Clinical Trials Register

Summary
EudraCT Number:	2014-003727-22
Sponsor's Protocol Code Number:	CER13266
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2014-11-27
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

2014-003727-22

A.3

Full title of the trial

A randomized controlled multicenter trial of a five day course of oral colistin and neomycin followed by restoration of the gut microbiota using fecal transplantation to eradicate intestinal carriage of extended spectrum beta-lactamase or carbapenemase-producing Enterobacteriaceae in high-risk patients

A.3.1

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

Eradication of antibiotic-resistant bacteria through antibiotics and fecal
bacteriotherapy.

A.3.2

Name or abbreviated title of the trial where available

R-GNOSIS WP3

A.4.1

Sponsor's protocol code number

CER13266

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02472600

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	Geneva University Hospitals
B.1.3.4	Country	Switzerland
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	European Commission
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Geneva University Hospitals
B.5.2	Functional name of contact point	Infection Control Programme
B.5.3	Address:
B.5.3.1	Street Address	Rue Gabrielle-Perret-Gentil 4
B.5.3.2	Town/ city	Geneva
B.5.3.3	Post code	1211
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	0041223729828
B.5.5	Fax number	0041223723987
B.5.6	E-mail	stephan.harbarth@hcuge.ch

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® mono
D.2.1.1.2	Name of the Marketing Authorisation holder	CNP Pharma GmbH
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.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 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	IU international unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2000000
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	Neomycin Sulfate Tablets, USP
D.2.1.1.2	Name of the Marketing Authorisation holder	X-Gen Pharmaceuticals inc.
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Tablet
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	NEOMYCIN SULFATE
D.3.9.3	Other descriptive name	NEOMYCIN SULFATE
D.3.9.4	EV Substance Code	SUB03409MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
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: 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	Omeprazol-Actavis 20 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Actavis Group PTC ehf.
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.3.4	Pharmaceutical form	Gastro-resistant capsule, hard
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	OMEPRAZOLE
D.3.9.3	Other descriptive name	OMEPRAZOLE
D.3.9.4	EV Substance Code	SUB09439MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
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: 4
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	Fecal microbiota transplantion preparation
D.3.4	Pharmaceutical form	Gastroenteral suspension
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Nasogastric use (Noncurrent) Gastroenteral use
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	Yes
D.3.11.13.1	Other medicinal product type	Fecal preparation

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 colonization with extended-spectrum beta-lactamse or carbapenemase producing enterobacteriaceae

E.1.1.1

Medical condition in easily understood language

Gut carriage with antibiotic resistant bacteria

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	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10071097
E.1.2	Term	Beta-lactam antibiotic resistance
E.1.2	System Organ Class	100000004862

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10069718
E.1.2	Term	Bacterial colonization
E.1.2	System Organ Class	100000004862

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10028152
E.1.2	Term	Multi-antibiotic resistance
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

Assess the impact of a five day course of oral colistin and neomycin followed by fecal microbiota transplantation compared to no intervention on detectable intestinal carriage (by stool culture) of extended spectrum beta-lactamase producing
and / or carbapenemase producing Enterobacteriaceae 35-48 days after randomization

E.2.2

Secondary objectives of the trial

- Assess the impact of a five day course of oral colistin and
neomycin followed by FMT compared to no intervention
on the susceptibility to colistin of ESBL-E and CRE
- Assess the safety and tolerability of a five day course of oral colistin and neomycin followed by FMT for eradication of intestinal ESBL-E and CRE carriage
- Assess the impact of a five day course of oral colistin and neomycin followed by FMT compared to no intervention on the intestinal microbiome and resistome over time
- Assess the impact of a five day course of oral colistin and neomycin followed by FMT compared to no intervention on the incidence of clinical infections with ESBL-E and
CRE over the entire study period
- Assess the impact of a five day course of oral colistin and
neomycin followed by FMT compared to no intervention
on systemic antibiotic use between both study groups
- Assess the stability of the microbiome of donor stools after
3, 6, 12 , and 24 months of frozen storage

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Adult patients (>= 18 years at date of inclusion)
- Documented intestinal carriage of ESBL-E and / or CRE by stool culture at baseline (visit 0)
- IF COLONIZED WITH ESBL-E ONLY (WITHOUT CRE): At least one episode of symptomatic infection
with ESBL-E requiring systemic antibiotic therapy within the last 180 days before date of inclusion
(based on the last day of antibiotic therapy for that infection)

E.4

Principal exclusion criteria

- Pregnancy or planned pregnancy
- Breastfeeding
- Difficult / impossible follow-up
- Allergy or other contraindication to one of the study drugs
- Anatomic contraindication to the placement of a nasogastric tube
- Recurrent aspirations
- Resistance to colistin (defined as MIC> 2 mg/l) of any of the ESBL-E or CRE strains isolated at baseline
- Estimated life expectancy < 6 months
- Treatment with any systemic antibiotic on the day of inclusion
- Severe immunodeficieny
○ Systemic chemotherapy ≤30 days from baseline or planned chemotherapy within the next 6 months
○ Human Immunodeficiency Virus (HIV) with CD4 count < 250/mcl
○ Prolonged use of steroids (prednisone equivalent ≥ 60 mg per day for >= 30 days) or other immunosuppressive medications
○ neutropenia with absolute neutrophil count <1000/μL,
○ Solid organ transplant recipient
○ Hematopoeitic stem cell transplant recepients
○ Other causes of severe immunodeficiency
- Hospitalization in an Intensive Care Unit
- Estimated glomerular filtration rate (CKD-EPI) < 15 ml/min/1.73m2
- Severe food allergy (anaphylaxis, urticaria)

E.5 End points

E.5.1

Primary end point(s)

Intestinal carriage of ESBL-E / CRE (absence / presence by stool culture of any ESBL-E and / or CRE with enrichment independent of type of carriage at baseline) 35 to 48 days after randomization

E.5.1.1

Timepoint(s) of evaluation of this end point

35 to 48 days after randomization

E.5.2

Secondary end point(s)

Safety and tolerability
• Occurrence of any adverse drug reaction
• Occurrence of any adverse event
• Occurrence of any serious adverse event
• Occurrence of gastrointestinal adverse events

Microbiome
• Change in intestinal microbiome and resistome in recipients over time
• Assess the stability of the microbiome of donor stools after 3, 6, 12 , and 24 months of frozen storage

Antibiotic resistance
• Isolation of any not intrinsically colistin resistant strain of Enterobacteriaceae during follow-up (MIC> 2mg/l)
• Change in colistin MIC between baseline and final follow-up

Infections
• Occurrence of any clinical infections with ESBL-E and CRE over the entire study period
• ESBL-E and CRE infections per 100 patient months at risk (first infection with either)

Antibiotic use
• Use of any systemic antibiotics during the study period
• Use of any antibiotics active against any of the colonizing ESBL-E / CRE strains
• Use of any antibiotics active against at least one of the colonizing ESBL-E / CRE strains

E.5.2.1

Timepoint(s) of evaluation of this end point

8 -14 days, 15 -28 days, 35 - 48 days, 5-7and 24 months after randomization

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

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

Yes

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

no specific treatment (current standard of care)

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

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

Israel

Switzerland

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

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

E.8.9.2

In all countries concerned by the trial years

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

Yes

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

104

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
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Assistance Publique – Hôpitaux de Paris
G.4.3.4	Network Country	France
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	Universitair Medisch Centrum Utrecht
G.4.3.4	Network Country	Netherlands
G.4 Investigator Network to be involved in the Trial: 3
G.4.1	Name of Organisation	Tel Aviv Sourasky Medical Center
G.4.3.4	Network Country	Israel
G.4 Investigator Network to be involved in the Trial: 4
G.4.1	Name of Organisation	Hôpitaux Universitaires de Genève
G.4.3.4	Network Country	Switzerland

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-11-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-05-26

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

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