Clinical Trials Register

Summary
EudraCT Number:	2015-005736-17
Sponsor's Protocol Code Number:	NL56697.041.16
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2016-06-27
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

Netherlands - Competent Authority

A.2

EudraCT number

2015-005736-17

A.3

Full title of the trial

Prevention of severe infectious complications after colorectal surgery using antimicrobial decontamination of the digestive tract (PreCaution trial)

Het voorkomen van ernstige infectieuze complicaties na colorectale chirurgische ingrepen middels preoperatieve orale antibiotische decontaminatie van het maagdarmkanaal

A.3.1

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

Prevention of wound infections after colorectal surgery using antibiotics prior to surgery

Het voorkomen van wond infecties na dikke darm operaties door middel van antibiotica voorafgaand aan de operatie

A.3.2

Name or abbreviated title of the trial where available

PreCaution

A.4.1

Sponsor's protocol code number

NL56697.041.16

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 Utrecht
B.1.3.4	Country	Netherlands
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	ZonMw
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Medical Center Utrecht
B.5.2	Functional name of contact point	Drs. Tessa Mulder
B.5.3	Address:
B.5.3.1	Street Address	Heidelberglaan 100
B.5.3.2	Town/ city	Utrecht
B.5.3.3	Post code	3584CX Utrecht
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	0031887568190
B.5.6	E-mail	t.mulder-2@umcutrecht.nl

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	No
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	SDD voor darmchirurgie
D.3.2	Product code	16059670
D.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	COLISTIN SULFATE
D.3.9.1	CAS number	1264-72-8
D.3.9.4	EV Substance Code	SUB01431MIG
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	Tobramycinum
D.3.9.3	Other descriptive name	TOBRAMYCIN
D.3.9.4	EV Substance Code	SUB11134MIG
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	16
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Oral solution
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

The medical condition under investigation: surgical site infections (bacterial) after elective colorectal surgery.

De medische conditie die wordt onderzocht gedurende deze studie: postoperatieve wondinfecties (bacterieel), ontstaan na electieve colorectale operaties.

E.1.1.1

Medical condition in easily understood language

Wound infections after colorectal surgery

Wondinfecties na operatie aan de dikke darm

E.1.1.2

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10053562
E.1.2	Term	Surgical wound infection
E.1.2	System Organ Class	100000004862

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10056641
E.1.2	Term	Post procedural site wound infection
E.1.2	System Organ Class	100000004862

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10074392
E.1.2	Term	Deep postoperative wound infection
E.1.2	System Organ Class	100000004862

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10074393
E.1.2	Term	Superficial postoperative wound infection
E.1.2	System Organ Class	100000004862

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 primary objective is to determine the effect of preoperative oral antibiotic prophylaxis (Pre-OP), in addition to standard perioperative intravenous antimicrobial prophylaxis, in patients undergoing elective colorectal surgery, on the cumulative incidence of deep SSI and/or mortality within 30 days after colorectal surgery.

De primaire doelstelling van de studie is het bepalen van het effect van preoperative orale antibiotische profylaxe (Pre-OP) in aanvulling op de standaard perioperatieve intraveneuze antibiotische profylaxe bij patiënten die electieve colorectale operaties ondergaan op de cumulatieve incidentie van diepe postoperatieve wondinfecties en/of mortaliteit binnen 30 dagen na de operatie

E.2.2

Secondary objectives of the trial

1. To determine the effect of Pre-OP, in addition to standard perioperative intravenous antibiotic prophylaxis, in patients undergoing elective colorectal surgery on:
a) The cumulative incidence of superficial incisional SSI within
b) The cumulative incidence of anastomotic leakage (AL)
c) The all-cause mortality
d) The cumulative incidence of relaparotomy
e) The cumulative incidence of bacteraemia
f) The cumulative incidence of infections
i. Highly-resistant micro-organisms (HRMO)
ii. Clostridium difficile
g) The postoperative length of hospital stay, including readmissions
h) The postoperative length of ICU stay, including readmissions
i) The in-hospital costs
j) The in-hospital use of antibiotics
k) The quality of life

2. To identify risk factors for SSI and assess whether these are dependent on:
a) The type of surgery (e.g. colon versus rectum)
b) The use of Pre-OP (active study medication versus placebo)

1. Het bepalen van het effect van Pre-OP, als aanvulling op de standaard perioperatieve intraveneuze antibiotische profylaxe bij patienten die electieve colorectale operaties ondergaan op:
a) de cumulatieve incidentie van oppervlakkige postoperatieve wondinfecties
b) de cumulatieve incidentie van naadlekkages
c) mortaliteit
d) de cumulatieve incidentie van relaparatomiën
e) de cumulatieve incidentie van bacteriemieen
f) de cumulatieve incidentie van infecties
i) multiresistente micro-organismen
ii) Clostridium difficile
g) de postoperatieve opnameduur, inclusief heropname
h) de postoperatieve opnameduur op de intensive care, inclusief heropname op de intensive care
i) Zorgkosten
j) Gebruik van antibiotica gedurende de opname
k) Quality of life

2. Het vaststellen van risicofactoren voor het ontwikkelen van postoperatieve wondinfecties en onderzoeken of deze afhankelijk zijn van:
a) het type operatie
b) het toepassen van Pre-OP

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Adult patients (18 years of age or older) undergoing elective colorectal surgery. Elective surgery is defined as surgery for which there is no need to be performed immediately, with the possibility to be scheduled at the patient’s and surgeon’s convenience
- Abovementioned patients may not meet any of the exclusion criteria

- Volwassen patiënten (18 jaar of ouder) die een colorectale operatie ondergaan. Onder electief wordt verstaan: operatieve ingrepen die niet direct uitgevoerd en planbaar zijn
- Op de bovengenoemde patiënten mogen geen van de exclusie criteria van toepassing zijn

E.4

Principal exclusion criteria

Patients who meet one or more of the following criteria will not be eligible to participate in this study:

- Patients aged <18 years
- Legally incapacitated patients or patients who refuse to sign informed consent.
- Patients with an inability to take oral medication
- Patients who have undergone abdominal surgery within 30 days before randomisation
- Patients who have a known and documented allergy to any of the medications or agents used (i.e. colistin, tobramycin or other aminoglycoside antibiotics)
- Patients diagnosed with myasthenia gravis
- Pregnant women and nursing mothers
- Patients undergoing colorectal surgery in an emergency setting (i.e. not elective)
- Patients with an ileostomy
- Patients who already participated in the PreCaution trial

Patiënten waarbij 1 of meer van de volgende exclusie criteria van toepassing is/zijn komen niet in aanmerking voor deelname aan de studie:

- Patiënten met een leeftijd onder de 18 jaar
- Wilsonbekwame patiënten of patiënten die weigeren het informed consent te tekenen
- Patiënten waarbij de inname van studiemedicatie niet mogelijk is of niet veilig wordt geacht (e.g. slikstoornissen)
- Patiënten die <30 dagen voor randomisatie een buikoperatie hebben ondergaan
- Patiënten met een bekende allergie voor colistine, tobramycine of andere aminoglycoside antibiotica
- Patiënten gediagnosticeerd met myastenia gravis
- Zwangere vrouwen of vrouwen die borstvoeding geven
- Patiënten die colorectale operatie ondergaan in een trauma/acute setting (i.e. niet electief)
- Patiënten met een reeds preoperatief bestaand ileostoma
- Patienten die al hebben deelgenomen aan de PreCaution studie

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is a composite endpoint, consisting of: deep surgical site infection and/or mortality

Het primaire eindpunt is een samengesteld eindpunt bestaande uit: diepe postoperatieve wondinfectie en/of mortaliteit

E.5.1.1

Timepoint(s) of evaluation of this end point

30 days after elective surgery

30 dagen na electieve operatie

E.5.2

Secondary end point(s)

1. The cumulative incidence of superficial incisional SSI
2. The cumulative incidence of anastomotic leakage
3. The all-cause mortality
4. The cumulative incidence of relaparotomy
5. The cumulative incidence of bacteraemia
6. The cumulative incidence of infections with:
- Highly-resistant Enterobacteriaceae (HRE)
- Clostridium difficile
7. The presence of HRE in the intestinal flora
8. The postoperative length of hospital stay, including readmissions
9. The postoperative length of ICU stay, including readmissions
10. The in-hospital use of antibiotics
11. The in-hospital costs
12. The quality of life

1. De cumulatieve incidentie van oppervlakkige postoperatieve wondinfecties
2. De cumulatieve incidentie van naadlekkage
3. Mortaliteit (alle oorzaken)
4. De cumulatieve incidentie van relaparatomie
5. De cumulatieve incidentie van bacteriemieën
6. De cumulatieve incidentie van infecties met
- Multi-resistentie Enterobacteriaceae (HRE)
- Clostridium difficile
7. De aanwezigheid van HRE in de intestinale flora
8. Postoperatieve opname duur, inclusief heropnames
9. Postoperatieve opnameduur op de Intensive Care, inclusief heropnames
10. Gebruik van antibiotica gedurende de opname
11. Zorgkosten
12. Kwaliteit van leven

E.5.2.1

Timepoint(s) of evaluation of this end point

30 days after elective colorectal surgery (endpoint 1,2,4-7,10)
6 months after elective colorectal surgery (endpoint 3,8,9,11,12)

30 dagen na electieve colorectale operatie (eindpunt 1,2,4-7,10)
6 maanden na electieve colorectale operatie (eindpunt 3,8,9,11,12)

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

Yes

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)

Yes

E.7.4

Therapeutic use (Phase IV)

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

Yes

E.8.2.3

Other

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

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

Information not present in EudraCT

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 end of the trial is when the 6-month follow-up of the last patient is completed (patient 966)

Het einde van de trial is wanneer de 6 maanden follow-up van de laatste patiënt is voltooid (patiënt 966)

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:

483

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

483

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

F.3.3.2

Women of child-bearing potential using contraception

Yes

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

966

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)

There will be no changes to the standard treatment when the subject has ended his or her participation in the trial

Er zal geen sprake zijn van een veranderde of aangepaste behandeling van de patient wanneer zijn of haar deelname aan de studie is beeindigd

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-06-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-09-20

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2018-08-22

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