Clinical Trials Register

Summary
EudraCT Number:	2014-002036-14
Sponsor's Protocol Code Number:	V3.10.5.2014
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-06-16
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

Denmark - DHMA

A.2

EudraCT number

2014-002036-14

A.3

Full title of the trial

The effect of epidural anaesthesia on systemic and splanchnic hemodynamic during gastroesophageal resections, a randomized controlled trial

Effekt af epidural anæstesi på systemisk og splanknisk hæmodynamik under esophagusresektion, et randomiseret kontrolleret studie

A.3.1

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

The effect of epidural anaesthesia on systemic and local blood flow during stomach cancer operation

Effekt af epidural bedøvelse på systemisk og lokal blodgennemstrømning under operation for mavemundscancer

A.3.2

Name or abbreviated title of the trial where available

The effect of epidural anaesthesia on blood flow

Effekt af epidural bedøvelse på blodgennemstrømning

A.4.1

Sponsor's protocol code number

V3.10.5.2014

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	Lars Bo Svendsen
B.1.3.4	Country	Denmark
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	The Danish Cancer Society
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Department of Surgical Gastroenterology, Rigshospitalet
B.5.2	Functional name of contact point	Rikard Bien Ambrus
B.5.3	Address:
B.5.3.1	Street Address	Blegdamsvej 9
B.5.3.2	Town/ city	Copenhagen Ø
B.5.3.3	Post code	2100
B.5.3.4	Country	Denmark
B.5.4	Telephone number	004560677929
B.5.6	E-mail	rikard.bien.ambrus.02@regionh.dk

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	Lidokain-adrenalin SAD.
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgros I/S
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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 injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Epidural use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	LIDOCAINE HYDROCHLORIDE
D.3.9.3	Other descriptive name	lidocain
D.3.9.4	EV Substance Code	SUB88133
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NOREPINEPHRINE BITARTRATE
D.3.9.1	CAS number	51-40-1
D.3.9.3	Other descriptive name	andrenaline
D.3.9.4	EV Substance Code	SUB03455MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Bupivacain SAD
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgros I/S
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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 injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Epidural use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	bupivacaine
D.3.9.3	Other descriptive name	BUPIVACAINE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB00902MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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: 3
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	Bupivacain-morfin SAD
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgros I/S
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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	Epidural use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	morphine
D.3.9.1	CAS number	52-26-6
D.3.9.3	Other descriptive name	MORPHINE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB14596MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	bupivacaine
D.3.9.3	Other descriptive name	BUPIVACAINE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB00902MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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

The effect of epidural anaesthesia on systemic and splanchnic hemodynamic during gastroesophageal cancer resection

Effekt af epidural anæstesi på systemisk og splanknisk hæmodynamik under esophagusresektion

E.1.1.1

Medical condition in easily understood language

The effect of epidural anaesthesia on systemic and local blood flow during stomach cancer operation

Effekt af epidural bedøvelse på systemisk og lokal blodgennemstrømning under operation for mavemundscancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10066354
E.1.2	Term	Adenocarcinoma of the gastroesophageal junction
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Epidural anaesthesia reduces the sympathetic response, thereby possibly inhibiting the microcirculation in the splanchnic system, especially in the gastric conduit. With this study, we wish to evaluate hemodynamic fluctuations and gastric circulation as well as vasodilatory substances (e.g. PGI2) in relevant intervals from the activation of epidural analgesia.

The hypothesis is that epidural analgesia reduces sympathetic nerve activity and thereby inhibiting the splanhcnic microcirculation, especially in the gastric conduit. Late activation of epidural analgesia is believed to be more advantageous.

Epidural anæstesi reducerer det systemiske response hvilket kan reducere microcirkulationen i splanchnicus, specielt i det gastriske konduit. Formålet med studiet er at vurdere de hæmodynamiske fluktuationer, microcrokulationen i det gastriske konduit, samt ændringer i de vasoaktive stoffers koncentrationer efter aktivering af epidural anæstesi.

Hypotesen er at epidural analgesi sænker sympatisk nerveaktivitet og hæmmer dermed microcirkulationen i splanchnicus og specielt i ventrikelrøret, hvorfor sen aktivering af epidural analgesi er fordelagtigt.

E.2.2

Secondary objectives of the trial

The secondary objective is to investigate the surgical stress response during and after surgery and the rate of postoperative complications, such as anstomotic leakage, infections, and pulmonary complications, in relation with early or late activation of epidural anaesthesia.

Det sekundære formål er at undersøge det kirurgiske stress-response under og efter kirurgi og forekomsten af postoperative komplikationer, såsom anstomose lækage, infektioner og pulmonale komplikationer i forbindelse med tidlig versus sen aktivering af epidural anæstesi.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patiens over 18 years of age planned for gastroesophageal resection due to adenocarcinoma of the gastroesophageal junction.
No discriminations of ethnic or gender.

Voksne (>18 år) og myndige patienter, der skal undergå åben esophagusresektion for biopsiverificeret adenocarcinom. Ingen krav til etnicitet eller køn.

E.4

Principal exclusion criteria

Lack of consent.
Patients planned for robot-assisted surgery.

Manglende samtykke.
Patienter der skal gennemgå robot-assisterede operationer

E.5 End points

E.5.1

Primary end point(s)

Significant alterations in microcirculation in the gastric conduit related to early versus late activation of epidural anaesthesia.

The study will be stopped when 50 patients have been randomised to early or late activation af epidural anaesthesia during surgery.

Signifikante ændringer i mikrocirkulationen i det gastriske konduit, relateret til tidlig versus sen aktivering af epidural anæstesi.

Undersøgelsen stoppes, når 50 patienter er blevet randomiseret til tidlig eller sen aktivering of epidural anæstesi under operation.

E.5.1.1

Timepoint(s) of evaluation of this end point

The first evaluation will be made when 20 patients have been included. During the study period, interim-analyzes will be made every sixth months until 50 patients have been included.

Den første interimanalyse foretages når 20 patienter er inkluderet. I løbet af undersøgelses perioden foretages interimanalyser hver sjette måned indtil 50 patienter er inkluderet.

E.5.2

Secondary end point(s)

Significant differences of intra- and postoperative levels of surgical response between the groups, defined as alterations in serum cortisol, aldosterone, adrenaline, noradrenaline, and ACTH.

Significant alterations in the plasmalevels og atrial natriuretic hormon (ANP), prostacyclin and GLP-1

Significant differences in the rate of postoperative complications between the groups, such as anastomotic leakage, infections, pulmonary complications, and death.

Signifikante forskelle i intra- og postoperative niveauer af kirurgisk stress response mellem grupperne , defineret som ændringer i cortisol, aldosteron, adrenalin, noradrenalin og ACTH.

Signifikante ændringer i plasmaniveauer af atrial natriuretisk hormon (ANP), prostacyclin og GLP-1

Signifikante forskelle i antallet af postoperative komplikationer mellem grupperne, såsom anastomotisk lækage, infektioner, pulmonale komplikationer og død.

E.5.2.1

Timepoint(s) of evaluation of this end point

The first evaluation will be made when 20 patients have been included. During the study period, interim-analyzes will be made every sixth months until 50 patients have been included.

Den første interimanalyse foretages når 20 patienter er inkluderet. I løbet af undersøgelses perioden foretages interimanalyser hver sjette måned indtil 50 patienter er inkluderet.

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

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

Yes

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

Early versus Late activation of epidura anaesthesia. No other medicinal products will de used

The effect of epidural anaesthesia is compared between a early and late activation.

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

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

Yes

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 study will be stopped if there the rate of anastomotic leakage is over 15 % at the interim-analyzes. If the high leakage-rate is due to time of activation of epidural anaesthesia, the study will be stopped permanently.

Also, the study will bee stopped at the occurence of a Serious Adverse Event/Suspected Unexpected Serious Adverse Reaction, related to the time of activation of epidural anaesthesia.

Forsøget stoppes hvis der ses en lækage-rate over 15 % ved interimanalyser. Såfremt konklusionen skulle være, at den høje lækage-rate skulle være forårsaget af sen aktivering af epidural analgesi, afsluttes forsøget med det samme.

Forsøget stoppes hvis en Serious Adverse Event/Suspected Unexpected Serious Adverse Reaction kan relateres til tidlig aktivering af epidural anæstesi.

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

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

Yes

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2014-06-16.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

Yes

F.3.3.4

Nursing women

Yes

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

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

Ingen

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

2014-08-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-09-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-06-30

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