Clinical Trials Register

Summary
EudraCT Number:	2014-000180-41
Sponsor's Protocol Code Number:	P000176
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2015-02-04
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

Germany - BfArM

A.2

EudraCT number

2014-000180-41

A.3

Full title of the trial

Carriage of 3GCREB in patients at risk for relapsing infection: randomized controlled trial of intestinal decolonization with colistin plus rifaximin.

Infektionsprävention durch intestinale Dekolonisierung mit Colistin/Rifaximin bei wiederholtem Nachweis von gramnegativen Enterobakterien mit Resistenz gegenüber Drittgenerationscephalosporinen („3GREB“)

A.3.1

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

randomized controlled trial of intestinal decolonization with colistin plus rifaximin.

Infektionsprävention durch intestinale Dekolonisierung mit Colistin/Rifaximin

A.3.2

Name or abbreviated title of the trial where available

Eradicate

A.4.1

Sponsor's protocol code number

P000176

A.5.4

Other Identifiers

Name:

Eradicate

Number:

N/A

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	Medical Center - University of Freiburg
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	BMBF
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	Clinical Trials University Medical Center Freiburg
B.5.2	Functional name of contact point	Clinical Trial Information
B.5.3	Address:
B.5.3.1	Street Address	Elsässer Str. 2
B.5.3.2	Town/ city	Freiburg
B.5.3.3	Post code	79110
B.5.3.4	Country	Germany
B.5.4	Telephone number	49761270-73800
B.5.5	Fax number	49761270-74250
B.5.6	E-mail	andrea.kunzmann@uniklinik-freiburg.de

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	Diarönt
D.2.1.1.2	Name of the Marketing Authorisation holder	CNP Pharma
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Colistin
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral 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)	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	Xifaxan
D.2.1.1.2	Name of the Marketing Authorisation holder	Norgine B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Xifaxan
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral 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)	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

Intestinal carriage of 3GCREB responsible for relapsing infection

Besiedlung von 3GCRE positiven Bakterien im Darm

E.1.1.1

Medical condition in easily understood language

Intestinal carriage of 3GCREB responsible for relapsing infection

Besiedlung von 3GCRE positiven Bakterien im Darm

E.1.1.2

Therapeutic area

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

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 assess whether decolonization treatment with oral non-absorbable drugs is superior to watch & wait in eradicating 3GCREB from the intestinal tract and prevent infection

Dekolonisierung von 3GCREB definiert durch den Nachweis von 3GCREB-negativen rektalen Abstrichen am Ende sowie 1-2 Wochen nach Ende der Behandlung im Vergleich zum Zuwarten („watch and wait“)

E.2.2

Secondary objectives of the trial

- early (rapid) 3GCREB decolonization (days 8-12 after treatment initiation=visit 2)
- late (sustained) 3GCREB decolonization (week 9 after end of treatment visit =visit 5)
- any infection which requires antibiotic therapy
- infection originating from gastrointestinal tract microflora (including urinary tract infection) which requires antibiotic therapy
- intestinal carriage of colistin- and rifaximin-resistant 3GCREB

- Frühe (schnelle) 3GCREB-Dekolonisierung (Tag 8-12 nach Behandlungsbeginn = Besuch 2)
- Nachhaltige 3GCREB-Dekolonisierung (Woche 9 nach Behandlungsende =Besuch 5)
- Infektionen (auch ohne Erregersicherung), die mit einem Antibiotikum behandelt werden mussten
- Infektionen mit Nachweis von Erregern aus der Magen-Darm-Mikroflora (einschließlich Harnwegsinfektionen), die mit einem Antibiotikum behandelt werden mussten
- Nachweis von 3GCREB mit Resistenz gegenüber Colistin und/oder Rifaximin während oder nach Behandlungsende

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written informed consent obtained according to international guidelines and local laws
2. Male or female patients aged 18 or older
3. Patients with at least two episodes of infection
- during the last 12 months,
- each time requiring specific antibiotic therapy and
- due to the same species of 3GCREB (ESBL and/or AmpC enterobacteria) but not necessarily with identical susceptibility test results.
A second infection WITHOUT microbiological documentation can be accepted if
- it can be considered as relapsing infection with the same clinical focus based on clinical judgement
- and there has been no other relevant pathogen for this episode
- and the episode required antibiotic treatment considered adequate and clinically effective
4. Patients with current colonization with the same species of 3GCREB as in (3)
- on two occasions within three weeks before day 0 of the study (i.e. day -21 to -1).
- proven by two cultures taken at least one week apart from each other, with the second culture taken within one week before day 0 of the study (i.e. day -7 to -1)
- with the first culture taken from any site (e.g. sputum, wound, urinary tract, rectal swab, stool) *
- and the second being a rectal swab, alternatively stool) **
- absence of antibiotic therapy, except
- if treatment stop is planned before day 0 of the trial
- short-term therapy for uncomplicated urinary tract infection (oral fosfomycin, norfloxacin, trimethoprim or trimethoprim-sulfamethoxazole for 3 days or less, or nitrofurantoin for no more than 5 days)
5. Known status concerning urinary tract colonisation before day 0 of the study. Result of urine culture which was routinely performed during medical care of a patient will be accepted.
6. Ability to understand the nature of the trial and the trial related procedures and to comply with them.

* Result of culture which was routinely performed during medical care of a patient will be accepted
** To obtain at least one baseline culture sample for analysis in the Microbiology Reference Center (see section
7.6.11), results of cultures routinely performed cannot be accepted

1. Vorliegen einer schriftlichen Patienten-Einwilligungserklärung entsprechend den internationalen Richtlinien und den entsprechenden deutschen Rechtsvorschriften
2. Männer und Frauen, die 18 Jahre und alter sind
3. Patienten mit mindestens zwei 3GCREB-Infektionsepisoden
- während der letzten 12 Monate
- mit Notwendigkeit einer Antibiotikabehandlung
- ausgelöst durch den gleichen 3GCREB-Stamm (aber nicht zwingend mit identischem Antibiogramm)
Mindestens zwei Infektionen mit dem gleichen 3GCREB*, die einer Antibiotika-Therapie bedurften. Eine zweite Infektion kann dann OHNE mikrobiologische Sicherung akzeptiert werden, wenn
- es sich nach klinischer Einschätzung um ein Rezidiv mit gleichem Fokus gehandelt hat
- und es dazu keine gesicherte Alternativdiagnose gab
- und Antibiotika verwendet wurden, die nach klinischer Erfahrung in diesem Fall als wirksam betrachtet werden können.
* 3GCREB = Drittgenerations-Cephalosporin-resistente Enterobakterien (ESBL- und oder AmpC). „Gleicher 3GCREB“ bedeutet gleiche Spezies, aber nicht notwendigerweise identisches Resistogramm bzgl. anderer Antibiotika.
4. Patienten mit aktueller intestinaler Kolonisierung mit demselben 3GCREB-Stamm wie in (3)
- Zweimaliger Nachweis innerhalb der letzten 3 Wochen vor Tag 0 der Studie (z.B. Tag -21 bis-1) mit mindestens 1 Woche Abstand zwischen den Probennahmen
- Der erste Nachweis aus Sputum, Wunde, Harntrakt, Rektalabstrich oder Stuhlprobe *
- Jüngster Nachweis nicht älter als 7 Tage (d.h. Probenentnahme Tag -7 bis -1) und aus Rektalabstrich oder Stuhlprobe **
- Keine Antibiotikabehandlung, außer:
- wenn Behandlungsende vor Tag 0 der Studie geplant ist
- Kurzzeittherapie bei unkomplizierter Harnwegsinfektion (mit oralem Fosfomycin, Norfloxacin, Trimethoprim oder Trimethoprim-Sulfamethoxazol für 3 Tage oder weniger oder Nitrofurantoin nicht länger als 5 Tage)
5. Zusätzliches Einschlusskriterium für Patienten mit rezidivierenden Harnwegsinfektionen: Der Befund einer Urinkultur, abgenommen innerhalb 3 Wochen vor Tag 0, liegt vor *.
6. Fähigkeit, die Inhalte der Studie sowie die studienspezifischen Abläufe zu verstehen und einzuhalten

* Ergebnis, einer Kultur die routinemäßig im Rahmen einer Untersuchung des Patienten genommen wurde, wird akzeptiert
** Ergebnisse von Kulturen, die im Rahmen einer Routineuntersuchung genommen wurden, können nicht akzeptiert werden, da mindestens eine Ausgangskultur für die Analyse im mikrobiologischen Referenzzentrum stattfinden muss

E.4

Principal exclusion criteria

1. Patients with rapidly fatal underlying disease (i.e. McCabe category 3)
2. Patients with severe diarrhea (defined as >5 bowel movements per day with loose stools) in the last three days
3. Patients with severe nausea/vomiting
4. Patients with inability to swallow
5. Patients who received recent (last 3 weeks) treatment with oral colistin and/or rifaximin
6. Patients with expected low compliance with drug regimen
7. Simultaneous participation in other interventional trials which could interfere with this trial and/or participation before the end of a required restriction period;
8. Patients with contraindications to the study drugs such as known intolerance of the study drugs (including other rifamycin derivatives like rifampin/rifampicin, rifabutin and rifapentine)
9. Co-medication with ibrutinib (recently approved tyrosine kinase inhibitor for treatment of patients with B cell lymphomas)
10. Known or persistent abuse of medication, drugs or alcohol
11. Persons who are in a relationship of dependence/employment with the sponsor or the investigator.

Specific exclusion criteria for female patients:
1. Current or planned pregnancy, nursing period;
2. Failure to use one of the following safe methods of contraception: female condoms, diaphragm or coil, each used in combination with spermicides; intra-uterine device; hormonal contraception in combination with a mechanical method of contraception

1. Grunderkrankung mit raschem tödlichem Verlauf (z.B. McCabe-Klassifizierung 3)
2. Starke Diarrhoe innerhalb der 3 letzten Tage (definiert als >5 Stuhlgänge/Tag mit flüssigem Stuhl
3. Patienten mit starker Übelkeit/Erbrechen
4. Patienten, die nicht schlucken können
5. Vorhergehende Behandlung (in den letzten 3 Wochen) mit einem der Studienmedikamente
6. Patienten, bei denen eine schlechte Therapieadhärenz anzunehmen ist
7. Gleichzeitige Teilnahme an einer anderen klinischen Studie welche diese Studie beeinträchtigen könnte und / oder Studienteilnahme innerhalb der letzten 30 Tage vor Einschluss in diese Studie
8. Patienten mit Kontraindikation gegenüber der Studienmedikation wie z.B. Intoleranz der Studienmedikation (einschließlich anderer Rifamycinderivate wie z.B. Rifampin/Rifampicin, Rifabutin und Rifapentin)
9. Begleitmedikation mit Ibrutinib (kürzlich genehmigter Tyrosinkinase-inhibitor zur Behandlung von Patienten mit B-Zell-Lymphom).
10. Missbrauch von Arzneimitteln, Drogen oder Alkohol
11. Personen die in einer Form der Abhängigkeit zum Sponsor oder Prüfer stehen

Besondere Ausschlusskriterien für weibliche Patienten:
1. Bestehende oder geplante Schwangerschaft und/oder stillende Frauen
2. Weigerung, Mittel zur Empfängnisverhütung während der Studie anzuwenden

E.5 End points

E.5.1

Primary end point(s)

3GCREB eradication defined as: no evidence for colonization with 3GCREB by preferably rectal swab, alternatively stool cultures performed at end of treatment visit (=visit 3) and at 1-2 weeks after end of treatment visit (=visit 4). The second sampling is needed to ascertain eradication rather than suppression.

Dekolonisierung von 3GCREB, definiert bezüglich des 3GCREB-Nachweises negative Rektalabstriche und/oder Stuhlproben
am Ende der Bahandlung (= Besuch 3) und 1-2 Wochen nach Behandlungsende (= Besuch 4).

E.5.1.1

Timepoint(s) of evaluation of this end point

evaluation at visit 3 (3 weeks) and at visit 4 (5 weeks)

E.5.2

Secondary end point(s)

- no evidence for colonization with 3GCREB by preferably rectal swab, alternatively stool cultures performed at days 8-12 after treatment initiation (=visit 2)
- no evidence for colonization with 3GCREB by preferably rectal swab, alternatively stool cultures performed 9 weeks after EOT visit (=visit 5)
- time to first infection and number of infections during and until 9 weeks after EOT visit (=visit 5) which requires antibiotic therapy
- time to first and number of infections originating from gastrointestinal tract microflora (including urinary tract
infection) during and until 9 weeks after EOT visit (=visit 5) which require antibiotic therapy

E.5.2.1

Timepoint(s) of evaluation of this end point

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

Yes

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

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

beobachten und abwarten

watsch and wait

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

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

LVLS

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:

154

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

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

174

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)

After end of the trial, patient's treatment will be performed according to standards of care

Nach Beendigung der Studie erfolgt die Weiterbehandlung der Patienten nach klinischen Standards

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

2015-03-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-04-08

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2016-12-02

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