Clinical Trials Register

Summary
EudraCT Number:	2023-000010-18
Sponsor's Protocol Code Number:	WATERLAND
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2023-02-09
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2023-000010-18

A.3

Full title of the trial

Normal saline versus lactated Ringer’s solution for acute pancreatitis resuscitation, an open-label multicenter randomized controlled trial: the WATERLAND trial

Efecto de fluidoterapia mediante suero fisiológico frente a solución de Ringer lactato en pacientes con pancreatitis, estudio abierto multicéntrico aleatorizado, estudio WATERLAND

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Normal saline versus lactated Ringer’s solution for acute pancreatitis

Solución salina normal frente a solución de Ringer lactato para la pancreatitis aguda

A.3.2

Name or abbreviated title of the trial where available

Normal saline versus lactated Ringer’s solution for acute pancreatitis

Solución salina normal frente a solución de Ringer lactato para la pancreatitis aguda

A.4.1

Sponsor's protocol code number

WATERLAND

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Enrique de Madaria
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Asociación Española de Gastroenterología(AEG, Spanish Association of Gastroenterology
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Servicio de Aparato Digestivo, Hospital General Universitario Dr Balmis
B.5.2	Functional name of contact point	Pancreatic Unit Coordinator
B.5.3	Address:
B.5.3.1	Street Address	Pintor Baeza12, Servicio de Aparato Digestivo,4ª planta C,Hospital General Universitario Dr. Balmis
B.5.3.2	Town/ city	Alicante
B.5.3.3	Post code	03010
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034965933468
B.5.5	Fax number	0034965933468
B.5.6	E-mail	enriquedemadaria@gmail.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Freeflex Lactated Ringer solution for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Fresenius Kabi España, S.A.U.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Salina Fisiológica Grifols 0,9% solución para perfusión
D.2.1.1.2	Name of the Marketing Authorisation holder	LABORATORIOS GRIFOLS, S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	Grifols Physiological Saline 0.9% solution for infusion

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Acute pancreatitis

Pancreatitis aguda

E.1.1.1

Medical condition in easily understood language

Acute pancreatitis

Pancreatitis aguda

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10033647
E.1.2	Term	Pancreatitis acute
E.1.2	System Organ Class	10017947 - Gastrointestinal disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The main objective of the trial is to investigate the effect of lactated Ringer solution compared to normal saline on the severity and safety of acute pancreatitis. The main efficacy endpoint is the frequency of moderately severe to severe acute pancreatitis according to the revision of the Atlanta classification. The main safety endpoint is a compound variable: fluid overload or acute kidney injury or hyperkalemia or hypercalcemia or acidosis.

El objetivo principal del ensayo es investigar el efecto de la solución de Ringer lactato en comparación con la solución salina normal sobre la gravedad y la seguridad de la pancreatitis aguda. El criterio principal de valoración de la eficacia es la frecuencia de pancreatitis aguda de moderadamente grave a grave según la revisión de la clasificación de Atlanta. El criterio principal de valoración de la seguridad es una variable compuesta: sobrecarga de líquidos o lesión renal aguda o hiperpotasemia o hipercalcemia o acidosis.

E.2.2

Secondary objectives of the trial

The secondary objectives of the trial are to investigate the effect of lactated Ringer solution compared to normal saline on the secondary efficacy and safety endpoints.

Los objetivos secundarios del ensayo son investigar el efecto de la solución de Ringer lactato en comparación con la solución salina normal en los criterios de valoración secundarios de eficacia y seguridad.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Patients 18 years or older
2.Diagnosis of acute pancreatitis according to the revision of the Atlanta classification (Banks et al, Gut 2013), which requires at least two of the following three criteria: A) typical abdominal pain, B) increase in serum amylase or lipase levels higher than three times the upper limit of normality, and C) signs of acute pancreatitis in imaging
3.Signature of informed consent

1.Pacientes con 18 años o mayores
2.Diagnóstico de pancreatitis aguda según la Clasificación Revisada de Atlanta (Banks et al, Gut 2013), que requiere al menos dos de los siguientes tres criterios: A) dolor abdominal típico, B) aumento de los niveles séricos de amilasa o lipasa superior a tres veces el límite superior de normalidad, y C) signos de pancreatitis aguda en pruebas de imagen
3. Firma de consentimiento informado

E.4

Principal exclusion criteria

1.New York Heart Association class II heart failure (slight limitation of physical activity; fatigue, palpitations, or dyspnea with ordinal physical activity) or worse, or ejection fraction <50% in the last echocardiography
2.Decompensated cirrhosis (Child’s class B or C)
3.Hyper or hyponatremia (<135 or >145 mEq/L)
4.Hyperkalemia (>5 mEq/L)
5.Hypercalcemia (albumin or protein-corrected calcium >10.7 mg/dL)
6. Criteria for moderately severe or severe acute pancreatitis (revision of the Atlanta classification, Banks et al, Gut 2013) at recruitment: any of the following: A) presence of creatinine ≥1.9 mg/dL or ≥170 mmol/l, B) PaO2/FiO2≤300, C) systolic blood pressure <90 mmHg despite initial fluid resuscitation, D) presence of local complications (acute peripancreatic fluid collections, acute necrotic collection, pseudocyst, walled-off necrosis, gastric outlet dysfunction, splenic or portal vein thrombosis, or colonic necrosis), E) exacerbation of previous comorbidity such as coronary artery disease or chronic lung disease, precipitated by the acute pancreatitis
7. Clinical symptoms (dyspnea) or signs (peripheral edema, pulmonary rales, or increased jugular ingurgitation at 45º) of volume overload or heart failure at recruitment
8. Time from pain onset to arrival to emergency room >12 h
9. Time from confirmation of pancreatitis to randomization >8 h
10. Chronic pancreatitis defined by a Wirsung duct ≥4mm and/or pancreatic calcifications
11. More than 1 previous episode of acute pancreatitis (only 2 episodes of acute pancreatitis are allowed, one of them the present episode)

1.Insuficiencia cardíaca clase II de la New York Heart Association (ligera limitación de la actividad física; fatiga, palpitaciones o disnea con la actividad física ordinaria) o mayor, o fracción de eyección <50% en la última ecocardiografía
2.Cirrosis descompensada (clase B o C de Child)
3.Hiper o hiponatremia (<135 o >145 mEq/L)
4.Hiperpotasemia (>5 mEq/L)
5. Hipercalcemia (albúmina o calcio corregido por proteínas >10,5 mg/dL)
6. Criterios para pancreatitis aguda moderada o grave (Clasificación Revisada de Atlanta, Banks et al, Gut 2013) en el momento del reclutamiento: cualquiera de los siguientes: A) presencia de creatinina ≥1,9 mg/dl o ≥170 mmol/l, B ) PaO2/FiO2≤300, C) presión arterial sistólica <90 mmHg a pesar de fluidoterapia, D) presencia de complicaciones locales (colecciones peripancreáticas agudas, colección necrótica aguda, pseudoquiste, necrosis encapsulada, obstrucción al vaciado gástrico, trombosis venosa esplénica o portal, o necrosis colónica), E) exacerbación de comorbilidad previa como enfermedad isquémica coronaria o enfermedad pulmonar crónica, precipitada por la pancreatitis aguda
7. Signos de sobrecarga de volumen o insuficiencia cardiaca al reclutamiento (edema periférico, estertores pulmonares o aumento de la ingurgitación yugular a 45º)
8. Tiempo desde el inicio del dolor hasta la llegada a urgencias > 12 h
9. Tiempo desde la confirmación de la pancreatitis hasta la aleatorización > 8 h
10. Pancreatitis crónica definida por un conducto de Wirsung ≥ 4 mm y/o calcificaciones pancreáticas
11. Más de 1 episodio previo de pancreatitis aguda (solo se permiten 2 episodios de pancreatitis aguda, uno de ellos el episodio actual)

E.5 End points

E.5.1

Primary end point(s)

The primary outcome will be moderately severe to severe AP, according to the RAC. (Atlanta classification)

Desarrollo de PA de moderadamente grave a grave definida por la clasificación revisada de Atlanta.

E.5.1.1

Timepoint(s) of evaluation of this end point

At hospital discharge

Al alta hospitalaria

E.5.2

Secondary end point(s)

Local complications (specific complications will be also recorded)
Necrotizing pancreatitis
SIRS
Number of SIRS criteria
PAN-PROMISE symptom scale
Time to oral refeeding
Invasive treatment
Nutritional support
Intensive care unit admission
Exacerbation of coexisting condition
Any organ failure
Persistent organ failure
Shock
Respiratory failure
Kidney failure
Death
Hospital stay
C-reactive protein

Complicaciones locales (también se registrarán las complicaciones específicas)
Pancreatitis necrosante
SIRS
Número de criterios SIRS
Escala de síntomas PAN-PROMISE
Tiempo hasta la realimentación oral
Tratamiento invasivo
Soporte nutricional
Ingreso en la unidad de cuidados intensivos
Exacerbación de la condición coexistente
Cualquier fallo orgánico
Insuficiencia orgánica persistente
Shock
Insuficiencia respiratoria
Insuficiencia renal
Muerte
Estancia en el hospital
Proteína C reactiva

E.5.2.1

Timepoint(s) of evaluation of this end point

Local complications: at discharge or death
Necrotizing pancreatitis: at discharge or death
SIRS: at 24 and 48h
Number of SIRS criteria: at 24 and 48h
PAN-PROMISE symptom scale: at 24 and 48h
Time to oral refeeding: at discharge or death
Invasive treatment: at discharge or death
Nutritional support: at discharge or death
Intensive care unit admission: at discharge or death
Exacerbation of coexisting condition: at discharge or death
Any organ failure: at discharge or death
Persistent organ failure: at discharge or death
Shock: at discharge or death
Respiratory failure: at discharge or death
Kidney failure: at discharge or death
Death: in case of mortality
Hospital stay: at discharge or death
C-reactive protein at 48hS

Complicaciones locales y específica:al alta o fallecimiento
Pancreatitis necrosante:al alta o fallecimiento
SIRS:24y48h
Nºde criterios SIRS:24y48h
Escala de síntomas PAN-PROMISE:24y48h
Tiempo hasta la realimentación oral:alta o fallecimiento
Tratamiento invasivo:alta o fallecimiento
Soporte nutricionalal:alta o fallecimiento
Ingreso en la unidad de cuidados intensivos:alta o fallecimiento
Exacerbación de la condición coexistente:alta o fallecimiento
Cualquier fallo orgánico:alta o fallecimiento
Insuficiencia orgánica persistente:alta o fallecimiento
Shock:alta o fallecimiento
Insuficiencia respiratoria:alta o fallecimiento
Insuficiencia renal:alta o fallecimiento
Muerte:alta o fallecimiento
Estancia en el hospital:alta o fallecimiento
Proteína Creactiva:a las 48 horas

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Suero salino

Normal saline

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Chile

Colombia

Mexico

Paraguay

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The trial will end:
A: After the last visit of the last subject undergoing the trial
B: If the Sponsor considers that recruitment is too slow
C: If the Sponsors considers that there is a safety issue
D: If an interim analysis suggests that Normal Saline is not associated to a lower incidence of acute pancreatitis or it is associated to a very important prophylactic effect (significant differences in the interim analysis)

El ensayo acabará:
A: tras la última visita del último paciente incluído
B: Si el promotor considera que el reclutamiento es demasiado lento
C: Si el promotor considera que hay un problema de seguridad
D: Si en un análisis intermedio no se observa beneficio del suero salino

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

720

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

720

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception