of randomization until 30 days after randomization |
| Measure | Description | Time Frame |
|---|---|---|
| Number of participants with local complications | Presence of acute peripancreatic fluid collections, acute necrotic collection, pseudocyst, walled-off necrosis, gastric outlet dysfunction, splenic or portal vein thrombosis, and colonic necrosis according to the revised Atlanta Classification (https://doi.org/10.1136/gutjnl-2012-302779). | From date of randomization until 30 days after randomization |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Enrique de-Madaria, MD PhD | Dr. Balmis General University Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Dr. Balmis General University Hospital | Alicante | 03010 | Spain |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23100216 | Background | 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. | |
| 36103415 |
| Label | URL |
|---|---|
| Published study protocol and statistical analysis plan | View source |
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Members of the ERICA consortium that recruited patients in the WATERLAND trial may claim access to the final dataset to perform post-hoc studies; these proposals will be studied by the steering committee.
Data will be available upon publication of the main study.
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Sep 18, 2023 | Jan 16, 2025 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D010195 | Pancreatitis |
| ID | Term |
|---|---|
| D010182 | Pancreatic Diseases |
| D004066 | Digestive System Diseases |
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| ID | Term |
|---|---|
| D000077325 | Ringer's Lactate |
| D000077330 | Saline Solution |
| ID | Term |
|---|---|
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |
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| OTHER |
| Hospital Clínico Universitario de Valencia | OTHER |
| Hospital Costa del Sol | OTHER |
| Corporacion Parc Tauli | OTHER |
| Hospital Clínico Universitario Lozano Blesa | OTHER |
| Hospital General Universitario Gregorio Marañon | OTHER |
| Hospital Universitario La Fe | OTHER |
| Hospital Miguel Servet | OTHER |
| Hospital Universitario Ramon y Cajal | OTHER |
| Hospital Universitario Insular Gran Canaria | OTHER |
| University Hospital Virgen de las Nieves | OTHER |
| Hospital Universitario de Burgos | OTHER |
| Hospital Universitario Lucus Augusti | OTHER |
| Hospital Universitario Marqués de Valdecilla | OTHER |
| Hospital Universitario Puerta del Mar | OTHER |
| Instituto de Investigación Sanitaria Hospital Universitario de la Princesa | OTHER |
| Hospital Universitario de Gran Canaria Doctor Negrín | OTHER |
| Hospital Regional de Alta Especialidad del Bajio | OTHER |
| Asian Institute Of Medical Sciences | OTHER |
| Hospital Dr. Jaime Mendoza Sucre Bolivia | UNKNOWN |
| Hayatabad Medical Complex | OTHER_GOV |
| University Hospital Olomouc | OTHER |
| SIDS Hospital & Research Centre Gujarat India | UNKNOWN |
| Sanatorio Allende | OTHER |
| University Hospital Bratislava | OTHER |
| University Hospital Sestre Milosrdnice | OTHER |
| Attikon Hospital | OTHER |
| Nuevo Hospital Iturraspe Santa Fe Argentina | UNKNOWN |
| Hospital Nacional Rosales | OTHER |
| Zagazig University | OTHER_GOV |
| University of Utah | OTHER |
| Hospitales Universitarios Virgen del Rocío | OTHER |
| University Hospital of Girona Dr. Josep Trueta | NETWORK |
| Hospital of Navarra | OTHER |
| Hospital Clínico Universitario de Valladolid | OTHER |
| Hospital Universitario Central de Asturias | OTHER |
| Kalinga Hospital, Bhubaneswar | OTHER |
| Ohio State University | OTHER |
| Zhengzhou University | OTHER |
| Jinling Hospital, China | OTHER |
| Hospital Privado de Cordoba, Argentina | OTHER |
| Prince of Wales Hospital, Shatin, Hong Kong | OTHER |
| Postgraduate Institute of Medical Education and Research in Chandigarh | OTHER |
| RML Specialty Hospital | OTHER |
| Wannan Medical College Yijishan Hospital | OTHER |
| Bucharest Emergency Hospital | OTHER |
| The First Affiliated Hospital of Henan University of Science and Technology | OTHER |
| Emergency County Hospital Pius Brinzeu; Timisoara, Romania | NETWORK |
| King Hamad University Hospital, Bahrain | OTHER |
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| Normal saline | Drug | Patients in the NS (Normal Saline) treatment arm will receive fluid therapy based on lactated Ringer's solution for a minimum of 48 hours. |
|
| Number of participants with necrotizing pancreatitis | Presence of acute necrotic collections according to the revised Atlanta Classification (https://doi.org/10.1136/gutjnl-2012-302779). | From date of randomization until 30 days after randomization |
| Number of participants with infection of pancreatic collections or necrosis | Extraluminal gas in the pancreatic and/or peripancreatic tissues on CT scan or when a sample from the collection/necrosis contains pus or is positive for bacteria and/or fungi on Gram stain or culture. | From date of randomization until 30 days after randomization |
| Number of participants with systemic inflammatory response syndrome | At least 2 criteria: A) pulse >90 beats/min, B) respirations >20/min or arterial blood PaCO2 <32 mm Hg, C) temperature <36°C or >38°C, D) white blood cell count <4,000 cells/mm3 or >12,000 cells/mm3 or >10% bands | At 24 and 48 hours |
| Number of systemic inflammatory response syndrome criteria | The criteria are: A) pulse >90 beats/min, B) respirations >20/min or arterial blood PaCO2 <32 mm Hg, C) temperature <36°C or >38°C, D) white blood cell count <4,000 cells/mm3 or >12,000 cells/mm3 or >10% bands | At 24 and 48 hours |
| PAN-PROMISE symptom scale | PAN-PROMISE scale: a 7-symptom scale patient-reported outcome (range, 0 to 10 for each symptom; overall range, 0 to 70, with higher scores indicating higher symptom intensity). Details: https://doi.org/10.1136/gutjnl-2020-320729 | At 24 and 48 hours (final value and change from baseline) |
| Time to oral refeeding | Days from baseline to oral refeeding | From date of randomization until 30 days after randomization |
| Number of participants with invasive treatment | Any of the following: thoracocentesis due to pancreatitis-induced pleural effusion, percutaneous and/or endoscopic drainage of pancreatic or peripancreatic fluid collections or necrosis, endoscopic or surgical necrosectomy, endoscopic retrograde cholangiopancreatography due to A) ruptured common bile duct, B) jaundice caused by compression of the common bile duct, C) main pancreatic duct leakage | From date of randomization until 30 days after randomization |
| Number of participants with nutritional support | Use of enteral (nasogastric or nasojejunal) or parenteral feeding | From date of randomization until 30 days after randomization |
| Number of participants with intensive care unit admission | Admission in the intensive care unit | From date of randomization until 30 days after randomization |
| Number of participants with exacerbation of coexisting condition | Exacerbation of pre-existing co-morbidity. The definition provided by the Revised Atlanta Classification is " Exacerbation of pre-existing co-morbidity, such as coronary artery disease or chronic lung disease, precipitated by the acute pancreatitis is defined as a systemic complication. In this document, we distinguish between persistent organ failure (the defining feature of severe acute pancreatitis) and other systemic complications, which are an exacerbation of pre-existing co-morbid disease." (revised Atlanta classification: https://doi.org/10.1136/gutjnl-2012-302779) For the WATERLAND trial we define exacerbation of pre-existing co-morbidity as | From date of randomization until 30 days after randomization |
| Number of participants with any organ failure | Definition according to the revised Atlanta classification (https://doi.org/10.1136/gutjnl-2012-302779): organ failure is defined by the presence of any of the following criteria: A) kidney failure as a creatinine ≥1.9 mg/dL or >170 micromol/L, B) cardiovascular failure as a systolic blood pressure <90 mmHg despite fluid resuscitation, and C) respiratory failure as a PaO2/FIO2≤300 | From date of randomization until 30 days after randomization |
| Number of participants with persistent organ failure | Organ failure lasting more than 48h (revised Atlanta classification: https://doi.org/10.1136/gutjnl-2012-302779) | From date of randomization until 30 days after randomization |
| Number of participants with shock | Systolic blood pressure <90 mmHg despite fluid resuscitation (revised Atlanta classification: https://doi.org/10.1136/gutjnl-2012-302779) | From date of randomization until 30 days after randomization |
| Number of participants with respiratory failure | PaO2/FIO2≤300 (revised Atlanta classification: https://doi.org/10.1136/gutjnl-2012-302779) | From date of randomization until 30 days after randomization |
| Number of participants with kidney failure | Creatinine ≥1.9 mg/dL or >170 micromol/L (revised Atlanta classification: https://doi.org/10.1136/gutjnl-2012-302779) | From date of randomization until 30 days after randomization |
| Mortality (number of participants) | Death | From date of randomization until 30 days after randomization |
| Hospital stay | Days from recruitment to discharge from index admission | From date of randomization until 30 days after randomization |
| C-reactive protein | C-reactive protein blood levels | At 48 hours from randomization |
| Number of participants with hypovolemia | WATERFALL trial criteria for hypovolemia (see https://www.nejm.org/doi/10.1056/NEJMoa2202884) | At 24 and 48 hours from randomization |
| Number of participants with fluid overload | WATERFALL trial criteria for fluid overload (see https://www.nejm.org/doi/10.1056/NEJMoa2202884) | From randomization to 72 h thereafter |
| Number of participants with acute kidney injury | KDIGO criteria: increase in serum creatinine of ≥0.3 mg/dL within 48 hr or ≥50% within 7 days or urine output of <0.5 mL/kg/hr for >6 hr (https://doi.org/10.1159/000339789) | At 24 and 48 hours from randomization |
| Number of participants with hyperkalemia | Venous potassium>5mEq/L | At 24 and 48 hours from randomization |
| Number of participants with hypercalcemia | Venous calcium corrected by proteins>10.5mg/dL or 2.62 mmol/L | At 24 and 48 hours from randomization |
| Number of participants with hyperchloremia | Venous chloride>106mEq/L | At 24 and 48 hours from randomization |
| Number of participants with acidosis | Venous blood pH <7.35 | At 24 and 48 hours from randomization |
| Number of participants with hyperchloremic acidosis | Patients with venous chloride>106mEq/L and venous blood pH <7.35 | At 24 and 48 hours from randomization |
| Number of participants with composite safety outcome (primary safety outcome) | Fluid overload or acute kidney injury or hyperkalemia or hypercalcemia or hyperchloremia or acidosis | At 24 and 48 hours from randomization |
| 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. |
| 32245906 | Background | de-Madaria E, Sanchez-Marin C, Carrillo I, Vege SS, Chooklin S, Bilyak A, Mejuto R, Mauriz V, Hegyi P, Marta K, Kamal A, Lauret-Brana E, Barbu ST, Nunes V, Ruiz-Rebollo ML, Garcia-Rayado G, Lozada-Hernandez EE, Pereira J, Negoi I, Espina S, Hollenbach M, Litvin A, Bolado-Concejo F, Vargas RD, Pascual-Moreno I, Singh VK, Mira JJ. Design and validation of a patient-reported outcome measure scale in acute pancreatitis: the PAN-PROMISE study. Gut. 2021 Jan;70(1):139-147. doi: 10.1136/gutjnl-2020-320729. Epub 2020 Apr 3. |
| 39434191 | Background | Guilabert L, Cardenas-Jaen K, Vaillo-Rocamora A, Garcia Garcia de Paredes A, Chhoda A, Sheth SG, Lopez-Valero C, Zapater P, Navarrete-Munoz EM, Maisonneuve P, Hernandez-Barco YG, Capurso G, Buxbaum JL, de-Madaria E; ERICA consortium. Normal saline versus lactated Ringer's solution for acute pancreatitis resuscitation, an open-label multicenter randomized controlled trial: the WATERLAND trial study protocol. Trials. 2024 Oct 21;25(1):699. doi: 10.1186/s13063-024-08539-2. |