Clinical Trials Register

Summary
EudraCT Number:	2018-000754-22
Sponsor's Protocol Code Number:	IBP-9414-020
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-04-09
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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2018-000754-22

A.3

Full title of the trial

A randomized, double blind, parallel-group, placebo controlled study to evaluate the efficacy and safety of IBP-9414 in premature infants 500-1500g birth weight in the prevention of necrotizing enterocolitis – The Connection study

Randomizált, kettős vak, párhuzamos csoportos, placebokontrollos vizsgálat az IBP-9414 hatásosságának és biztonságosságának értékelésére a nekrotizáló enterokolitisz megelőzésében 500–1500 g születési súlyú koraszülött csecsemőknél – „Connection” vizsgálat

A.3.1

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

Study on the prevention of necrotizing enterocolitis (a severe inflammation and death go intestines) in premature infants

A.3.2

Name or abbreviated title of the trial where available

The Connection study

A.4.1

Sponsor's protocol code number

IBP-9414-020

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/330/2017

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Infant Bacterial Therapeutics AB (IBT)
B.1.3.4	Country	Sweden
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Infant Bacterial Therapeutics AB (IBT)
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Infant Bacterial Therapeutics AB (IBT)
B.5.2	Functional name of contact point	Clinical Developement
B.5.3	Address:
B.5.3.1	Street Address	Bryggargatan 10
B.5.3.2	Town/ city	Stockholm
B.5.3.3	Post code	111 21
B.5.3.4	Country	Sweden
B.5.4	Telephone number	+46 72 448 7358
B.5.6	E-mail	clinical@ibtherapeutics.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	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/15/1436
D.3 Description of the IMP
D.3.1	Product name	IBP-9414
D.3.2	Product code	IBP-9414
D.3.4	Pharmaceutical form	Powder for oral suspension
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Nasogastric use (Noncurrent) Other use (Noncurrent) Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	not available
D.3.9.1	CAS number	not availabl
D.3.9.2	Current sponsor code	IBP-9414
D.3.9.3	Other descriptive name	LACTOBACILLUS REUTERI
D.3.9.4	EV Substance Code	SUB32256
D.3.10	Strength
D.3.10.1	Concentration unit	CFU/ml colony forming unit(s)/millilitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	1400000000 to 70000000000
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	Lactobacillus reuteri (DSM 17938) as a live bacterial therapy

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	Solvent for...
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

Necrotizing Enterocolitis (NEC)

E.1.1.1

Medical condition in easily understood language

Necrotizing Enterocolitis (NEC)

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10052818
E.1.2	Term	Necrotizing enterocolitis neonatal
E.1.2	System Organ Class	100000004856

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the efficacy of IBP-9414 vs. placebo on the prevention of necrotizing enterocolitis and on sustained feeding tolerance in very low birth weight premature infants, as well as the safety of IBP-9414 vs. placebo. The study is powered on the necrotizing enterocolitis endpoint.

E.2.2

Secondary objectives of the trial

To evaluate the effect of IBP-9414 on different severities of NEC, all cause mortality, duration of hospitalization, growth and feeding tolerance in very low birth weight premature infants.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Gestational age at birth of 23 weeks + 0 days -32 weeks + 0 days
2. Birth weight 500-1500g. (First infants with birth weights 750-1000g will be included. After a DMC recommendation, infants with birth weights 500-1000g will then be included. After 1400 subjects in the study, infants with birth weights 500-1500g will then be included.)
3. ≤ 48 hours of age
4. Written informed consent from the subject´s legally authorized representative (LAR)

E.4

Principal exclusion criteria

1. Participation in any other interventional clinical trial
2. Infants in extremis to whom no further intensive care is offered by attending neonatologist (e.g., infant being provided only hospice/comfort care)
3. Infants with, or at a high probability for, early onset sepsis (positive blood cultures or with clinical/histological chorioamnionitis (according to Higgins et al, 2016), and with the expectation of empirical antimicrobial therapy for > five days)
4. Infants with recognized chromosomal anomalies
5. Congenital or acquired gastrointestinal disease
6. Earlier or planned administration of formulas, foods or supplements that contain added live bacteria, including all infant formulas or food supplement products with added so-called ”probiotic” or added live bacterial content during the study
7. Infants with known positive maternal HIV status

E.5 End points

E.5.1

Primary end point(s)

There are 2 primary endpoints:
Primary Endpoint 1: Confirmed NEC
Necrotizing enterocolitis (NEC) from the first dose until the infant reaches 34 weeks + 6 days post-menstrual age (PMA), where a NEC event is diagnosed by one of the following:
A. At least one clinical sign of NEC as reported by the investigator AND abdominal X-ray evidence of intestinal pneumatosis and/or portal venous gas confirmed by independent adjudication.
OR
B. Surgery (or autopsy) with confirmation of necrotizing enterocolitis.

Primary Endpoint 2:
Time to sustained feeding tolerance measured as the number of days from the first dose to the first day (Day F) when:
1) criteria A and B are fulfilled:
A) enteral feeding at ≥120 ml/kg/day every day until the subject reaches 34w+6d post menstrual age or is discharged if earlier.
B) no use of parenteral nutrition (defined as intravenous use of any macronutrients (amino and/or lipids)) until the subject reaches 34w+6d post menstrual age or is discharged if earlier.
and 2) where there is weight gain between Day F and the day the subject reaches 34w+6d post menstrual age or is discharged if earlier.

E.5.1.1

Timepoint(s) of evaluation of this end point

daily

E.5.2

Secondary end point(s)

1. At least one clinical sign of NEC as reported by the investigator AND abdominal X-ray evidence of intestinal pneumatosis and/or portal venous gas confirmed by independent adjudication.
2. Surgery (or autopsy) with confirmation of necrotizing enterocolitis.
3. Death all causes
4. Number of days of hospitalization measured in the period from first dose to 34 weeks + 6 days PMA.
5. Weight gain in g/kg during weeks 3 and 4 of age.
6. Number of subjects growing at ≥100 g/kg/week measured during weeks 3 and 4 of age.
7. Days with clinical signs of feeding intolerance as reported in case record form by investigator measured from the first dose of study product to 34 weeks + 6 days post-menstrual age.

E.5.2.1

Timepoint(s) of evaluation of this end point

daily

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

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)

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

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

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

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

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

France

Hungary

Israel

Spain

United Kingdom

United States

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

Last visit of the last patient

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

Yes

F.1.1

Number of subjects for this age range:

2158

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

Yes

F.1.1.2.1

Number of subjects for this age range:

2158

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)

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

Yes

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

premature infants 500-1500g birth weight

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

200

F.4.2

For a multinational trial

F.4.2.1

In the EEA

1000

F.4.2.2

In the whole clinical trial

2158

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)

standard of care

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

2019-06-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-05-31

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

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