Normal Saline Versus Lactated Ringer's Solution for Acute Pancreatitis Resuscitation, an Open-label Multicenter Randomized Controlled Trial: the WATERLAND Trial
Phase: PHASE4
Conditions: Acute Pancreatitis
Sponsor: Enrique de-Madaria

 
1 
Official Title of the Study: 
Normal saline versus lactated Ringer’s solution for acute pancreatitis resuscitation, an 
open-label multicenter randomized controlled trial: the WATERLAND trial study 
protocol 
 
NTC number: NCT05781243 
 
Date of the document: Version 4, September 18, 2023 
 
 

 
2 
Protocol contributors 
Lucía Guilabert, 1 Karina Cárdenas-Jaén, 1 Alicia Vaillo-Rocamora, 1 Ana García García de 
Paredes, 2 3 Ankit Chhoda, 4 Sunil G. Sheth, 4 Carlos López-Valero, 5 Pedro Zapater, 3 6 7 
Eva M. Navarrete-Muñoz, 8 9 Patrick Maisonneuve, 10 Yasmin G. Hernández-Barco, 11 
Gabriele Capurso, 12 James L. Buxbaum, 13 Enrique de-Madaria, 1 14 for the ERICA 
consortium 15 
 
1 Gastroenterology Department, Dr. Balmis General University Hospital, ISABIAL, 
Alicante, Spain.  
2 Department of Gastroenterology and Hepatology, Hospital Universitario Ramón y 
Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, Universidad de Alcalá, Madrid, 
Spain. 
3 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas 
(CIBEREHD), Madrid, Spain. 
4 Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical 
School, Boston, USA.  
5 Acute pancreatitis patient advocate. 
6 Clinical Pharmacology Department, Dr. Balmis General University Hospital, ISABIAL, 
Alicante, Spain. 
7 IDiBE, Miguel Hernandez University, Elche, Spain. 
8 Grupo de Investigación en Terapia Ocupacional (InTeO), Department of Surgery and 
Pathology, Miguel Hernandez University-ISABIAL, Alicante, Spain. 
9 Joint research unit UMH-Fisabio (STATSALUT), Alicante, Spain. 

 
3 
10 Division of Epidemiology and Biostatistics, IEO European Institute of Oncology IRCCS, 
Milan, Italy. 
11 Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical 
School, Boston, USA. 
12 Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational 
and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Vita-Salute San 
Raffaele University, Milan, Italy. 
13 Division of Gastroenterology, University of Southern California, Los Angeles, USA. 
14 Department of Clinical Medicine, Miguel Hernandez University, Elche, Spain. 
15 ERICA: International League Against Biliary-Pancreatic Diseases. 
 

 
4 
Abstract 
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. 

 
5 
 
Trial registration: EudraCT number 2023-000010-18, registration date January 4, 2023. 
ClinicalTrials.gov Identifier: NCT05781243, first posted March 23, 2023 
Keywords 
Acute pancreatitis. Fluid resuscitation. Lactated Ringer solution. Normal saline. 
Randomized controlled trial.  
 
 
 

 
6 
Administrative information 
Title {1} 
Normal saline versus lactated Ringer’s solution for acute pancreatitis resuscitation, an 
open-label multicenter randomized controlled trial: the WATERLAND trial 
Trial registration {2a 
and 2b} 
EudraCT number 2023-000010-18, date of registration January 4, 2023. ClinicalTrials.gov 
Identifier: NCT05781243, first posted March 23, 2023 
Protocol version (1) 
Version 4, September 18, 2023. Version 1 was approved by the central ethics committee 
(Comité Ético de Investigación con Medicamentos, Hospital General Universitario Dr. 
Balmis, Alicante, Spain, project code 2023-031) on March 9, 2023. Version 4 was 
approved on September 29, 2023. 
Funding {4} 
Proyectos de I+D+I en Salud 2022, Acción Estratégica en Salud 2021-2023, grant number: 
PI22/00980, Instituto de Salud Carlos III, Ministry of Science and Innovation, Government 
of Spain, Madrid, Spain. Beca Gonzalo Miño, Spanish Association of Gastroenterology 
(Asociación Española de Gastroenterología, AEG), grant number: Gonzalo Miño Grant 
2024, Madrid, Spain. Beca Intramural, Alicante Institute of Health and Biomedical 
Research (ISABIAL), grant number: ayudas intramurales de ISABIAL modalidad C 2023, 
Alicante, Spain. UEG Research Prize, United European Gastroenterology (UEG), grant 
number: UEG Research Prize 2024, Vienna, Austria.  
Author details {5a} 
Lucía Guilabert, 1 Karina Cárdenas-Jaén, 1 Alicia Vaillo-Rocamora, 1 Ana García García de 
Paredes, 2 3 Ankit Chhoda, 4 Sunil G. Sheth, 4 Carlos López-Valero, 5 Pedro Zapater, 3 6 7 Eva 
M. Navarrete-Muñoz, 8 9 Patrick Maisonneuve, 10 Yasmin G. Hernández-Barco, 11 Gabriele 
Capurso, 12 James L. Buxbaum, 13 Enrique de-Madaria, 1 14 for the ERICA consortium 15 
 
1 Gastroenterology Department, Dr. Balmis General University Hospital, ISABIAL, 
Alicante, Spain.  
2 Department of Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, 
Instituto Ramón y Cajal de Investigación Sanitaria, Universidad de Alcalá, Madrid, Spain. 
3 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas 
(CIBEREHD), Madrid, Spain. 
4 Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical 
School, Boston, USA.  
5 Acute pancreatitis patient advocate. 
6 Clinical Pharmacology Department, Dr. Balmis General University Hospital, ISABIAL, 
Alicante, Spain. 
7 IDiBE, Miguel Hernandez University, Elche, Spain. 
8 Grupo de Investigación en Terapia Ocupacional (InTeO), Department of Surgery and 
Pathology, Miguel Hernandez University-ISABIAL, Alicante, Spain. 
9 Joint research unit UMH-Fisabio (STATSALUT), Alicante, Spain. 
10 Division of Epidemiology and Biostatistics, IEO European Institute of Oncology IRCCS, 
Milan, Italy. 
11 Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical 
School, Boston, USA. 
12 Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational and 
Clinical Research Center, San Raffaele Scientific Institute IRCCS, Vita-Salute San Raffaele 
University, Milan, Italy. 
13 Division of Gastroenterology, University of Southern California, Los Angeles, USA. 
14 Department of Clinical Medicine, Miguel Hernandez University, Elche, Spain. 
15 ERICA: International League Against Biliary-Pancreatic Diseases. 
Name 
and 
contact 
information for the trial 
sponsor {5b} 
Enrique de-Madaria. Gastroenterology Department, Dr. Balmis General University 
Hospital, ISABIAL, Alicante, Spain. Email: demadaria@ericaresearch.com. Address: 
Servicio de Aparato Digestivo, 4ª planta C (pabellón general), Hospital General 
Universitario Dr. Balmis- Pintor Baeza 12, 03010, Alicante, Spain.  
Role of sponsor {5c} 
 
This is a researcher-driven study. The sponsor participated in the study design and will 
participate in the collection, management, analysis, and interpretation of data, writing of 
the report, and the decision to submit the report for publication. The sponsor declares 

 
7 
no conflicts of interest. Funders are not directly involved in the study. Private companies 
with economic interest in fluid resuscitation will not be involved in this study.  
{}: SPIRIT checklist item numbers. (2)  
Introduction 
Background and rationale (SPIRIT checklist item number {6a}) (2) 
Acute pancreatitis (AP) is the third leading cause of hospital admission and readmission 
for digestive diseases (nearly 300,000 diagnoses in the United States in 2018). (3) 
Furthermore, its incidence is increasing, and the median total cost per hospitalization in 
2018 amounted to $22,817. (3) AP is an acute inflammatory disease with variable 
severity. According to the revision of the Atlanta classification (RAC), severe AP is 
defined by the development of persistent organ failure (lasting more than 48 hours), 
moderately severe by the presence of local complications, exacerbation of comorbidity, 
or transient organ failure (lasting ≤ 48 hours), and mild AP by the absence of organ 
failure, exacerbation of comorbidity and local complications. (4) Mild cases have 
minimal local and systemic inflammation with an uncomplicated clinical course and 
often a prompt recovery. Local complications, e.g. acute peripancreatic fluid collections, 
pancreatic or peripancreatic fat necrosis (4), occur in one-third of patients and are 
associated with a longer hospital stay, greater morbidity, and increased hospital costs. 
(5, 6) Of greatest concern are patients who develop uncontrolled systemic inflammatory 
response syndrome (SIRS) that can lead to organ failure, which is associated with 
significant mortality (5).  
 
The control of inflammation in the initial phase of AP may alter the clinical course of the 
disease by reducing the development of local and systemic complications and thus 
decreasing patient suffering, mortality, and costs. Unfortunately, no treatment has 

 
8 
consistently been shown to decrease the incidence of moderately severe or severe AP. 
(7-9) The current early management of AP consists of supportive treatment in which 
fluid resuscitation has played a central role in the last two decades. (10) Research in fluid 
resuscitation has focused on the volume of fluids (aggressive or moderate) (11-14) and 
the type of fluid. The recently published WATERFALL study demonstrated that early 
aggressive fluid resuscitation was associated with three times more episodes of fluid 
overload than moderate hydration and does not appear to reduce the severity of AP 
compared to moderate hydration. (15)  
 
Regarding the type of fluid which is best for AP, published results are conflicting. The 
two major types of fluids used in medicine are crystalloids and colloids. Crystalloids have 
an osmotic pressure equivalent to plasma and contain water-soluble electrolytes such 
as sodium. (16) Colloids, which have a higher oncotic pressure, were designed to allow 
the supplied water to remain more effectively and durably in the intravascular 
compartment than crystalloids. However, published trials do not suggest that they 
improve clinical results in intensive care patients (16-18) which has dampened 
enthusiasm for their widespread use. The two crystalloids most frequently used in 
clinical practice include normal saline (NS) and lactated Ringer's solution (LR). NS 
contains water and 0.9% sodium chloride (154 mEq/L of sodium and chlorine). With a 
chlorine content higher than plasma, large-volume infusions of NS may result in 
hyperchloremic acidosis. (16) LR contains less sodium and chloride (130 and 109 mEq/L 
respectively) and contains 28 mEq/L of lactate, in addition to calcium and potassium. LR 
is a balanced crystalloid due to its more neutral effect on acid-base physiology. (16) In 

 
9 
vitro studies suggest that the lactate present in the LR may have an anti-inflammatory 
effect. (19) 
 
In 2011, Wu et al. published an open-label clinical trial that included 40 patients with 
double randomization to A) LR or NS, and B) to a goal-directed volume protocol (titration 
to blood urea nitrogen levels) or standard management. No differences were detected 
in goal-directed versus standard management, but patients treated with LR had a lower 
incidence of SIRS and lower C-reactive protein (CRP) blood levels 24 hours after 
recruitment. (20) In 2018, our group published a triple-blind randomized clinical trial 
with 40 patients from a single center. We described that LR was associated with lower 
CRP levels at 48 and 72 hours. (19) In a 2018 open-label randomized clinical trial by 
Choosakul et al., 47 patients received LR or NS, demonstrating a lower proportion of 
patients with SIRS at 24 hours but not thereafter. (21) We conducted a larger double-
blind randomized clinical trial with 121 patients with predicted mild AP. In this study, LR 
was associated with a similar degree of inflammation as NS but with a shorter hospital 
stay and lower intensive care unit (ICU) admission. (22) A recent single-center 
randomized clinical trial with 51 patients (Karki et al.) also described less inflammation 
with LR. (23) There have been several meta-analyses of these studies, including our 
review, which incorporated unpublished data by contacting trial authors (248 patients 
from 4 trials were included). (24) In these studies, patients who received LR were less 
likely to suffer moderately severe or severe pancreatitis (odds ratio [OR] 0.49, 95% 
confidence interval [CI] 0.25-0.97), there were no differences in inflammation (SIRS) or 
organ failure, but they were less likely to be admitted to the ICU (OR 0.33, 95% CI 0.13-
0.81) or to develop local complications (OR 0.42, 95% CI 0.20-0.88). It has been 

 
10 
described in other different clinical scenarios than AP that NS is associated with renal 
failure. (25) Clinical trials in other diseases have shown conflicting results. In a double-
blind clinical trial at 4 hospital centers of critically ill patients, no benefit was shown for 
balanced fluids (Plasma-Lyte 148, which does not contain lactate) compared to NS. (26) 
In another single-center open-label clinical trial of critically ill patients comparing 
Plasma-Lyte A or LR versus NS, it was shown that NS was associated with a greater 
probability of renal failure. (25) Very recently, a double-blind study was published of 
critically ill patients from 53 ICUs that did not observe advantages of Plasma-Lyte 148 
compared to NS. (27) 
 
Reporting guidelines 
This protocol follows the recommendations of SPIRIT 2013 Statement: Definition of 
Standard Protocol Elements for Clinical Trials. (2) Numbers in curly brackets, e.g. {5a} 
are SPIRIT element identifiers. 
 
Objectives {7} 
The null hypothesis is that there is no difference in the incidence of moderately severe 
or severe disease in patients with AP receiving fluid resuscitation based on LR compared 
to NS. The alternative hypothesis is that fluid resuscitation based on LR is associated 
with a lower incidence of moderately severe or severe AP. 
 
The primary objective of the WATERLAND trial is to investigate the effect of fluid 
resuscitation based on LR versus NS on the severity of AP (frequency of moderately 
severe or severe disease).  

 
11 
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. 
 
Trial design {8} 
The WATERLAND trial is an international multicenter, open-label, parallel-group, 
randomized, controlled, superiority trial promoted by the ERICA (intERnational league 
agaInst biliary-pancreatiC diseAses) consortium. Patients will be randomly assigned in a 
1:1 ratio to receive LR versus NS-based fluid resuscitation. WATERLAND trial is a low-risk 
interventional pharmacological clinical trial.  
Methods 
Participants, interventions, and outcomes 
Study setting {9} 
The WATERLAND study is open to international academic or non-academic level 2 and 
level 3 hospitals. Current participating centers can be found on the following link: 
https://clinicaltrials.gov/ct2/show/NCT05781243 
 
Eligibility criteria {10} 
Center eligibility: hospitals that care for patients admitted for AP that can offer 
continuous care, with the availability of blood tests, abdominal ultrasound, abdominal 
computed tomography (CT), magnetic resonance imaging, endoscopic retrograde 
cholangiopancreatography (ERCP), interventional radiology, and ICU.  
Patient eligibility: Inclusion and exclusion criteria are provided in Table 1.  

 
12 
 
Informed consent {26a} 
The local study collaborators will obtain informed consent from potential trial 
participants or authorized surrogates. Informed consent is provided in the protocol 
Appendix.  
 
Additional consent provisions for collection and use of participant data and biological 
specimens {26b} 
Biological samples will not be obtained.  
 
Interventions 
Explanation for the choice of comparators {6b} 
As discussed in the background, some randomized clinical trials suggest that LR may be 
associated with less inflammation and better outcomes than NS. WATERLAND will 
compare LR—and NS-based fluid resuscitation in patients with AP.  
 
Intervention description {11a} 
The volume of fluids is based on the moderate treatment arm of the WATERFALL trial 
(1.5 mL/kg/hour preceded by bolus 10 mL/kg if the patient has hypovolemia). (15) The 
“participant timeline” shows more details; see below.  
 
Criteria for discontinuing or modifying allocated interventions {11b} 
LR and NS are fluids routinely used to treat AP and other diseases. The incidence of 
adverse effects in both is very low. In case of hyperkalemia or hypercalcemia, the 

 
13 
treating physician may discontinue the infusion of LR, which has a small amount of 
potassium and calcium, and the adverse effect will be recorded. NS can be associated 
with hyperchloremic acidosis if administered in massive amounts, so the treating 
physician may decide to suspend this fluid in case of this complication, as mentioned 
above. Patients may leave the study at any time after signing the informed consent. 
 
Strategies to improve adherence to interventions {11c} 
Adherence is assessed based on the percentage of subjects receiving ≥80% of the 
planned amount of fluids according to the study protocol in the first 48 hours. No 
measures are required to improve adherence to the interventions since it is an acute 
disease, and the study fluid is administered during the first days of hospitalization. 
 
Relevant concomitant care permitted or prohibited during the trial {11d} 
Potassium administration should be 40 mEq per day in both arms of treatment during 
fasting unless a higher or lower dose is clinically indicated. LR contains potassium at a 
concentration of 4 mEq/l and NS contains no potassium, which will be considered in the 
calculation of daily potassium administration. The attending physician will decide on 
feeding, treatment with analgesics, antibiotics, indications for ERCP, drainage, and all 
other treatment measures and administer as clinically appropriate. 
 
Provisions for post-trial care {30} 
Patients will be managed after the trial by the attending physician at his or her 
discretion. 
 

 
14 
Outcomes {12} 
Most outcomes will be assessed between randomization and 30 days after 
randomization unless assessment at 24, 48, or 72 hours is specified; see Tables 2 and 4. 
 
Efficacy outcomes 
The primary outcome will be moderately severe or severe AP, defined according to the 
RAC. (4) Moderately severe AP is defined in the first four weeks after disease onset as 
the presence of local complications (acute peripancreatic fluid collections, acute 
necrotic collection, gastric outlet dysfunction, splenic or portal vein thrombosis, and 
colonic necrosis) or systemic complications (exacerbation of a preexisting coexisting 
condition, such as coronary artery disease or chronic lung disease, precipitated by AP) 
or transient organ failure (organ failure that resolves within 48 hours). Severe AP is 
defined as persistent (lasting more than 48 hours) organ failure. Organ failure is defined 
according to the modified Marshall score by the presence of any of the following criteria: 
A) kidney failure as a creatinine ≥1.9 mg/dL or >170 µmol/L, B) cardiovascular failure as 
a systolic blood pressure <90 mmHg despite fluid resuscitation, and C) respiratory failure 
as a PaO2/FIO2≤300. (4) Patients with moderately severe or severe AP have increased 
morbidity (more time to oral refeeding, greater need for invasive treatment, more 
frequency of ICU admission, higher hospital stay, and increased mortality risk). (5) 
Moderately severe or severe AP was the primary efficacy outcome used in the 
WATERFALL trial, which compared aggressive versus moderate fluid resuscitation in 
acute pancreatitis. (15) RAC definitions for local complications diagnosed within the first 
4 weeks after disease onset (4) are as follows:  

 
15 
Acute peripancreatic fluid collections: peripancreatic fluid associated with interstitial 
edematous pancreatitis with no associated peripancreatic necrosis. This term applies 
only to areas of peripancreatic fluid seen within the first four weeks after the onset of 
interstitial edematous pancreatitis and without the features of a pseudocyst.  
Acute necrotic collection: a collection containing variable amounts of both fluid and 
necrosis associated with necrotizing pancreatitis; the necrosis can involve the pancreatic 
parenchyma and/or the peripancreatic tissues. Heterogeneous and non-liquid density 
of varying degrees in different locations (some appear homogeneous early in their 
course). No definable wall encapsulating the collection. Location: intrapancreatic and/or 
extrapancreatic. 
Gastric outlet dysfunction: Gastric outlet dysfunction typically presents with early 
satiety, weight loss, nausea, vomiting, and abdominal pain. (28) RAC provides no 
definition. In WATERLAND, it will be defined as a delay in gastric emptying that requires 
medical treatment (fasting, nasogastric or nasojejunal tube, prokinetics, etc.) or invasive 
treatment. Paralytic ileus should be ruled out.  
Splenic or portal vein thrombosis: RAC provides no definition. In WATERLAND it will be 
defined as partial or complete thrombosis in the splenic or portal vein in imaging. 
Mesenteric vein thrombosis will also be recorded.  
Colonic necrosis: RAC provides no definition. In WATERLAND it will be defined as colonic 
necrosis in imaging, endoscopy, or evidenced in surgical intervention.  
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 it is positive for bacteria and/or fungi on Gram stain or culture (adapted 
from RAC). 

 
16 
Mild AP without imaging tests: If a patient has mild AP, with rapid resolution of pain, 
absence of SIRS 48 hours after admission, and discharge within the first five days of 
admission, it is assumed that the patient has no local complications even without 
imaging evidence. 
Table 2 lists secondary outcome variables and their definitions. The PAN-PROMISE scale 
will be used to measure patient wellness. PAN-PROMISE is a Patient-Reported Outcome 
Measurement (PROM) that measures seven symptoms (range 0 to 10 for each symptom; 
overall range 0 to 70, with higher scores indicating higher symptom intensity). (6) 
 
Safety outcomes 
The safety outcomes will be a A) a composite variable involving any of the following: 
fluid overload, acute kidney injury, hyperkalemia, hypercalcemia, hyperchloremia, or 
acidosis; B) the individual components of the composite variable.  The attending 
physician will manage these complications as clinically appropriate. Fluid overload is 
defined in Table 3. (15) Safety outcomes are defined in Table 4.  
Severity of fluid overload is defined (15) as:  
A. Mild: patients respond to medical treatment or decrease in volume infusion rate, 
and the PaO2/FIO2 never decreases <300 
B. Moderate: patients respond to medical treatment or decrease in volume/infusion 
rate and have at least one measurement with PaO2/FIO2 <300 
C. Severe: patients require invasive or non-invasive mechanical ventilation, and/or 
hemofiltration, or expire due to overload 
NS has been associated with an increased risk of renal failure. (25) Acute kidney injury 
will be defined according to the KDIGO classification: increase in serum creatinine of 

 
17 
≥0.3 mg/dL within 48 hours or ≥50% within 7 days or urine output of <0.5 mL/kg/hour 
for >6 hours. (29) LR contains small quantities of potassium and calcium, so 
hyperkalemia and hypercalcemia are safety outcomes. As mentioned, the 
recommended daily potassium administration will be 40 mEq/day in both treatment 
arms during fasting unless a higher or lower dose is clinically indicated. NS has high 
chloride content, and this fluid has been associated with hyperchloremic acidosis, (30) 
so levels of chloride and pH will be measured.  
 
Other variables 
The volume of fluids administered in the first 48 hours after recruitment will be 
provided. This trial promotes the participation of patients from diverse backgrounds. 
Race will be recorded following the "Collection of Race and Ethnicity Data in Clinical 
Trials" 2016 recommendations of the FDA. (31) Sex will be recorded as sex assigned at 
birth (male/female).  
 
Participant timeline {13} 
The participant timeline is summarized in Figure 1.  
STEP 1. AT RECRUITMENT: check for baseline hypovolemia criteria (Table 3) and SIRS 
(Table 2). Patients without hypovolemia will receive a continuous LR or NS intravenous 
infusion of 1.5 mL/kg/hour. Patients who meet hypovolemia criteria will first receive an 
LR or NS 10 mL/kg intravenous bolus (over 2 hours) of the study fluid, followed by an LR 
or NS infusion of 1.5 mL/kg/hour. Oral food is allowed if the patient is willing to start 
oral feeding. The baseline PAN-PROMISE scale will be assessed. (6) 
 

 
18 
STEP 2. FOLLOW-UP UNTIL THE 24-HOURS CHECKPOINT: in case of systolic blood 
pressure < 90 mmHg or urine output <0.5 mL/kg/hour, a 10 mL/kg intravenous bolus 
over 30 to 120 minutes will be administered, depending on the physician's assessment 
of the patient's condition. The bolus can be repeated if needed, as many times as 
necessary. In case of suspicion of fluid overload (Table 3), the attending physician can 
decrease or stop fluid resuscitation and administer treatment for fluid overload if 
needed. Tests to rule out other medical conditions (ischemic heart disease, lung 
embolism, etc...) will be performed according to the attending physician's assessment 
of the patient.  
 
STEP 3. 24-HOURS CHECKPOINT. Anamnesis, blood test, and physical examination will 
be performed. Oral feeding will be considered in patients under null per mouth. All 
patients will maintain an infusion of 1.5 mL/kg/hour except those suspected of fluid 
overload (in that case, the physician will proceed as in step 2). PAN-PROMISE, 
hypovolemia, fluid overload, SIRS, and outcomes based on blood determinations 
(except for CRP) will be assessed. 
 
STEP 4. FOLLOW-UP UNTIL THE 48 HOURS CHECKPOINT: the patient will be managed as 
in step 2.  
 
STEP 5. 48 HOURS CHECKPOINT. Anamnesis, blood test, and physical examination will 
be performed. Fluid resuscitation will be stopped in those patients tolerating oral 
feeding for more than 8 hours, with normal or hypervolemia. In case of hypovolemia or 
patients without tolerance to oral food, proceed as in step 2 until normal volemia and 

 
19 
oral tolerance are reached. PAN-PROMISE, SIRS, hypovolemia, fluid overload, and 
outcomes based on blood determinations will be assessed.  
 
STEP 6. FOLLOW-UP UNTIL DISCHARGE. The patient can be discharged at the 48 hours 
checkpoint in case of mild pancreatitis and tolerance to oral diet or later, according to 
the patient status determined by the attending physician. Fluid overload will be assessed 
also at 72h. CT scan for the diagnosis of local complications should be performed on day 
three or later in case of SIRS at 48 hours, increased CRP at 48 hours (more than 15 mg/dL 
or more than 150 mg/L), or when clinically indicated according to the attending 
physician.  
 
STEP 7. FOLLOW-UP UP TO 30 DAYS AFTER RANDOMIZATION. Many outcome variables 
are assessed 30 days after randomization (Table 2). When this period has elapsed, an 
assessment will be performed to determine whether the patient has been readmitted; 
this can be done by phone call.  
 
Sample size {14} 
The WATERFALL trial had a frequency of moderately severe or severe AP in the 
moderate fluid resuscitation arm of treatment (based on LR) of 17%. (15) In a recent 
systematic review, patients who received LR-based fluid resuscitation were less likely to 
develop moderately severe or severe pancreatitis than patients receiving NS, with an 
OR of 0.49, 95 % CI 0.25-0.97. (24) The differences in the incidence of moderately severe 
or severe pancreatitis in the four included randomized controlled trials between LR and 
NS ranged from 10 to 14%, favoring LR. (24) For this reason, we expect an incidence of 

 
20 
moderately severe or severe AP in the NS arm of 27%. Patients will be assigned in a 1:1 
ratio. 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% (the 
smaller difference observed in the four RTCs (24)), assuming that the frequency of 
moderately severe or severe AP in LR group will be 17%. The frequency in the NS group 
is assumed to be 17% under the null hypothesis and 27% under the alternative 
hypothesis. A loss to follow-up of 10% of patients is expected, so the sample size will be 
396 patients in each treatment arm (792 patients in total). The test statistic used is the 
two-sided Z test with pooled variance set at a 0.05 significance level. 
 
Recruitment {15} 
WATERLAND is an international multicenter study. Current participating centers can be 
found on the following link: https://clinicaltrials.gov/ct2/show/NCT05781243 
The study has been shared through these communication channels:  
1. Previous ERICA consortium collaborators (5, 6, 14, 15) 
2. National and international gastroenterology, surgery, and pancreatology 
associations (see acknowledgements) 
3. ERICA consortium website (ericaresearch.com) 
4. ERICA consortium and the researchers ‘personal social networks 
5. Meetings and symposiums 
 
Assignment of interventions: allocation 
Sequence generation {16a} 

 
21 
Sequence assignment will be performed using computer-generated random numbers. 
Random assignments will be stratified by center, presence or absence of baseline SIRS, 
and presence or absence of baseline hypovolemia. The randomization process will be 
performed using the block.random function of the "psych" library of R. Only the study 
coordinator (AVR) and the Dr. Balmis General University Hospital's Department of 
Clinical Pharmacology will have access to the sequence. 
 
Concealment mechanism {16b} 
Randomization will be integrated into the web-based electronic case report form 
(REDCap). (32).  
 
Implementation {16c} 
The allocation sequence will be generated by the Department of Clinical Pharmacology 
of the Dr. Balmis General University Hospital and entered in REDCap by the study 
coordinator. REDCap will randomize every new patient the study collaborators enter in 
their centers.  
 
Assignment of interventions: Blinding  
Who will be blinded {17a} 
Only data analysts will be blinded. For this purpose, they will be administered a database 
in which the arm of treatment (NS or LR) will be replaced by randomly assigned labels A 
and B. 
 
Procedure for unblinding if needed {17b} 

 
22 
The design is open label so unblinding will not occur.  
 
Data collection and management 
Plans for assessment and collection of outcomes {18a} 
Before recruitment begins, collaborators will receive training on the study through a 
teleconference with the study coordinator. Video tutorials on the study will be available 
in the electronic case report form (REDCap). The electronic case report form, the 
randomization process, the importance of avoiding missing data, and the importance of 
accurate data entry will be explained and highlighted. The web-based electronic case 
report is based on the REDCap platform, (32, 33) provided by the Spanish Association of 
Gastroenterology (AEG). The promotors have extensive experience in this platform.  
 
Plans to promote participant retention and complete follow-up {18b} 
The WATERLAND trial only covers from randomization to 30 days thereafter, so 
complete follow-up will be easily achievable. Centers that do not adequately follow 
patients may be dropped from the study. The study coordinator, AVR, will oversee 
patient and center monitoring.  
 
Data management {19} 
The forms have been designed to explain every variable to promote data quality. 
Quantitative variables will include alarms for extreme values. To minimize errors and 
ensure timely monitoring, filling out the web form directly online will be required. 
Logical alarms will be set when two or more variables are contradictory, e.g., classifying 

 
23 
AP as severe in a patient without persistent organ failure. Local collaborators caring for 
patients with AP will enter the study data into the electronic case report form. 
 
Confidentiality {27} 
The data will be stored in the REDCap node of the AEG, a secure database. Each center 
has a "Data Access Group" that ensures that only patient records from their center can 
be accessed. Patient data are entered after the informed consent of the patient or their 
legal guardian has been obtained, which will have been previously approved by the 
ethics committees of the participating centers after checking compliance with current 
legislation (in terms of data protection in Europe: Organic Law 3/2018 of December 5, 
Regulation 2016/679 of the European Parliament and of the Council of April 27, 2016), 
which includes information to the patient on the processing of their data, with the right 
to access, rectification, cancellation, and opposition.  
The data are anonymized. Participants will be allocated using an individual trial 
identification number; information that can identify the patient is not included in the 
database. The Steering Committee, coordination committee, and data analysts will have 
access to the final dataset. The ownership of the data belongs to the ERICA consortium; 
collaborating centers are offered the possibility of access to the global database if they 
wish to carry out an ancillary study (post hoc studies with different objectives to the 
original) to WATERLAND trial based on its database, after submitting a report containing 
an introduction, hypothesis, objectives, methodology, and expected impact. The 
decision will be made unanimously by the trial Steering Committee. After the central 
Institutional Review Board approval, the database exported to a statistical package 
(SPSS or Stata) will be shared in a password-protected zip file that will be sent to the 

 
24 
collaborator by another means of communication from which he/she receives the file. 
The provision of specific anonymized data to other researchers for meta-analysis will be 
encouraged. To this end, data will be provided (see {31a}) without providing granular 
details that could compromise patient privacy.  
 
Plans for collection, laboratory evaluation, and storage of biological specimens for 
genetic or molecular analysis in this trial/future use {33} 
Biological samples will not be collected. 
 
Statistical methods 
The Statistical Analysis Plan version 1, June 30, 2024, available in the protocol Appendix, 
specifies detailed statistical methods.  
 
Statistical methods for primary and secondary outcomes {20a} 
Normality will be assessed using the Lilliefors-corrected Kolmogorov-Smirnov test. The 
number and percentage of primary and secondary categorical outcomes will be 
reported for each treatment group. Continuous data will be reported by mean and 
standard deviation if data are normal and median and interquartile range if data are 
skewed. To calculate the p-value for the primary outcome and secondary safety 
outcomes, the Cochran–Mantel–Haenszel method will be utilized, with adjustments 
made for randomization stratification factors including center, baseline SIRS presence, 
and baseline hypovolemia presence. In addition, this procedure will yield adjusted 
relative risks and their corresponding 95% confidence intervals for all outcomes, also 
accounting for any variables that display imbalances among randomized groups. For 

 
25 
continuous variables, adjusted relative risks will be calculated using multiple regression 
models adjusted for randomization stratification factors and any variable that display 
imbalances among randomized groups to analyze the effect of the continuous variable 
itself. Additionally, the Cochran-Mantel-Haenszel method will be applied to compare 
high values (above the median) to low values (at or below the median), providing a 
comprehensive analysis of the data. Briefly (see more details in the Statistical Analysis 
Plan version 1, June 30, 2024, available in the protocol Appendix), the intention-to-treat 
population will include all randomized patients, following the intention-to-treat 
principle. The safety (per-protocol) population will include all randomized patients, 
according to the fluid that was actually received. Patients receiving no fluid will not be 
included in the safety population. Efficacy outcomes will be tested in the intention-to-
treat population, and safety outcomes will be tested in the safety population. 
The analysis will be conducted using SPSS version 29 or higher (IBM), SAS software 
version 9.4 or higher (SAS Institute), and R software version 4.4.1 or higher.  Statistical 
analysis will be performed by PM, PZ, and EMNM.  
 
Interim analyses {21b} 
Given the low expected incidence of adverse events in both arms of treatment, no 
interim analysis has been predefined. There will be two a priori stopping rules: clear 
evidence of harm in one trial group over the other (safety) as adjudicated by the Data 
and Safety Monitoring Committee and a slow recruitment rate determined by the 
Steering Committee. 
 
Methods for additional analyses {20b} 

 
26 
The following pre-specified subgroup analyses will be performed on the primary and 
secondary outcomes:  
• Baseline presence and absence of SIRS 
• Baseline presence and absence of hypovolemia 
• Sex 
There is no provision for correction for multiplicity for subgroup analysis, so results will 
be reported as point estimates with two-sided 95% CI. 
 
Methods in analysis to handle protocol non-adherence and any statistical methods to 
handle missing data {20c} 
Adherence is assessed based on the percentage of subjects receiving ≥80% of the 
planned volume of fluids according to the study protocol in the first 48 hours after 
randomization. The attending physician will assess it. Details about intention-to-treat 
and per-protocol populations are available in the paragraph "Statistical methods for 
primary and secondary outcomes" above. More details are specified in the Statistical 
Analysis Plan version 1, June 30, 2024, available in the protocol Appendix. 
Our goal is to reduce or eliminate missing data during recruitment through concerted 
efforts. If, despite these efforts, missing data occur, we will assess the amount and 
pattern of missing data. The purpose of this assessment is to analyze the amount of 
missing data on the primary variables and other variables and determine the nature of 
the missingness (missing completely random, missing at random, or missing at non-
random). We will use the Multivariate Imputation by Chained Equations (MICE) using 
creating multiple datasets for ten times and results will be combined using Rubin’s Rules. 
(34) MICE is useful when the pattern of missing data is random (MAR) or when the 

 
27 
proportion of missing data exceeds 5% and does not follow a Missing Not at Random 
(MNAR) pattern. (35) In cases where missing data follow a Missing Not at Random 
(MNAR) pattern, we will employ sensitivity analyses to examine the impact of different 
assumptions about the missing data mechanism on our results. Additionally, we will 
consider Bayesian imputation methods to address the potential bias introduced by 
MNAR data. 
 
Plans to give access to the full protocol, participant level-data and statistical code {31c} 
Members of the ERICA consortium that recruited patients in the WATERLAND trial may 
claim access to the final dataset to perform ancillary studies; as discussed above, the 
Steering Committee will study these proposals. The datasets analyzed during the current 
study will be published in an open-access repository. Statistical codes are available from 
the corresponding author on reasonable request, as is the full protocol.  
 
Oversight and monitoring 
Composition of the coordinating center and trial Steering Committee {5d} 
The study will be coordinated by the Gastroenterology and the Clinical Pharmacology 
Departments of the Dr. Balmis General University Hospital, Alicante, Spain. The 
Coordination Committee will include the principal investigator and promotor (EdM, 
gastroenterologist), the study coordinator (AVR), and a clinical pharmacologist (PZ). This 
committee will provide daily support to the study collaborators. The Coordination 
Committee will meet every month or in situations requiring important decisions.  
The trial Steering Committee comprises a group of international pancreatologists (LG, 
AGGP, AC, YHB, GC, JLB), an acute pancreatitis patient advocate (CLV) and an expert in 

 
28 
statistics (PM). They will meet (via teleconference) every three months or in situations 
requiring important decisions. The Steering Committee had the following tasks: A) to 
supervise the overall progress of the trial, B) to review and consider the Data and Safety 
Monitoring Committee (DSMC) reports and recommendations, C) to discuss and decide 
post hoc analyses after the study is complete, D) to participate in writing the final 
publication.  
 
Composition of the Data and Safety Monitoring Committee, its role, and reporting 
structure {21a} 
The DSMC will comprise a nephrologist, an intensivist, and a clinical pharmacologist. It 
will evaluate all reported adverse events. Safety reports will be issued as reported and 
analyzed by the Steering Committee.  
 
Adverse event reporting and harms {22} 
The WATERLAND trial investigates two fluids used routinely for over 100 years; adverse 
events and harms are expected to be very low. The DSMC oversees the detection of 
possible adverse events and harms and proposes to the Steering Committee how to 
proceed. The local collaborators can report safety problems to the study coordinator, 
who would contact the DSMC.  
 
Frequency and plans for auditing trial conduct {23} 
AVR, the study coordinator, will oversee the study audits. Participant enrolment, 
eligibility, allocation to study groups, adherence to trial interventions, reporting of 
harms, and completeness, accuracy, and timeliness of data collection will be monitored. 

 
29 
Given the international nature of the study, the audits will be carried out through the 
analysis of the electronic case report form (REDCap) and telematic contact with the 
collaborating researchers. An initial audit of the participating centers (completeness, 
accuracy, and timeliness of data collection) will be performed after the complete data 
entry of the first three patients, then every ten patients. Also, the funding institutions 
(particularly Instituto de Salud Carlos III, the main funding source) can decide to perform 
external audits.  
 
Plans for communicating important protocol amendments to relevant parties {25} 
The Steering Committee can decide to make protocol amendments. In that case, the 
study coordinator will inform the Institutional Review Boards, change the study 
registries, and inform the study collaborators. All amendments will be registered, and 
the changes and their dates will be explained in the final publication supplementary 
material. All changes from this protocol will be identified as post hoc analyses in the final 
publication.  
 
Dissemination plans {31a} 
The results of the WATERLAND trial will be presented at international meetings and 
published in a peer-reviewed scientific journal. The article will be published with an 
open-access license if the scientific journal has that possibility. The results will be shared 
through the social networks of the ERICA consortium (Twitter: @ERICAconsortium) and 
its website (www.ericaresearch.com). The authors will write a lay summary to share 
with all participants. With the help of the patient advocate, informative material will be 
produced for the general public, and a press release will be issued. The data will be 

 
30 
available in a public open data repository. The register records will be updated for 
EudraCT and ClincalTrials.gov 
 
Authorship criteria:  
1 to 15 patients. Two investigators from the center will be acknowledged as 
collaborators in the supplementary appendix of the final publication. 
16 to 30 patients. One investigator will be included as a co-author of the study, and two 
other investigators from the center will be acknowledged as collaborators in the 
supplementary appendix of the final publication.  
31 to 50 patients. Two investigators will be included as co-authors of the study, and 1 
investigator from the center will be acknowledged as a collaborator in the 
supplementary appendix of the final publication. 
51 or more. Three investigators will be included as co-authors of the study. 
Discussion 
The WATERLAND trial is an international multicenter, open-label, parallel-group, 
randomized, controlled, superiority trial aiming to compare the efficacy and safety of 
moderate fluid resuscitation based on LR versus NS in AP. The study has been designed 
to recruit both patients with predicted mild and predicted severe AP, thus, with different 
ranges of severity of disease, but patients that have baseline criteria for moderately 
severe or severe disease will be excluded, as this is the main efficacy outcome, and the 
hypothesis of the study is that fluid therapy may improve the course of the disease, 
preventing the development of complications. The study will be open-label, as the 
logistics for an international double-blinded randomized controlled trial on fluid 

 
31 
resuscitation are challenging. The efficacy outcome is moderately severe or severe 
disease, a compound variable that includes local complications, organ failure, and 
exacerbation of previous comorbidity. (4) Patients with those complications have more 
morbidity and risk of mortality. (5) Both arms of treatment are safe, but concerns about 
hyperchloremic acidosis have been raised in patients receiving high doses of NS. (30) LR 
and NS administration will be based on the results of the WATERFALL trial, which 
demonstrated that 1.5 mL/kg/hour (preceded by a bolus of 10 mL/kg only in patients 
with hypovolemia) is safer that a more aggressive strategy (20 mL/kg bolus in all 
patients, followed by 3 mL/kg/hour). (15) LR and NS are fluids used in AP daily for more 
than 100 years, so this is a low interventional pharmacological randomized controlled 
trial. Low interventional clinical trials, according to the European Union Clinical Trials 
Regulation No 536/2014 should fulfill the following requirements: A) the investigational 
medicinal products, excluding placebos, are authorized; B) according to the protocol of 
the clinical trial, the investigational medicinal products are used in accordance with the 
terms of the marketing authorization or the use of the investigational medicinal 
products is evidence-based and supported by published scientific evidence on the safety 
and efficacy of those investigational medicinal products in any of the Member States 
concerned, and C) the additional diagnostic or monitoring procedures do not pose more 
than minimal additional risk or burden to the safety of the subjects compared to normal 
clinical practice in any Member State concerned. Most countries do not require 
insurance for patients included in low interventional trials, which helps the WATERLAND 
trial to be performed in an international scenario; If a center or country requires 
insurance, an attempt will be made to cover it through the grants that support this 
project.  

 
32 
Finally, the ERICA consortium has experience in international multicenter studies (5-7) 
and studies on fluid resuscitation. (14, 15, 19) 
Trial status 
Protocol version 4, September 18, 2023. Recruitment started in June 2023. Recruitment 
is expected to be completed in December 2024. 
Abbreviations 
AEG: Spanish association of gastroenterology.  
AP: acute pancreatitis.  
CI: confidence intervals. 
CRP: c-reactive protein. 
CT: computed tomography. 
DSMC: data safety and monitoring committee. 
ERCP: endoscopic retrograde cholangiopancreatography. 
ERICA: international league against biliary-pancreatic diseases. 
ICU: intensive care unit. 
ISCIII: Instituto de Salud Carlos III. 
LR: lactated Ringer's solution. 
NS: normal saline. 
OR: odds ratio.  
RAC: revision of the Atlanta classification.  
SIRS: systemic inflammatory response syndrome. 
 

 
33 
Declarations  
Acknowledgments 
The researchers acknowledge the Spanish Association of Gastroenterology (AEG) for 
providing the REDCap electronic case report form, and AEG, the European Pancreatic 
Club (EPC), and the Spanish Association of Pancreatology (AESPANC) for their 
endorsement and support in sharing the trial through their communication channels to 
help recruiting centers. The researchers would like to thank the Scientific Committee of 
the United European Gastroenterology (UEG) for the UEG Research Prize 2024 to 
Enrique de-Madaria and the research grant that it entails, and the scientific committee 
of AEG for the Gonzalo Miño grant. Finally, thanks to the Instituto de Salud Carlos III 
(ISCIII) for making this study possible through a public competitive grant; the ISCIII has 
supported all our randomized controlled trials with these grants.  
 
Authors' contributions {31b} 
EdM is the principal investigator; he conceived the study, applied for grants, and led the 
proposal and protocol development. PM, PZ and EMNM were the lead trial 
methodologists. The other authors contributed to the study design and the proposal's 
development. All authors read and approved the final manuscript for this protocol. 
 
Funding {4} 
The WATERLAND trial is funded by a grant (grant number PI22/00980) from ISCIII, 
Madrid, Spain, the national and international reference in biomedical research and 
public health in Spain. It is the Public Research Organization of the Government of Spain, 

 
34 
responsible for funding and executing national biomedical research. It depends on the 
Ministry of Science, Innovation, and Universities.  
Other grants:  
• UEG Research Prize, United European Gastroenterology, grant number: UEG 
Research Prize 2024, Vienna, Austria. 
• Beca Gonzalo Miño, Spanish Association of Gastroenterology (Asociación 
Española de Gastroenterología, AEG), grant number: Gonzalo Miño Grant 2024, 
Madrid, Spain.  
• Beca Intramural, Alicante Institute of Health and Biomedical Research (ISABIAL), 
grant number: ayudas intramurales de ISABIAL modalidad C 2023, Alicante, 
Spain.  
None of the funders were or will be involved in the study design, collection, analysis, 
data interpretation, or manuscript writing. 
 
Availability of data and material {29} 
The Steering Committee, coordination committee, and statistical advisors will have 
access to the final dataset. Members of the ERICA consortium that recruited patients in 
the WATERLAND trial may claim access to the final dataset to perform ancillary studies; 
the Steering Committee will study these proposals. Any data required to support the 
protocol can be supplied on request. 
 
Ethics approval and consent to participate {24} 
Dr. Balmis General University Hospital's research ethics committee (Comité de 
Investigación con Medicamentos, CEiM) will be considered as the central institutional 

 
35 
review board. All participating centers must have permission from their local 
institutional review boards to participate in WATERLAND.  
Consent for publication {32} 
Not applicable - no identifying images or other personal or clinical details of participants 
are presented here or will be presented in reports of the trial results. The participant 
information materials and informed consent form available from the corresponding 
author on request. 
 
Competing interests {28} 
This is a researcher-driven study. There is little if any, commercial interest in the results 
of the WATERLAND trial. No industry involvement will be allowed in this study, and the 
study committee members and collaborators will not be able to participate in this trial 
in case of conflicts of interest. A declaration of conflicts of interest will be mandatory to 
be part of the WATERLAND trial.  
 
 
 

 
36 
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1 
 
Appendix 
Contributors ___________________________________________________________ 4 
Trial Design: ________________________________________________________________ 4 
Statistical Analysis Plan: ______________________________________________________ 4 
Section 1: Administrative Information ______________________________________ 6 
Section 2: Introduction __________________________________________________ 7 
Background and Rationale (R7) ________________________________________________ 7 
Objectives (R8) _____________________________________________________________ 8 
Research hypothesis: _____________________________________________________________ 8 
Study objectives: _________________________________________________________________ 9 
Section 3: Trial Methods _________________________________________________ 9 
Trial Design (R9) ____________________________________________________________ 9 
Randomization (R10) ________________________________________________________ 9 
Sample Size (R11) _________________________________________________________ 10 
Framework (R12) _________________________________________________________ 10 
Statistical Interim Analyses and Subgrouping Guidance. __________________________ 11 
Information on interim analyses specifying what interim analyses will be carried out and listing of 
time points (R13a) _______________________________________________________________ 11 
Any planned adjustment of the significance level due to interim analysis (R13b) _____________ 11 
Details of guidelines for stopping the trial early (R13c) __________________________________ 11 
Timing for Final Analysis (R14) _______________________________________________ 11 
Timing of Outcome Assessments (R15) ________________________________________ 11 

2 
 
Section 4: Statistical Principles ___________________________________________ 12 
Confidence Intervals and P Values ____________________________________________ 12 
Level of statistical significance (R16) ________________________________________________ 12 
Description and rationale for any adjustment for multiplicity and, if so, detailing how the type 1 
error is to be controlled (R17) _____________________________________________________ 12 
Confidence intervals to be reported (R18) ____________________________________________ 12 
Adherence and Protocol Deviations __________________________________________ 13 
Definition of adherence to the intervention and how this is assessed, including extent of exposure 
(R19a) ________________________________________________________________________ 13 
Description of how adherence to the intervention will be presented (R19b) _________________ 13 
Definition of protocol deviations for the trial (R19c) ____________________________________ 13 
Description of which protocol deviations will be summarized (R19d) _______________________ 14 
Analysis populations (R20) ________________________________________________________ 14 
Section 5: Trial Population ______________________________________________ 15 
Screening Data (R21) ______________________________________________________ 15 
Eligibility (R22) ___________________________________________________________ 15 
Recruitment (R23) _________________________________________________________ 15 
Withdrawal/Follow-Up _____________________________________________________ 16 
Level of withdrawal (R24a) ________________________________________________________ 16 
Timing of withdrawal/lost to follow up data (R24b) ____________________________________ 16 
Reasons and details of how withdrawal/lost to follow-up data will be presented (R24c) _______ 16 
Baseline Patient Characteristics ______________________________________________ 16 
List of baseline characteristics to be summarized (R25a) ________________________________ 16 
Details of how baseline characteristics will be descriptively summarized (R25b) ______________ 17 
Section 6: Analysis _____________________________________________________ 18 

3 
 
Outcome Definitions _______________________________________________________ 18 
Specification of outcomes and timings (R26a), specific measurement and units (R26b), and any 
calculation or transformation used to derive the outcome (R26c) _________________________ 18 
Analysis methods _________________________________________________________ 18 
What analysis method will be used, and how the treatment effects will be presented (R27a) ___ 18 
Any adjustment for covariates (R27b) _______________________________________________ 19 
Methods used for assumptions to be checked for statistical methods (R27c) ________________ 19 
Details of alternative methods to be used if distributional assumptions do not hold (R27d) _____ 19 
Any planned sensitivity analyses for each outcome where applicable (R27e) ________________ 20 
Any planned subgroup analyses for each outcome including how subgroups are defined (R27f) _ 20 
Missing data (R28) ________________________________________________________ 20 
Additional analyses (R29) ___________________________________________________ 21 
Harms (R30) ______________________________________________________________ 21 
Statistical software (R31) ___________________________________________________ 21 
References _______________________________________________________________ 21 
32a References to be provided for nonstandard statistical methods (R32a) _________________ 21 
32b Reference to Data Management Plan (R32b) ______________________________________ 22 
32c Reference to the Trial Master File and Statistical Master File (R32c) ____________________ 22 
32d Reference to other standard operating procedures or documents to be adhered to (R32d) _ 22 
Statistical Analysis Plan, Figure 1. Flow diagram, based on CONSORT 2010 
recommendations. (24) _________________________________________________ 23 
References ___________________________________________________________ 24 
PATIENT INFORMATION SHEET ___________________________________________ 28 
 

4 
 
Statistical Analysis Plan, Version 1, June 30, 2024 
Normal saline versus lactated Ringer’s solution for acute pancreatitis resuscitation, an 
open-label multicenter randomized controlled trial: the WATERLAND trial  
Contributors 
Trial Design:  
Lucía Guilabert, 1 Karina Cárdenas-Jaén, 1 Alicia Vaillo-Rocamora, 1 Ana García García de 
Paredes, 2 3 Ankit Chhoda, 4 Sunil G. Sheth, 4 Pedro Zapater, 3 5 6 Eva M. Navarrete-Muñoz, 
7 8 Patrick Maisonneuve, 9 Yasmin G. Hernández-Barco, 10 Gabriele Capurso, 11 James L. 
Buxbaum, 12 Enrique de-Madaria, 1 13 for the ERICA consortium 14 
 
Statistical Analysis Plan:  
Ankit Chhoda, 4 Pedro Zapater, 3 5 6 Patrick Maisonneuve, 9 Eva M. Navarrete-Muñoz 7 8 
and Enrique de-Madaria. 1 13 
Affiliations:  
1 Gastroenterology Department, Dr. Balmis General University Hospital, ISABIAL, 
Alicante, Spain.  
2 Department of Gastroenterology and Hepatology, Hospital Universitario Ramón y 
Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, Universidad de Alcalá, Madrid, 
Spain. 
3 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas 
(CIBEREHD), Madrid, Spain. 
4 Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical 
School, Boston, USA.  

5 
 
5 Clinical Pharmacology Department, Dr. Balmis General University Hospital, ISABIAL, 
Alicante, Spain. 
6 IDiBE, Miguel Hernandez University, Elche, Spain. 
7 Grupo de Investigación en Terapia Ocupacional (InTeO), Department of Surgery and 
Pathology, Miguel Hernandez University-ISABIAL, Alicante, Spain. 
8 Joint research unit UMH-Fisabio (STATSALUT), Alicante, Spain. 
9 Division of Epidemiology and Biostatistics, IEO European Institute of Oncology IRCCS, 
Milan, Italy. 
10 Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical 
School, Boston, USA. 
11 Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational 
and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Vita-Salute San 
Raffaele University, Milan, Italy. 
12 Division of Gastroenterology, University of Southern California, Los Angeles, USA. 
13 Department of Clinical Medicine, Miguel Hernandez University, Elche, Spain. 
14 ERICA: International League Against Biliary-Pancreatic Diseases. 
 
This plan follows the Guidelines for the Content of Statistical Analysis Plans (SAP) in 
Clinical Trials by Gamble et al, JAMA 2017. (1) The numbers in parentheses preceded by 
an R (e.g., R1a: recommendation 1a) are the recommendations provided in the table 
entitled "SAP Guidance Document: Recommended Items to Address in a Clinical Trial 
SAP".  
 

6 
 
Section 1: Administrative Information 
Title (R1a) 
Normal saline versus lactated Ringer’s solution for acute pancreatitis 
resuscitation, an open-label multicenter randomized controlled trial: the 
WATERLAND trial  
 
Trial 
registration 
(R1b) 
 EudraCT number 2023-000010-18, date of registration January 4, 2023.  
ClinicalTrials.gov Identifier: NCT05781243, first posted March 23, 2023 
SAP version (R2) 
June 2024, version 1 
Protocol 
version 
(R3) 
Version 4, September 18, 2023. Version 1 was approved by the central 
ethics committee (Comité Ético de Investigación con Medicamentos, 
Hospital General Universitario Dr. Balmis, Alicante, Spain, project code 
2023-031) on March 9, 2023. Version 4 was approved on September 29, 
2023. 
SAP revisions (R4a, 
R4b, R4c) 
This is the first version of the SAP. 
Roles 
and 
responsability (R5) 
Ankit Chhoda, 1 Pedro Zapater, 2 3 4 Patrick Maisonneuve, 5 Eva M. 
Navarrete-Muñoz 6 7 and Enrique de-Madaria. 8 9 
 
1 Division of Gastroenterology, Beth Israel Deaconess Medical Center, 
Harvard Medical School, Boston, USA. 
2 Clinical Pharmacology Department, Dr. Balmis General University 
Hospital, ISABIAL, Alicante, Spain. 
3 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y 
Digestivas (CIBEREHD), Madrid, Spain. 
4 IDiBE, Miguel Hernandez University, Elche, Spain. 
5 Division of Epidemiology and Biostatistics, IEO European Institute of 
Oncology IRCCS, Milan, Italy. 
6 Grupo de Investigación en Terapia Ocupacional (InTeO), Department of 
Surgery and Pathology, Miguel Hernandez University-ISABIAL, Alicante, 
Spain. 
7 Joint research unit UMH-Fisabio (STATSALUT), Alicante, Spain. 
8 Gastroenterology Department, Dr. Balmis General University Hospital, 
ISABIAL, Alicante, Spain.  
9 Department of Clinical Medicine, Miguel Hernandez University, Elche, 
Spain. 
 
 
AC and EdM wrote the first draft of the SAP. PZ, EMNM, and PM critically 
reviewed and contributed to this SAP. 
Signatures of 
Persons writing the SAP (R6a): Ankit Chhoda and Enrique de-Madaria 
Senior statistician responsible (R6b): Patrick Maisonneuve 
Chief investigator/clinical lead (R6c): Enrique de-Madaria 
 
 

7 
 
Section 2: Introduction 
Background and Rationale (R7) 
Acute pancreatitis (AP) is the third leading cause of hospital admission and readmission 
for digestive diseases, with increasing incidence and high costs. (2) AP is characterized 
by varying severity, with mild cases having minimal inflammation and favorable 
outcomes, while moderately severe and severe cases involve morbidity, and increased 
risk of mortality. (3-5) The control of inflammation in the initial phase of AP may alter 
the clinical course of the disease by reducing the development of local and systemic 
complications and thus, overall morbidity, mortality, and costs. However, no treatment 
has consistently been shown to decrease the incidence of moderately severe or severe 
AP. (6-8) Fluid resuscitation has been attributed a central role in AP management over 
the last two decades. (9) Research in fluid resuscitation has been focused on the volume 
and the type of fluids. (10-13)  The recently published WATERFALL study demonstrated 
superior safety of moderate hydration over aggressive fluid resuscitation since the latter 
was associated with three times higher fluid overload and similar severity of AP. (14)  
 
Regarding the type of fluid best for AP, published results are conflicting. The two major 
types of fluids are crystalloids and colloids. (15) Colloids, although suspected to remain 
more effectively and durably in the intravascular compartment than crystalloids, were 
shown not to improve clinical results in intensive care patients. (15-17). Among the 
crystalloids, normal saline (NS) contains water, and 0.9% sodium chloride (154 mEq/L of 
sodium and chlorine), and lactated Ringer's solution (LR) contains less sodium and 
chloride (130 and 109 mEq/L, respectively), 28 mEq/L of lactate, in addition to calcium 
and potassium. With a chlorine content higher than plasma, large-volume infusions of 

8 
 
NS may result in hyperchloremic acidosis, whereas LR is a balanced crystalloid due to its 
more neutral effect on acid-base physiology, and in-vitro studies suggest an anti-
inflammatory effect of lactate. (15, 18) 
 
Prior clinical trials have shown conflicting results regarding using LR versus NS in AP 
management. Some studies have reported a lower incidence of systemic inflammatory 
response syndrome (SIRS) or reduced c-reactive protein blood levels with LR, (18-20) 
while others found no significant difference in inflammation. (21, 22) In the study by Lee 
et al, (22)  LR was associated with a shorter hospital stay and lower intensive care unit 
(ICU) admission. A meta-analysis of original studies, including unpublished data 
suggested that LR may be associated with a lower likelihood of developing severe AP 
(odds ratio[OR] 0.49, 95% confidence interval [CI] 0.25-0.97), reduced odds of intensive 
care unit (ICU) admission (OR 0.33, 95% CI 0.13-0.81), and fewer local complications (OR 
0.42, 95% CI 0.20-0.88) but no differences in inflammation (SIRS) or organ failure. (23) 
In conclusion, the optimal fluid choice for AP management remains uncertain; LR has 
shown some potential benefits, including reduced inflammation and improved clinical 
outcomes; however, more research is needed to establish definitive recommendations 
regarding fluid resuscitation in AP. 
 
Objectives (R8) 
Research hypothesis:  
The null hypothesis is that there is no difference in the incidence of moderately severe 
or severe disease in patients with AP receiving fluid resuscitation based on LR compared 

9 
 
to NS. The alternative hypothesis is that fluid resuscitation based on LR is associated 
with a lower incidence of moderate severe or severe AP.  
 
Study objectives:  
The primary objective of the WATERLAND trial is to investigate the effect of fluid 
resuscitation based on LR versus NS on the severity of AP (frequency of moderately 
severe or severe disease).  
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 
(see “outcomes” below). 
 
Section 3: Trial Methods 
Trial Design (R9) 
The WATERLAND trial is an international multicenter, randomized, open-label, parallel-
group, controlled, superiority trial promoted by the ERICA (intERnational league agaInst 
biliary-pancreatiC diseAses) consortium. The patients will be randomly assigned to 
receive either LR or NS-based fluid resuscitation in a 1:1 ratio.  
 
Randomization (R10) 
Random assignment will be performed centrally, using a computer-based central 
randomization system integrated in a Web-based electronic case-report form (REDCap) 
to guarantee adequate allocation concealment. Random assignments will be stratified 
by center, presence or absence of baseline SIRS, and presence or absence of baseline 
hypovolemia. Permuted 12-patients blocks will be used.  

10 
 
Sample Size (R11) 
The WATERFALL trial had a frequency of moderately severe or severe AP in the 
moderate fluid resuscitation arm of treatment (based on LR) of 17%. (14) In a recent 
systematic review, patients who received LR-based fluid resuscitation were less likely to 
develop moderately severe or severe pancreatitis than patients receiving NS, with an OR 
of 0.49, 95 % CI 0.25-0.97. (23) The differences in the incidence of moderately severe or 
severe pancreatitis in the four included randomized controlled trials between LR and NS 
ranged from 10 to 14% favoring LR. (23) For this reason, we expect an incidence of 
moderately severe or severe AP in the NS arm of 27%. Patients will be assigned in a 1:1 
ratio. 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% 
(smaller difference observed in the 4 RTCs (23)), assuming that the frequency of 
moderately severe or severe AP in LR group will be 17%. The frequency in the NS group 
is assumed to be 17% under the null hypothesis and 27% under the alternative 
hypothesis. A loss to follow-up of 10% of patients is expected, so the sample size will be 
396 patients in each treatment arm (792 patients in total). The test statistic used is the 
two-sided Z test with pooled variance set at a 0.05 significance level. 
 
Framework (R12) 
The WATERLAND trial is a superiority trial.  
 

11 
 
Statistical Interim Analyses and Subgrouping Guidance. 
Information on interim analyses specifying what interim analyses will be carried out and 
listing of time points (R13a) 
Given that NS and LR are both commonly used and effective IV fluids for resuscitation 
and generally safe and well tolerated, no interim analysis has been predefined. The Data 
and Safety Monitoring Committee will evaluate all reported adverse events. Safety 
reports will be issued as reported and analyzed by the Steering Committee.  
 
Any planned adjustment of the significance level due to interim analysis (R13b) 
Not applicable. 
 
Details of guidelines for stopping the trial early (R13c) 
This is a low-intervention study, with fluids that have been shown to be safe. There will 
be two a priori stopping rules: clear evidence of harm in one trial group over the other 
(safety) as adjudicated by the Data and Safety Monitoring Committee and a slow 
recruitment rate determined by the Steering Committee.  
 
Timing for Final Analysis (R14) 
The final analysis is planned at the end of the study. All outcomes will be analyzed 
collectively. 
 
Timing of Outcome Assessments (R15) 
The timing of outcome assessments is provided in Table 2 and 4 of the protocol.  

12 
 
 
Section 4: Statistical Principles 
Confidence Intervals and P Values 
Level of statistical significance (R16) 
All statistical tests for will be two-sided using a 5% significance level.  
 
Description and rationale for any adjustment for multiplicity and, if so, detailing how the 
type 1 error is to be controlled (R17) 
The WATERLAND trial aims to test the primary outcome and safety secondary outcomes 
for superiority (a two-sided P value of less than 0.05 will be considered to indicate 
statistical significance for the primary efficacy outcome and safety outcomes). There is 
no provision for correction for multiplicity for secondary efficacy outcomes, so their 
results will be reported as point estimates with 95% confidence intervals.  
 
Confidence intervals to be reported (R18) 
Primary and secondary outcomes will be reported as relative risk, adjusted for 
randomization stratification factors (center, presence or absence of SIRS at recruitment, 
and presence or absence of hypovolemia at recruitment) with 95% CI. Additionally, 
adjustments may also include variables that exhibit imbalances across randomized 
groups. 
 

13 
 
Adherence and Protocol Deviations 
Definition of adherence to the intervention and how this is assessed, including extent of 
exposure (R19a) 
Adherence is defined as receiving ≥80% of the planned volume of fluids according to the 
study protocol in the first 48 hours after randomization. Non-adherence refers to 
discontinuing study-allocated fluid (<80% of the total amount of fluids planned for the 
first 48 hours after randomization) as per the patient's decision and will be assessed by 
the attending physician. The protocol allows to decrease or stop fluid resuscitation in 
case of fluid overload. In such cases, it is not considered non-adherence; this is part of 
the goal-directed protocol to avoid dangerous fluid overload.  
 
Description of how adherence to the intervention will be presented (R19b) 
The number and % of participants per arm of treatment receiving ≥80% of the prescribed 
fluids will be presented in a table in the final manuscript, together with the number and 
% of participants with fluid overload. 
 
Definition of protocol deviations for the trial (R19c) 
The following are pre-defined protocol violations: 
A) Deviations type A: protocol deviations that are not considered to affect the study 
outcomes as those patients will not be included in the final analysis, thus not 
affecting the scientific value of the trial. Includes A1: patients who are randomized 
by mistake (e.g., patients meeting exclusion criteria), A2: computer error that 
prevents randomization of the patient; A3: patients who, once randomized, refuse 
to participate in the study before the study fluid is started, and A4: patients who 

14 
 
were randomized, received the study fluid, but then refuse to participate in the study 
and revoke the permission for their data to be analyzed. Those patients will not be 
analyzed, as A1 are patients who do not meet the criteria to enter the study; in A2, 
randomization was not possible; A3 patients are not willing to participate before 
receiving the study fluid, and A4 revoked their consent for the data to be included in 
the analysis.  
B) Deviations type B: protocol deviations that may affect the study outcomes as those 
patients will be included in the final analysis. Thus, they could affect the trial's 
scientific value. Includes B1: patients with inaccurate collection and/or 
documentation of data in RedCAP database, B2: patients receiving <80% planned 
volume of fluids according to the study protocol in the first 48h after randomization 
due to mistakes or patient decisions, and B3: patients receiving the wrong fluid, LR 
instead of NS or vice versa. In case of missing data, the multiple imputation 
technique will be performed, see below.   
 
 
Description of which protocol deviations will be summarized (R19d) 
Deviations type A will be summarized (number of cases) in the study flow chart. Type B 
deviations (number of cases per arm of treatment) will be summarized in the final 
manuscript.   
 
Analysis populations (R20)  
The intention-to-treat population will include all randomized patients without type A 
deviation from the study protocol, following the intention-to-treat principle (see R19c). 

15 
 
The safety (per-protocol) population will include all randomized patients without type 
A deviations from study protocol, according to the fluid that was actually received. 
Patients receiving no fluid will not be included in the safety population.  
Efficacy outcomes will be tested in the intention-to-treat population, and safety 
outcomes will be tested in the safety population.  
See also, "Any planned sensitivity analyses for each outcome where applicable (R27e)" 
 
Section 5: Trial Population 
Screening Data (R21) 
The following summaries will be presented for all screened patients: Enrolment: the 
number of patients screened, the number of patients recruited, the number of screened 
patients not recruited, and the reason for non-recruitment. 
 
Eligibility (R22)  
The trial inclusion and exclusion criteria are specified in protocol Table 1.  The number 
of ineligible patients randomized, if any, will be reported, with reasons for ineligibility. 
 
Recruitment (R23)  
A CONSORT flow diagram (Statistical Analysis Plan Figure 1) (24) will be used to 
summarize the number of patients who were eligible, consented, randomized, receiving 
study-allocated intravenous fluids, withdrawing, or lost to follow-up. 
 

16 
 
Withdrawal/Follow-Up  
Level of withdrawal (R24a) 
Participants may A) withdraw from the intervention but continue with follow-up; B) 
withdraw from follow-up but allow data collected to date to be used; C) withdraw from 
follow-up and withdraw consent for data collected to date to be used; or D) be lost to 
contact/follow-up.  
 
Timing of withdrawal/lost to follow up data (R24b) 
A time-to-event Kaplan Meier Curve will incorporate the timing of withdrawal or loss of 
follow-up. 
 
Reasons and details of how withdrawal/lost to follow-up data will be presented (R24c) 
The numbers (with reasons) of losses to follow-up (drop-outs and withdrawals) 
throughout the trial will be summarized in the CONSORT flow diagram.  
 
Baseline Patient Characteristics  
List of baseline characteristics to be summarized (R25a) 
Patients will be described for age, sex assigned at birth, first episode of pancreatitis, 
gallstone cause of pancreatitis, body-mass index, Charlson comorbidity index, BISAP 
score, HAPS score, PAN-PROMISE score, urea, hematocrit, creatinine, SIRS, 
hypovolemia, potassium, calcium, pH, and chlorine, both overall and separately for the 
two randomized groups. The representativeness of the study participants will be 
discussed in another table in the supplementary material containing information about 

17 
 
the disease studied, special considerations about sex and gender, age, race, geography, 
other considerations, and the overall representativeness of this trial. (25) 
 
 
Details of how baseline characteristics will be descriptively summarized (R25b) 
Categorical data will be summarized by numbers and percentages. Continuous data will 
be summarized by mean and SD if data are normal and median and interquartile range 
if data are skewed. Tests of statistical significance will not be undertaken for baseline 
characteristics; instead, the clinical importance of any imbalance will be noted. 

18 
 
Section 6: Analysis 
Outcome Definitions  
Specification of outcomes and timings (R26a), specific measurement and units (R26b), 
and any calculation or transformation used to derive the outcome (R26c) 
The specifications on outcomes and timings, specific measurements and units, and 
calculations used to derive outcomes are explained in the study protocol (main text: 
"Outcomes," and Tables 2, 3, and 4). To calculate the change from the baseline PAN-
PROMISE scale at 24 and 48 hours, we will subtract the baseline value from the values 
at those time points. In addition, we will analyze the data at 24 and 48 hours, considering 
both baseline-adjusted and non-adjusted values. 
 
Analysis methods  
What analysis method will be used, and how the treatment effects will be presented 
(R27a) 
Normality will be assessed using the Lilliefors-corrected Kolmogorov-Smirnov test. The 
number and percentage of primary and secondary categorical outcomes will be reported 
for each treatment group. Continuous data will be reported by mean and SD if data are 
normal and median and interquartile range if data are skewed.  
To calculate the p-value for the primary outcome and secondary safety outcomes, the 
Cochran–Mantel–Haenszel method will be utilized, with adjustments made for 
randomization stratification factors including center, baseline SIRS presence, and 
baseline hypovolemia presence. In addition, this procedure will yield adjusted relative 
risks and their corresponding 95% confidence intervals for all outcomes, also accounting 

19 
 
for any variables that display imbalances among randomized groups. For continuous 
variables, adjusted relative risks will be calculated using multiple regression models 
adjusted for randomization stratification factors and any variable that display 
imbalances among randomized groups to analyze the effect of the continuous variable 
itself. Additionally, the Cochran-Mantel-Haenszel method will be applied to compare 
high values (above the median) to low values (at or below the median), providing a 
comprehensive analysis of the data 
Any adjustment for covariates (R27b) 
As explained in R27a, p-values and relative risk will be adjusted for randomization 
stratification factors (center, baseline presence or absence of SIRS, and baseline 
presence or absence of hypovolemia). Additionally, adjustments may also include 
variables that exhibit imbalances across randomized groups. 
 
Methods used for assumptions to be checked for statistical methods (R27c) 
The Lilliefors-corrected Kolmogorov-Smirnov test will be used to assess the normality of 
continuous data. We will also assess the assumptions of the regression models used in 
the data analysis  
 
Details of alternative methods to be used if distributional assumptions do not hold (R27d) 
If continuous variables do not adhere to normal distribution assumptions, alternative 
methods such as variable transformations, robust regression techniques, or bootstrap 
methods will be considered. Similarly, if regression models do not meet assumptions, 
non-parametric models or robust models will be explored to ensure robustness of the 
findings. 

20 
 
Any planned sensitivity analyses for each outcome where applicable (R27e) 
The intention-to-treat population will be used to test efficacy outcomes, while safety 
outcomes will be tested in the safety population with complete cases (see R20). For 
sensitivity analyses, we will perform per-protocol analyses to ensure the robustness of 
the primary efficacy outcomes and the safety outcomes in the intention-to-treat 
population, and we will include multiple imputation for missing data to account for 
potential biases and provide a more comprehensive assessment of the treatment 
effects.  
 
Any planned subgroup analyses for each outcome including how subgroups are defined 
(R27f) 
The following pre-specified subgroup analyses will be performed on the primary and 
secondary outcomes:  
• Baseline presence and absence of SIRS 
• Baseline presence and absence of hypovolemia 
• Sex 
There is no provision for correction for multiplicity for subgroup analysis, so results will 
be reported as point estimates with two-sided 95% CI. 
 
Missing data (R28)  
Our goal is to reduce or eliminate missing data during recruitment through concerted 
efforts. If, despite these efforts, missing data occur, we will assess the amount and 
pattern of missing data. The purpose of this assessment is to analyze the amount of 
missing data on the primary variables and other variables and determine the nature of 

21 
 
the missingness (missing completely random, missing at random, or missing at non-
random). We will use the Multivariate Imputation by Chained Equations (MICE) using 
creating multiple datasets for ten times and results will be combined using Rubin’s Rules. 
(26) MICE is useful when the pattern of missing data is random (MAR) or when the 
proportion of missing data exceeds 5% and does not follow a Missing Not at Random 
(MNAR) pattern. In cases where missing data follow a Missing Not at Random (MNAR) 
pattern, we will employ sensitivity analyses to examine the impact of different 
assumptions about the missing data mechanism on our results. Additionally, we will 
consider Bayesian imputation methods to address the potential bias introduced by 
MNAR data. 
 
Additional analyses (R29)  
No additional analyses have been planned.  
 
Harms (R30)  
Safety outcomes (Study Protocol Table 4) have been addressed above in this section.  
 
Statistical software (R31) 
The analysis will be conducted using SPSS version 29 or higher (IBM), SAS software 
version 9.4 or higher (SAS Institute), and R software version 4.4.1 or higher.  
 
References  
32a References to be provided for nonstandard statistical methods (R32a) 
No non-standard statistical method is planned. 

22 
 
 
32b Reference to Data Management Plan (R32b) 
The study protocol includes a reference to this Statistical Analysis Plan (see “Data 
management and confidentiality”): “Data analysis is specified in the Statistical Analysis 
Plan version 1, June 30, 2024, available in the protocol Appendix.”  
 
32c Reference to the Trial Master File and Statistical Master File (R32c) 
Access to the Trial Master File is restricted to the clinical trial coordinator, the Dr. Balmis 
General University Hospital's Clinical Pharmacology Department, and collaborators in 
charge of statistical analysis. 
 
32d Reference to other standard operating procedures or documents to be adhered to 
(R32d) 
None provided. 
 
 
 

23 
 
Statistical Analysis Plan, Figure 1. Flow diagram, based on 
CONSORT 2010 recommendations. (24)  
 

24 
 
References 
1. 
Gamble C, Krishan A, Stocken D, Lewis S, Juszczak E, Dore C, et al. Guidelines for 
the Content of Statistical Analysis Plans in Clinical Trials. JAMA. 2017;318(23):2337-43. 
2. 
Peery AF, Crockett SD, Murphy CC, Jensen ET, Kim HP, Egberg MD, et al. Burden 
and Cost of Gastrointestinal, Liver, and Pancreatic Diseases in the United States: Update 
2021. Gastroenterology. 2022;162(2):621-44. 
3. 
Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, et al. 
Classification of acute pancreatitis--2012: revision of the Atlanta classification and 
definitions by international consensus. Gut. 2013;62(1):102-11. 
4. 
Sternby H, Bolado F, Canaval-Zuleta HJ, Marra-Lopez C, Hernando-Alonso AI, Del-
Val-Antonana A, et al. Determinants of Severity in Acute Pancreatitis: A Nation-wide 
Multicenter Prospective Cohort Study. Ann Surg. 2019;270(2):348-55. 
5. 
de-Madaria E, Sanchez-Marin C, Carrillo I, Vege SS, Chooklin S, Bilyak A, et al. 
Design and validation of a patient-reported outcome measure scale in acute 
pancreatitis: the PAN-PROMISE study. Gut. 2021;70(1):139-47. 
6. 
de-Madaria E, Mira JJ, Carrillo I, Afif W, Ang D, Antelo M, et al. The present and 
future of gastroenterology and hepatology: an international SWOT analysis (the 
GASTROSWOT project). Lancet Gastroenterol Hepatol. 2022;7(5):485-94. 
7. 
Garcia-Rayado G, Cardenas-Jaen K, de-Madaria E. Towards evidence-based and 
personalised care of acute pancreatitis. United European Gastroenterol J. 
2020:2050640620903225. 
8. 
Singh VK, Moran RA, Afghani E, de-Madaria E. Treating acute pancreatitis: what's 
new? Expert Rev Gastroenterol Hepatol. 2015;9(7):901-11. 

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9. 
de-Madaria E, Garg PK. Fluid therapy in acute pancreatitis - aggressive or 
adequate? Time for reappraisal. Pancreatology. 2014;14(6):433-5. 
10. 
de-Madaria E, Martinez JF, Aparicio JR, Lluis F. Aggressive Fluid Resuscitation in 
Acute Pancreatitis: In Aqua Sanitas? Am J Gastroenterol. 2017;112(10):1617-8. 
11. 
de-Madaria E, Martinez J, Perez-Mateo M. The dynamic nature of fluid 
resuscitation in acute pancreatitis. Clin Gastroenterol Hepatol. 2012;10(1):95-6; author 
reply 6. 
12. 
de-Madaria E, Soler-Sala G, Sanchez-Paya J, Lopez-Font I, Martinez J, Gomez-
Escolar L, et al. Influence of fluid therapy on the prognosis of acute pancreatitis: a 
prospective cohort study. Am J Gastroenterol. 2011;106(10):1843-50. 
13. 
Singh VK, Gardner TB, Papachristou GI, Rey-Riveiro M, Faghih M, Koutroumpakis 
E, et al. An international multicenter study of early intravenous fluid administration and 
outcome in acute pancreatitis. United European Gastroenterol J. 2017;5(4):491-8. 
14. 
de-Madaria E, Buxbaum JL, Maisonneuve P, Garcia Garcia de Paredes A, Zapater 
P, Guilabert L, et al. Aggressive or Moderate Fluid Resuscitation in Acute Pancreatitis. N 
Engl J Med. 2022;387(11):989-1000. 
15. 
Gordon D, Spiegel R. Fluid Resuscitation: History, Physiology, and Modern Fluid 
Resuscitation Strategies. Emerg Med Clin North Am. 2020;38(4):783-93. 
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Investigators SS, Australian, New Zealand Intensive Care Society Clinical Trials G, 
Australian Red Cross Blood S, George Institute for International H, Myburgh J, et al. 
Saline or albumin for fluid resuscitation in patients with traumatic brain injury. N Engl J 
Med. 2007;357(9):874-84. 

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starch or saline for fluid resuscitation in intensive care. N Engl J Med. 
2012;367(20):1901-11. 
18. 
de-Madaria E, Herrera-Marante I, Gonzalez-Camacho V, Bonjoch L, Quesada-
Vazquez N, Almenta-Saavedra I, et al. Fluid resuscitation with lactated Ringer's solution 
vs normal saline in acute pancreatitis: A triple-blind, randomized, controlled trial. United 
European Gastroenterol J. 2018;6(1):63-72. 
19. 
Wu BU, Hwang JQ, Gardner TH, Repas K, Delee R, Yu S, et al. Lactated Ringer's 
solution reduces systemic inflammation compared with saline in patients with acute 
pancreatitis. Clin Gastroenterol Hepatol. 2011;9(8):710-7 e1. 
20. 
Karki B, Thapa S, Khadka D, Karki S, Shrestha R, Khanal A, et al. Intravenous 
Ringers lactate versus normal saline for predominantly mild acute pancreatitis in a 
Nepalese Tertiary Hospital. PLoS One. 2022;17(1):e0263221. 
21. 
Choosakul S, Harinwan K, Chirapongsathorn S, Opuchar K, Sanpajit T, Piyanirun 
W, et al. Comparison of normal saline versus Lactated Ringer's solution for fluid 
resuscitation in patients with mild acute pancreatitis, A randomized controlled trial. 
Pancreatology. 2018. 
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Lee A, Ko C, Buitrago C, Hiramoto B, Hilson L, Buxbaum J, et al. Lactated Ringers 
vs Normal Saline Resuscitation for Mild Acute Pancreatitis: A Randomized Trial. 
Gastroenterology. 2021;160(3):955-7 e4. 
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for acute pancreatitis. Pancreatology. 2021;21(8):1405-10. 

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PATIENT INFORMATION SHEET  
Project Name: Normal saline versus lactated Ringer’s solution for acute pancreatitis 
resuscitation, an open-label multicenter randomized controlled trial: the WATERLAND 
trial 
Principal Investigator: PI OF THE CENTER 
Department: DEPARTMENT 
Center: CENTER 
 
We are writing to request your consent to participate in a research project. This project 
has been approved by the CENTER'S ETHICS COMMITTEE. The project will be conducted 
in accordance with the standards of Good Clinical Practice and international ethical 
principles applicable to medical research in humans (Declaration of Helsinki and its latest 
revision).  
In order for you to decide whether you wish to participate in this project, it is important 
that you understand why this research is necessary, what your participation will involve, 
how your information will be used, and its potential benefits, risks, and discomforts. 
Detailed information about the project can be found in this document. Please take the 
time to read the information provided below carefully and we will answer any questions 
you may have. Once you have understood the project you will be asked to sign the 
informed consent form if you wish to participate. 
If you decide to participate in this study, you should know that you do so voluntarily and 
that you may withdraw from the study at any time. In the event that you decide to 
discontinue your participation, this will not entail any type of penalty or loss or 
detriment to your rights and medical care. 

29 
 
The project will be carried out in the CENTER'S HEALTH AREA. 
 
WHY IS THIS PROJECT BEING CARRIED OUT? 
Acute pancreatitis is a common disease; it is the third leading cause of hospital 
admission due to digestive disease. It is manifested by pain in the upper abdomen and 
requires hospital admission. Most patients (2/3 of cases) have a mild course of disease, 
with discomfort that subsides quickly, and a short hospital stay. However, in 1/3 of 
patients there are local or distant complications of the pancreas that make the recovery 
slower, with more discomfort, longer hospital stay, with greater need for invasive 
treatments and greater risk to life, although fortunately mortality from pancreatitis is 
very low, less than 3%. 
Medical researchers have been searching for decades for treatments that, when 
administered early in the course of acute pancreatitis, can improve its prognosis, 
allowing more patients to have mild pancreatitis by preventing the onset of 
complications. No such treatment has been found, but there are clinical trials suggesting 
that the administration of certain types of fluids may have an anti-inflammatory effect 
in this early phase of acute pancreatitis. There are two types of fluids that are 
administered intravenously in patients with acute pancreatitis during the first few days 
of admission: normal saline and lactated Ringer's solution. These intravenous fluids 
consisting of water and salts are administered to ensure hydration and sodium intake in 
patients with acute illnesses, especially those involving nil by mouth since the patient is 
unable to drink. Some studies have described that lactated Ringer's solution has an anti-
inflammatory effect in acute pancreatitis and could improve the evolution of this 

30 
 
disease, but other studies do not show that it is better than saline, which is the most 
frequently used.  
In the WATERLAND study we want to check whether patients receiving lactated Ringer's 
solution or normal saline have a better evolution, or whether there are no significant 
differences between the two types of fluids. 
 
WHAT IS THE AIM OF THE PROJECT? 
Our objective is to test the effect of lactated Ringer's solution or normal saline on the 
severity of pancreatitis.  
 
HOW WILL THE STUDY BE PERFORMED? 
After being informed of the objectives, procedure, potential benefits, and risks of this 
study, we will proceed to decide randomly, thanks to a computer program, whether you 
will receive lactated Ringer's solution or normal saline. You will then receive this type of 
fluid for the first few days of admission for acute pancreatitis (at least for the first 48 
hours). 
It is of utmost importance that you understand that these two types of fluids are 
routinely and daily used in the management of acute pancreatitis, so you are going to 
receive one of these two fluids anyway, the only thing that changes is that instead of 
being decided by the attending physician, it will be drawn by a computer program, but 
you will be exposed to the same risks and benefits as both are a recommended 
treatment in the guidelines for the management of acute pancreatitis. 
Your participation in the study is simply limited to the duration of hospital admission. 
This study will recruit patients over two years, although it could be extended if it has not 

31 
 
achieved the total number of patients we have calculated are needed to see if there is a 
treatment that is better. As soon as you start eating after that period and it is not 
clinically indicated, we will proceed to suspend the treatment of the fluid under study. 
To participate you only have to sign this document.  
 
WHAT ARE THE BENEFITS OF PARTICIPATING IN THIS STUDY?  
As we have mentioned, whether you participate in this study, you will receive one of the 
two types of fluids that we are studying, the only difference is that it is done in a 
controlled manner in order to be able to compare the two groups of patients. Your help 
in this study will allow us to know if one of the two types of fluids has a beneficial effect 
on the evolution of acute pancreatitis, or on the contrary both are the same and it is not 
worthwhile to continue asking this question in new studies. You will not receive financial 
compensation for your participation in the study. This study is sponsored by physicians 
and researchers who have no financial interest in these types of fluids, which are very 
cheap and of little or no interest to the pharmaceutical industry. The researchers 
participating in this study do not receive financial compensation for collaborating in the 
recruitment and follow-up of patients, they participate, just as you do, out of altruism, 
so that science advances and we know more about the treatment of acute pancreatitis.  
 
WHAT ARE THE RISKS OF PARTICIPATING IN THE STUDY?  
This study does not involve exposure to risks that you will not suffer anyway, since 
regardless of whether or not you participate in it, you will be given one of the two fluids. 
It has been speculated that saline may slightly more frequently produce renal failure, 
and blood acidity, and that lactated Ringer's solution may give increases in blood calcium 

32 
 
and potassium. Despite this, these are fluids that are used daily on any hospital floor, 
and we have a great deal of experience in the handling of both fluids, and the problems 
they cause are anecdotal.  
 
WHAT DATA WILL BE COLLECTED?  
We will collect your age, sex, weight, and other variables present at the beginning of the 
study. Throughout the admission we will note a series of variables that give an idea of 
the evolution of the disease, and we will compare these variables between the group of 
patients who received lactated Ringer's solution and those who received saline. For 
example, we will see if one of the two groups of patients has a greater severity of 
disease. We will measure other variables such as the presence of local complications in 
and around the pancreas, the presence of organ problems at a distance from the 
pancreas, inflammation measured by different ways, time taken to eat, analytical 
parameters and similar variables. 
HOW WILL MY PERSONAL DATA BE TREATED AND HOW WILL CONFIDENTIALITY BE 
PRESERVED?  
The collection, processing and use of the data required by this study will be in 
accordance with the provisions of Organic Law 3/2018, of December 5, 2018, on the 
Protection of Personal Data and guarantee of digital rights, and with the provisions of 
Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 
2016 on Data Protection (GDPR).  
Access to your personal information will be restricted to the study doctor/collaborators, 
health authorities and the advisory bodies of the Instituto de Investigación Sanitaria y 
Biomédica de Alicante (ISABIAL), when required, to check the data and procedures of 

33 
 
the study, but always maintaining the confidentiality of the same in accordance with 
current legislation. The Researcher, when processing and treating your data will take 
appropriate measures to protect them and prevent access to them by unauthorized 
third parties. 
You may exercise your rights of access (to request information about your information 
stored in the database), of opposition (to refuse to provide the data), of cancellation (to 
request that the data be destroyed) and rectification (if over time any data is modified, 
or an error is detected). You may revoke your consent to the processing of your personal 
data by contacting the researcher. 
In addition to these rights, and in accordance with the GDPR, you can also limit the 
processing of data that are incorrect, request a copy or that the data you have provided 
for the study be transferred to a third party (portability). To exercise your rights, please 
contact the principal investigator of the study. We remind you that the data cannot be 
deleted even if you no longer participate in the study to ensure the validity of the 
research and to comply, if applicable, with legal obligations and drug authorization 
requirements. You also have the right to contact the Data Protection Agency if you are 
not satisfied. 
Both the Center and the Sponsor are respectively responsible for the processing of your 
data and undertake to comply with the data protection regulations in force. The data 
collected for the study will be identified by a code, so that no information that can 
identify you is included, and only your study doctor/collaborators will be able to relate 
this data to you and your medical history. Therefore, your identity will not be disclosed 
to any other person except to health authorities, when required or in cases of medical 
emergency. The Research Ethics Committees, the representatives of the Health 

34 
 
Authority for inspection and the personnel authorized by the Sponsor, will only have 
access to check the personal data, the procedures of the clinical study and the 
compliance with the rules of good clinical practice (always maintaining the 
confidentiality of the information). 
The Investigator and the Sponsor are obliged to keep the data collected for the study for 
at least 25 years after its completion. Thereafter, your personal information will only be 
retained by the Center for your health care and by the Sponsor for other scientific 
research purposes if you have given your consent to do so, and if permitted by applicable 
law and ethical requirements. 
If we transfer your encrypted data outside the EU to our group entities, service providers 
or scientific researchers collaborating with us, the participant's data will be protected 
by safeguards such as contracts or other mechanisms by data protection authorities. If 
the participant wants to know more about this, he/she can contact the CENTER'S 
PRINCIPAL RESEARCHER. 
 
WHO CAN I CONTACT IF I HAVE ANY QUESTIONS?  
If you need more information about the study, you can contact the CENTER'S PRINCIPAL 
INVESTIGATOR, Telephone: TELEPHONE