Clinical Trials Register

Summary
EudraCT Number:	2019-000788-26
Sponsor's Protocol Code Number:	WATERFALL
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2019-04-30
Trial results	View 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

2019-000788-26

A.3

Full title of the trial

Effect of early weight-based aggressive versus non-aggressive goal-directed fluid resuscitation in the early phase of acute pancreatitis: an open-label multicenter randomized-controlled trial

Efecto de fluidoterapia agresiva frente a fluidoterapia no agresiva basada en metas en la fase precoz de la pancreatitis aguda: ensayo clínico controlado aleatorizado multicéntrico

A.3.1

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

WATERFALL trial: Aggressive fluid resuscitation in the initial phase of acute pancreatitis

Ensayo WATERFALL:Fluidoterapia agresiva en la fase inicial de la pancreatitis aguda

A.3.2

Name or abbreviated title of the trial where available

Aggressive fluid resuscitation in the acute pancreatitis

Fluidoterapia agresiva en la pancreatitis aguda

A.4.1

Sponsor's protocol code number

WATERFALL

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 de Alicante
B.5.2	Functional name of contact point	Pancreatic Unit Coordinator
B.5.3	Address:
B.5.3.1	Street Address	Pintor Baezas/n, Servicio de Aparato Digestivo,4ºplanta C,Hospital General Universitario de Alicante
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	madaria@hotmail.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
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 RINGER LACTATO
D.2.1.1.2	Name of the Marketing Authorisation holder	FRESENIUS KABI ESPAÑA,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	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	lactated Ringer Solution
D.3.9.1	CAS number	8026-79-7
D.3.9.3	Other descriptive name	RINGER'S LACTATE SOLUTION
D.3.9.4	EV Substance Code	SUB33298
D.3.10	Strength
D.3.10.1	Concentration unit	mEq/l milliequivalent(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0
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.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

to compare the effect of early aggressive fluid resuscitation versus a more restricted fluid resuscitation strategy in the incidence of moderate-to-severe AP

comparar la incidencia de pancreatitis aguda moderada a grave entre una fluidoterapia agresiva y una fluidoterapia restrictiva.

E.2.2

Secondary objectives of the trial

Secondary objectives: comparison with an aggressive fluidity versus a restrictive one in terms of:
A) Incidence of local and systemic complications of acute pancreatitis.
B) Safety of treatment: incidence of fluid overload, renal failure and hypotension.
C) Hospital stay, need for ICU, stay in ICU
D) Need for invasive treatment and nutritional support.
E) Mortality

Objetivos secundarios: comparar una pauta de fluidoterapia agresiva frente a otra restrictiva en cuanto a:
A) Incidencia de complicaciones locales y sistémicas de la pancreatitis aguda
B) Seguridad del tratamiento: incidencia de sobrecarga de fluidos, insuficiencia renal e hipotensión
C) Estancia hospitalaria, necesidad de UCI, estancia en UCI
D) Necesidad de tratamiento invasivo y de soporte nutricional
E) Mortalidad

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

adult (≥18) patients with AP according to the revision of the Atlanta classification (RAC) (Banks et al, Gut 2013): at least 2 of the following 3 criteria: A) Typical abdominal pain, B) Increase in serum amylase or lypase levels higher than 3 times the upper limit of normality, and C) Signs of AP in imaging techniques (CT scan or MRI). This study requires signed informed consent.

- Edad ≥18 años
- PA diagnosticada de acuerdo a los criterios de la clasificación revisada de Atlanta (13), definida como al menos 2 de los siguientes 3 criterios: 1) dolor abdominal típico (epigástrico, intenso, agudo, puede irradiar a flanco su espalda en cinturón); 2) aumento de amilasa y/o lipasa en sangre mayor de tres veces el límite superior de normalidad y 3) pruebas de imagen compatibles con pancreatitis aguda, principalmente TAC y/o RMN
- Firma del consentimiento informado por parte del paciente o sus representantes

E.4

Principal exclusion criteria

Exclusion criteria: non-controlled arterial hypertension (>160 (Systolic BP) and/or 100 mmHg (diastolic BP), heart failure (New York Hear Association Class II-IV) or ejection fraction <50%, decompensated cirrhosis (Child’s Class B or C), Hyper or hyponatremia (<135 or >145 mEq/l), hyperpotassemia (>5 mEq/l), hypercalcemia (albumin or protein-corrected calcium>10.5 mg/dl), chronic kidney failure (basal glomerular filtration rate <60 mL/min/1.73m2), clinical signs of volume overload (peripheral edema, pulmonary rales, and ascites), organ failure according to the RAC (Marshall≥2), time from pain onset to arrival to emergency room >24h, time from confirmation of pancreatitis to randomization >8h, severe comorbidity associated with an estimated life expectancy <1 year and confirmed chronic pancreatitis (in case of recurrent alcoholic pancreatitis a recent (<6 months) CT scan/MRI or endoscopic ultrasound is needed to rule out chronic pancreatitis).

Criterios de exclusión:
- Hipertensión arterial no controlada (TA sistólica > 160 mmHg y/o TA diastólica >100 mmHg
- Enfermedad cardíaca o pulmonar asociada a una clase funcional New York Heart Association (NYHA) de II (ligera i itaci de a actividad f sica) o mayor o bien fracción eyección menor al 50% en última ecocardiografía realizada
- Cirrosis hepática descompensada (Child B o C)
- Hipo (<135 mEq/l) o hipernatremia (>145 mEq/l)
- Hiperpotasemia (>5 mEq/l)
- Hipercalcemia (calcemia corregida por proteínas o albúmina >10,5 mg/dl)
- Insuficiencia renal crónica (filtrado glomerular basal <60 mL/min/1,73 m2)
- Síntomas o signos clínicos de sobrecarga de fluidos o insuficiencia cardíaca en el momento de evaluación (disnea, edema periférico, crepitantes pulmonares, ingurgitación yugular clara a 45º)
- Fallo orgánico circulatorio o respiratorio al ingreso definido por la clasificación revisada de Atlanta (tensión arterial sistólica < 90 mmHg que no responde a fluidoterapia, PaO2/FIO2≤300 mmHg)
- Tiempo entre inicio del dolor que le hace ingresar y llegada a urgencias mayor de 24h
- Tiempo entre confirmación de pancreatitis aguda y aleatorización mayor de 8h
- Comorbilidad grave con esperanza de vida menor a 1 año
- Pancreatitis crónica confirmada (en caso de pancreatitis alcohólica recurrente se necesita un TAC, RMN o ecoendoscopia reciente (<6 meses) o en urgencias que descarte pancreatitis crónica)

E.5 End points

E.5.1

Primary end point(s)

Incidence of moderate-to-severe AP according to the RAC

Incidencia de pancreatitis aguda moderada a grave según la clasificación de Atlanta revisada

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)

combined variable mortality and / or persistent organic failure and / or pancreatic necrosis infection. Fluid overload, local complications (acute peripancreatic fluid collection, pancreatic and peripancreatic necrosis, pancreatic necrosis infection), organic and persistent failure, and hospitalization, hospital stay, stay in the ICU, need for organ failure. Need for nutritional support (enteral and / or parenteral nutrition).

variable combinada mortalidad y/o fallo orgánico persistente y/o infección de necrosis pancreática . Sobrecarga de fluidos , complicaciones locales (colección aguda de líquido peripancreático, necrosis pancreática y peripancreática , infección de necrosis pancreática), fallo orgánico transitorio y persistente, y en qué órganos , mortalidad, estancia hospitalaria, estancia en UCI, necesidad de tratamiento invasivo o del fallo orgánico. Necesidad de soporte nutricional (nutrición enteral y/o parenteral).

E.5.2.1

Timepoint(s) of evaluation of this end point

At hospital discharge

Al alta hospitalaria

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

RINGER LACTATO

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 Aggressive fluid resuscitation 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 en la fluidoterapia agresiva

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:

350

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

350

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

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

534

F.4.2

For a multinational trial

F.4.2.1

In the EEA

166

F.4.2.2

In the whole clinical trial

700

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-06-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-05-29

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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