Clinical Trials Register

Summary
EudraCT Number:	2017-001479-22
Sponsor's Protocol Code Number:	NCT03021525
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:	2017-07-04
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

2017-001479-22

A.3

Full title of the trial

Individualized perioperative hemodynamic goal-directed therapy in major abdominal surgery (iPEGASUS-trial)

Terapia hemodinámica individualizada perioperatoria dirigida por objetivos en cirugía mayor abdominal (Estudio iPEGASUS)

A.3.1

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

Hemodynamic therapy in abdominal surgery

Manejo hemodinámico en cirugía abdominal

A.3.2

Name or abbreviated title of the trial where available

iPEGASUS

A.4.1

Sponsor's protocol code number

NCT03021525

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03021525

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	University Medical Center Hamburg-Eppendorf, Germany
B.1.3.4	Country	Germany
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	Pulsion Medical Systems SE
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Hospital Clinico Universitario
B.5.2	Functional name of contact point	Javier Belda
B.5.3	Address:
B.5.3.1	Street Address	Blasco Ibañez, 17
B.5.3.2	Town/ city	Valencia
B.5.3.3	Post code	46010
B.5.3.4	Country	Spain
B.5.4	Telephone number	34963862653
B.5.6	E-mail	soromarina@gmail.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	Norepinephrine
D.2.1.1.2	Name of the Marketing Authorisation holder	B. BRAUN MEDICAL, 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.3.1	Product name	Norepinephrine
D.3.2	Product code	656019
D.3.4	Pharmaceutical form	Solution for injection/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	NOREPINEPHRINE
D.3.9.1	CAS number	51-41-2
D.3.9.4	EV Substance Code	SUB09360MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg/kg microgram(s)/kilogram
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	0.5 to 1
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	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	Dobutamine
D.2.1.1.2	Name of the Marketing Authorisation holder	INIBSA HOSPITAL, S.L.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.3.1	Product name	Dobutamine
D.3.4	Pharmaceutical form	Concentrate for 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	DOBUTAMINE
D.3.9.1	CAS number	34368-04-2
D.3.9.4	EV Substance Code	SUB06343MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg/kg microgram(s)/kilogram
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	2.5 to 10
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

- Hemodynamic Instability
- Cardiac Output
- High Peroperative Complication

- Inestabilidad hemodinámica
- Gasto cardiaco
- Complicación peroperatoria mayor

E.1.1.1

Medical condition in easily understood language

High Peroperative Complication

Complicación perioperatoria mayor

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

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 evaluate the impact of perioperative, algorithm driven, hemodynamic therapy based on individualized fluid and cardiac output optimization on postoperative moderate and severe complications as a major determinant for the patients' postoperative quality of life as well as for health care costs and mortality.

Evaluar el impacto de la terapia hemodinámica conducida por el algoritmo basado en la optimización individualizada del fluido y el rendimiento cardíaco en las complicaciones postoperatorias moderadas y severas como determinante principal de la calidad de vida postoperatoria de los pacientes, así como en los costos y mortalidad de los servicios de salud.

E.2.2

Secondary objectives of the trial

The before mentioned perioperative outcome measures are also used for assessment of morbidity at postoperative day 1, 3, 5, 7, and 28 as secondary endpoints.

Las medidas de resultado perioperatorias antes mencionadas también se utilizan para evaluar la morbilidad en los días 1, 3, 5, 7 y 28 postoperatorios como criterios de valoración secundarios.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- To provide high generalizability and representativeness the high number of patients with laparotomy and major surgical trauma is included into this study.
- Therefore, open visceral, urological, and gynecological surgery is covered by this study.
- Expected duration of surgery must be ≥ 120 minutes and requirement of volume therapy needs to be expected ≥ 2 liters.
- Risk for any postoperative complications needs to be ≥10% assessed by the ACS (American College of Surgery)- NSQUIP (National Surgical Quality Improvement Program) risk calculator.

- Para proporcionar alta generalización y representatividad, el alto número de pacientes con laparotomía y traumatismo quirúrgico mayor se incluye en este estudio.
- Por lo tanto, la cirugía abierta visceral, urológica y ginecológica está cubierta por este estudio.
- La duración esperada de la cirugía debe ser ≥ 120 minutos y se requiere un requerimiento de terapia de volumen ≥ 2 litros.
- El riesgo de complicaciones postoperatorias debe ser ≥10% evaluado por el calculador de riesgo de la NSCA (National Surgical Quality Improvement Program) de la ACS (American College of Surgery).

E.4

Principal exclusion criteria

-Patients <18 years,
-Laparoscopic approach,
-Patients not having sinus rhythm,
-Patients having highly impaired left ventricular function (ejection fraction <30%) or severe aortic valve stenosis (aortic valve area <1 cm2, mean gradient >40 mmHg),
-Pregnant women,
-Emergency surgeries (surgery required within 24 hours),
-Primarily vascular surgery,
-Patients suffering from septic shock,
-Patients having phaeochromocytoma,
-Patients suffering from non-cardiac chest pain,
-Refusal of consent,
-Patients receiving palliative treatment only (likely to die within 6 months) and patients suffering from acute myocardial ischemia (within 30 days before randomization) are excluded from the study.
-Further, in case that clinicians intended to use cardiac output monitoring for clinical reasons patients should also not be included in the study.

-Pacientes menores de 18 años,
-Abordaje laparoscópico,
-Pacientes que no tienen ritmo sinusal,
-Pacientes con insuficiencia de la función ventricular izquierda (fracción de eyección <30%) o estenosis valvular aórtica grave (área de la válvula aórtica <1 cm2, gradiente medio> 40 mmHg)
-Mujeres embarazadas,
-Cirugías de emergencia (cirugía requerida dentro de 24 horas), principalmente cirugía vascular
-Pacientes que sufren de choque séptico,
-Pacientes con feocromocitoma,
-Pacientes con dolor torácico no cardíaco,
-Rechazo del consentimiento,
-Los pacientes que reciben tratamiento paliativo solamente (probablemente mueren dentro de los 6 meses) y los pacientes que sufren de isquemia miocárdica aguda (dentro de los 30 días antes de la aleatorización) están excluidos del estudio.
-Además, en caso de que los clínicos tengan la intención de utilizar el control del gasto cardíaco por razones clínicas, los pacientes tampoco deben ser incluidos en el estudio.

E.5 End points

E.5.1

Primary end point(s)

•Morbidity [ Time Frame: Day 1,3,5,7 and 180 ]
At these days both, number of complications and number of patients having at least one moderate or severe complication, will be assessed in total and for every complication. The additional secondary endpoints including days alive and free of mechanical ventilation at 7 days and 28 days, days alive and free of vasopressor therapy at 7 days and 28 days, days alive and free of renal replacement therapy at 7 days and 28 days, length of ICU and hospital stay further characterize perioperative morbidity and its socioeconomic impacts.
•Quality of life [ Time Frame: Time point of enrolment and on day180 ]
For assessment of quality of life an interview (personal or by telephone) based on the EQ-5D-5L (EuroQol Research Foundation) questionnaire is performed at the time point of enrolment and 6 months after surgery.
•Mortality [ Time Frame: Day 180 ]
Mortality is assessed 6 months after surgery.

•Morbilidad [Duración: Día 1,3,5,7 y 180]
En estos días, tanto el número de complicaciones como el número de pacientes que tienen al menos una complicación moderada o grave, se evaluarán en total y por cada complicación. Los puntos finales secundarios adicionales, incluidos días vivos y libres de ventilación mecánica a los 7 días y 28 días, días vivos y libres de terapia vasopresora a los 7 días y 28 días, días vivos y libres de terapia de reemplazo renal a los 7 días y 28 días, UCI y estancia hospitalaria caracterizan la morbilidad perioperatoria y sus impactos socioeconómicos.
•Calidad de vida [Calendario: Hora de la inscripción y el día 180]
Para la evaluación de la calidad de vida se realiza una entrevista (personal o por teléfono) basada en el cuestionario EQ-5D-5L (EuroQol Research Foundation) al momento de la inscripción y 6 meses después de la cirugía.
•Mortalidad [Plazo: Día 180]
La mortalidad se evalúa 6 meses después de la cirugía.

E.5.1.1

Timepoint(s) of evaluation of this end point

Composite of morbidity and mortality on day 28 [ Time Frame: 28 days ]

Compuesto de morbilidad y mortalidad al día 28 [Marco temporal: 28 días]

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

•Morbidity [ Time Frame: Day 1,3,5,7 and 180 ]

•Quality of life [ Time Frame: Time point of enrolment and on day180 ]

•Mortality [ Time Frame: Day 180 ]
Mortality is assessed 6 months after surgery.

•Morbilidad [Duración: Día 1,3,5,7 y 180]

•Calidad de vida [Calendario: Hora de la inscripción y el día 180]

•Mortalidad [Plazo: Día 180]
La mortalidad se evalúa 6 meses después de la cirugía.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

El grupo de control se tratará de acuerdo con los objetivos básicos establecidos del tratam

The control group will be treated according to established basic treatment goals (heart rate <100 bp

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

E.8.6.2

Trial being conducted completely outside of the EEA

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 lack of subsequent examinations of the patient after d28 loss to follow up

La falta de exámenes posteriores del paciente después de la pérdida de d28 para el seguimiento

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:

380

F.1.3

Elderly (>=65 years)

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

380

F.4.2

For a multinational trial

F.4.2.1

In the EEA

380

F.4.2.2

In the whole clinical trial

380

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

2017-08-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-07-26

P. End of Trial
P.	End of Trial Status	Ongoing

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