Clinical Trials Register

Summary
EudraCT Number:	2016-002927-27
Sponsor's Protocol Code Number:	OY20167
National Competent Authority:	Finland - Fimea
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2016-07-14
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

Finland - Fimea

A.2

EudraCT number

2016-002927-27

A.3

Full title of the trial

Effect of antimicrobial treament of acute otitis media on the intestinal micobiome in children: A randomized controlled trial

Korvatulehduksen antibioottihoidon vaikutus lapsen suoliston mikrobiomiin: Satunnaistettu, kontrolloitu kliininen koe

A.3.1

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

Effects of antibiotics used for ear infections on normal gut bacteria in children

Korvatulehduksen antibioottihoidon vaikutus suolen normaaleihin bakteereihin

A.3.2

Name or abbreviated title of the trial where available

AOMMi - trial (Acute Otitis Media and Microbiome)

AOMMi-tutkimus

A.4.1

Sponsor's protocol code number

OY20167

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 of Oulu, Department of Pediatrics, PEDEGO-Research unit
B.1.3.4	Country	Finland
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	Pediatric Reseach Foundation, Finland
B.4.2	Country	Finland
B.4.1	Name of organisation providing support	Snellman Foundation, Finland
B.4.2	Country	Finland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University of Oulu, Finland
B.5.2	Functional name of contact point	Oulu University Hospital
B.5.3	Address:
B.5.3.1	Street Address	Kajaanintie
B.5.3.2	Town/ city	Oulu
B.5.3.3	Post code	90029
B.5.3.4	Country	Finland
B.5.4	Telephone number	35883155185
B.5.5	Fax number	35883155559
B.5.6	E-mail	terhi.tapiainen@oulu.fi

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	Amorion comp
D.2.1.1.2	Name of the Marketing Authorisation holder	Orion Oyj
D.2.1.2	Country which granted the Marketing Authorisation	Finland
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	Amorion comp oral suspension 80/11.4 mg/ml
D.3.2	Product code	24781
D.3.4	Pharmaceutical form	Oral suspension
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.3	Other descriptive name	AMOXICILLIN TRIHYDRATE
D.3.9.4	EV Substance Code	SUB00504MIG
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CLAVULANIC ACID
D.3.9.1	CAS number	58001-44-8
D.3.9.4	EV Substance Code	SUB06642MIG
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)	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	Comparator
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	Amorion 100 mg/ml
D.2.1.1.2	Name of the Marketing Authorisation holder	Orion Oyj
D.2.1.2	Country which granted the Marketing Authorisation	Finland
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	Amorion
D.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.3	Other descriptive name	AMOXICILLIN TRIHYDRATE
D.3.9.4	EV Substance Code	SUB00504MIG
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	Comparator
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	Zithromax
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Oyj
D.2.1.2	Country which granted the Marketing Authorisation	Finland
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	Zithromax 40 mg/ml oral mixture
D.3.4	Pharmaceutical form	Oral suspension
D.3.4.1	Specific paediatric formulation	Yes
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	AZITHROMYCIN DIHYDRATE
D.3.9.4	EV Substance Code	SUB16399MIG
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Tutkimuspopulaatio koostuu 6 kk-7 vuoden ikäisistä lapsista, joilla todetaan äkillinen välikorvatulehdus käyttäen otoskopiaa ja tympanometriaa. Tutkimuslääkäreinä toimivat avohoidossa toimivat lastenlääkärit ja korvalääkärit. Korvatulehduksen määritelmä on :
• Äkilliset hengitystie- ja/tai korvaoireet JA
• Tärykalvon inflammaation merkit JA
• Välikorvaerite otoskopialla todettuna
Päävastemuuttuja on ulosteen mikrobiomin muutos antibioottihoidon aikana.

E.1.1.1

Medical condition in easily understood language

Alle kouluikäisen lapsen korvatulehduksen hoito

E.1.1.2

Therapeutic area

Body processes [G] - Microbiological Phenomena [G06]

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

Tutkimuksen tavoitteena on selvittää lasten korvatulehdusten hoitoon käytettävien antibioottien vaikutus suoliston mikrobiomin välittömiin muutoksiin. Tutkimuksemme hypoteesi on, että laajakirjoisemmat antibiootit muokkaavat suolistomikrobiotaa voimakkaammin kuin kapeakirjoiset antibiootit ja jo yksi antibioottikuuri voi muokata suoliston mikrobiomia merkittävästi.

E.2.2

Secondary objectives of the trial

Ulostenäytteistä tutkitaan myös metagenomiikan keinoin antibioottiresistenssigeeninen yleisyys ja ilmeneminen ryhmissä ja lisäksi kliinisen mikrobiologian laboratorion keinoin C.difficilen esiintyminen eri ryhmissä.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Tutkimuspopulaatio koostuu 6 kk-7 vuoden ikäisistä lapsista, joilla todetaan äkillinen välikorvatulehdus käyttäen otoskopiaa ja tympanometriaa. Tutkimuslääkäreinä toimivat avohoidossa toimivat lastenlääkärit ja korvalääkärit. Korvatulehduksen määritelmä on [11]:
• Äkilliset hengitystie- ja/tai korvaoireet JA
• Tärykalvon inflammaation merkit JA
• Välikorvaerite otoskopialla todettuna

E.4

Principal exclusion criteria

Poissulkukriteerit
Epäilty tai todettu välikorvatulehduksen komplikaatio kuten mastoidiitti tai tärykalvon perforaatio
Vakava korvatulehdus (kipu ja kuume yli 39 astetta) kaiken ikäisillä lapsilla
Alle 2 vuotiaan (6-23 kk) molemminpuolinen korvatulehdus
Todettu immuniteettiin vaikuttava sairaus kuten primaari immuunivajavuus tai Downin oireyhtymä
Yleistilan alentuminen tai epäily vakavasta bakteeri-infektiosta
Yhdistetty amoksisilliini ja makrolidi-allergia
Vuotavat tympanostomiaputkikorvat
Jo parhaillaan menossa oleva antibioottihoito tai lapsi on saanut antibioottia edeltävän 7 vrk aikana
Jos lapsella on amoksisilliini-allergia, potilas voi osallistua tutkimuksen ei-satunnaistettuun osioon, jossa lapset saavat makrolidia otiitin hoitoon.

E.5 End points

E.5.1

Primary end point(s)

Analysoimme ja vertaamme alla lueteltuja muuttujia satunnaistettujen ryhmien välillä käyttäen vertailussa suoraan suhteellisten osuuksia (bakteerien ja pääjaksojen suhteelliset osuudet) tai absoluuttisia arvoja (indeksit ja OTU:jen lukumäärä). Lisäksi vertaamme samoja muuttujia käyttämällä yksilön sisäistä muutosta 0-näytteen ja 10 vrk välillä vertailuun ryhmien välillä. Analysoimme näin seuraavat muuttujat:
1. Ryhmien kokonaismikrobiomin vertailu käyttäen principal coordinate analysis (PCA) –tarkastelua
2. Diversiteettiä kuvaavat muuttujat eri ryhmien välillä
a. Bakteerilajien kokonaismäärä arvioituna 16SrRNA-lajien OTU-lukumäärällä (operational taxonomic units)
b. Shannonin ja Chaon biodiversiteetti-indeksit
3. Tärkeimpien pääjaksojen suhteelliset osuudet eri ryhmien välillä:
a. Firmikuuttien suhteellinen osuus (käytetty otoskoon laskuun)
b. Aktinobakteerien suhteellinen osuus (käytetty otoskoon arviointiin)
c. Bacteroidetes-pääjakson suhteellinen osuus
d. Proteobacteria-pääjakson suhteellinen osuus
e. Verrucomicrobia-pääjakson suhteellinen osuus
4. Aiempien tutkimusten mukaan terveydelle mahdollisesti hyödyllisten bakteerien suhteelliset osuudet eri ryhmissä:
a. Laktobasillien suhteelliset osuudet
b. Bifidobakteerien suhteelliset osuudet
c. Faecalibacterium prausnitziin suhteelliset osuudet
d. Clostridium-bakteerien suhteelliset osuudet

E.5.1.1

Timepoint(s) of evaluation of this end point

Ulostenäytteet 0 vrk ja 10 vrk. Kliininen arvio 2-3 vrk, 10 vrk ja 30 vrk. Kliininen arvio on potilaan tilan seuraamiseksi eikä ole varsinainen vastemuuttuja.

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

Ulostenäytteet 0 vrk ja 10 vrk kohdissa.

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

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

Yes

E.6.13.1

Other scope of the trial description

Effects on human microbiome

Antibioottihoidon vaikutus ulosteen mikrobiomiin.

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

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

Ei välitöntä antibioottihoitoa vaan tarkka seuranta

Close follow up without antimicrobials

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.8.4.1

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

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

Tutkimus päättyy kun satunnaistettuun osioon on saatu mukaan yhteensä 150 lasta ja viimeisen lapsen seuranta on kestänyt 1 kk.

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

Yes

F.1.1

Number of subjects for this age range:

150

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

150

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

150

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

Infants and pre-school children whose parents give informed consent

6 kk -7 v lapset, joiden vanhemmat antavat suostumuksen

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

150

F.4.2.2

In the whole clinical trial

200

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

2016-08-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-08-15

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

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