Clinical Trials Register

Summary
EudraCT Number:	2017-000332-34
Sponsor's Protocol Code Number:	NL-07051985
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-06-27
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

2017-000332-34

A.3

Full title of the trial

Topical or oral antibiotics for children with acute otitis media presenting with ear discharge?

Lokaal (oordruppels) of oraal antibioticum voor kinderen met otitis media acuta en een loopoor?

A.3.1

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

Is treatment with eardrops as good as oral treatment for children with acute otitis media presenting with ear discharge?

Is behandeling met oordruppels net zo goed als een behandeling met een drankje voor een loopoor bij kinderen met een acute middenoorontsteking?

A.3.2

Name or abbreviated title of the trial where available

PLOTS

Pijnlijk LoopOor Therapie Studie

A.4.1

Sponsor's protocol code number

NL-07051985

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	Julius Center for Health Sciences and Primary Care, 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	University Medical Center Utrecht
B.4.2	Country	Netherlands
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	Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht
B.5.2	Functional name of contact point	study physician
B.5.3	Address:
B.5.3.1	Street Address	Universiteitsweg 100
B.5.3.2	Town/ city	Utrecht
B.5.3.3	Post code	3508 GA
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	031030088 75 69241
B.5.6	E-mail	s.hullegie@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	Yes
D.2.1.1.1	Trade name	BACICOLINE-B®
D.2.1.1.2	Name of the Marketing Authorisation holder	Daleco Pharma bv
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Auricular 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)	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	Amoxicillin
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Capsule
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)	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	Amoxicillin
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Concentrate for oral suspension
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)	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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Acute otitis media with ear discharge

Otitis media acuta met een loopoor

E.1.1.1

Medical condition in easily understood language

Acute middle ear infection with ear discharge

Acute middenoorontsteking met een loopoor

E.1.1.2

Therapeutic area

Diseases [C] - Ear, nose and throat diseases [C09]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10033080
E.1.2	Term	Otitis media acute NOS
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

Are antibiotic-corticosteroid eardrops non-inferior to oral antibiotics in children aged 6 months to 12 years visiting their GP with acute otitis media with discharge due to a spontaneous perforation of the eardrum (AOMd) and ear pain and/or fever, in terms of the proportion of children without ear pain and fever at day 3 (72 hours after randomisation)?

E.2.2

Secondary objectives of the trial

Secondary outcomes are ear pain intensity/severity; fever intensity/severity; ear discharge; time to resolution of total symptoms, persistent eardrum perforation; middle ear effusion; adverse events; disease-specific quality of life; antibiotic consumption; AOM recurrences; costs and cost-effectiveness; antimicrobial resistance.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

We will ask parents of a subset of 25 children (participant number 51-75) to swab the otorrhoea themselves in addition to the physician. In a further sample of 25 children (participant number 76-100), the otorrhoea will be swabbed twice by the study physician. One sample will be transported to the laboratory by the physician as described above and one sample will be transported by mail using a transportation kit.

Research objectives
1. What is the agreement between parental self-swabbing and staff-swabbing of otorrhoea in children, regarding the presence of bacteria in cultures?
2. What is the agreement between transport of (otorrhoea and nasopharynx) swabs to the lab by the physician and by mail, regarding the number of swabs able to be analysed and the presence of bacteria in cultures?

Outcome
For research question 1:
- the agreement in prevalence of bacteria in otorrhoeal cultures collected by parental self-swabbing and staff-swabbing.

For research question 2:
- the agreement in the number of otorrhoeal swabs that can be analysed;
- the agreement in the presence of bacteria in otorrhoeal cultures of swabs transported to the microbiology laboratory by the physician and by mail.

E.3

Principal inclusion criteria

Children aged 6 months to 12 years whose parents are consulting the GP with AOM and ear discharge in one or both ears (≤ 7 days duration) and either parent-reported ear pain in the previous 24 hours or fever (child’s body temperature of ≥ 38.0°C in the previous 24 hours as reported by parents or as measured by the GP during consultation) or both.

Kinderen worden geïncludeerd indien zij een leeftijd tussen 6 maanden en 12 jaar hebben en zich bij de huisarts presenteren met een otitis media acuta met een loopoor van een of beiden oren (duur ≤ 7 dagen) en daar ook pijn in de afgelopen 24 uur en/of koorts (temperatuur ≥ 38.0°C in de afgelopen 24 uur) bij hebben.

E.4

Principal exclusion criteria

Children will be excluded from participation if they
1. are systemically very unwell and requires immediate oral antibiotics or immediate hospitalization (e.g. child has signs and symptoms of serious illness and/or complications such as mastoiditis/meningitis);
2. are at high risk of serious complications including children with known immunodeficiency other than partial IgA or IgG2 deficiencies, craniofacial malformation such as cleft palate, children with Down syndrome, previous ear surgery other than grommet insertion;
3. have grommets in place;
4. have a pre-existing perforation of the eardrum;
5. had an prior AOM episode (with or without ear discharge) in previous 28 days;
6. used oral antibiotics or topical antibiotics in previous 2 weeks;
7. have a known allergy or sensitivity to oral amoxicillin or hydrocortisone-bacitracin-colistin;
8. have already participated in this trial.

Exclusiecriteria:
Kinderen:
1. die systemisch ziek zijn en waarbij directe antibiotische therapie of directe verwijzing naar een ziekenhuis noodzakelijk is (bij symptomen van ernstige ziekte en/of
complicaties als mastoïditis/meningitis);
2.die een hoog risico op ernstige complicaties hebben, zoals kinderen met een immuundeficiëntie anders dan een partiële IgA of IgG2 deficiëntie, een craniofaciale afwijking, het syndroom van Down, een ooroperatie in de voorgeschiedenis anders dan het plaatsen van buisjes;
3. die nu een buisje in het aangedane oor hebben;
4. die reeds bekend zijn met een gaatje in het trommelvlies;
5. die tijdens de afgelopen 28 dagen een acute middenoorontsteking (met of zonder loopoor) gehad hebben;
6. die tijdens de afgelopen 14 dagen een antibioticum gebruikt hebben;
7. die een allergie of overgevoeligheid voor Bacicoline-B of amoxicilline hebben;
8. die al eerder aan de PLOTS studie hebben deelgenomen.

E.5 End points

E.5.1

Primary end point(s)

The proportion of children without ear pain and fever at day 3.

Hoeveelheid kinderen zonder oorpijn en/of koorts op dag 3.

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 3

dag 3

E.5.2

Secondary end point(s)

Duur en ernst van OMA klachten (oorpijn en koorts); aantal dagen met loopoor; totale duur symptomen, trommelvliesperforatie; middenoor effusie; adverse events; ziekte specifieke kwaliteit van leven; antibiotica gebruik; OMA recidieven; kosteneffectiviteit; antimicrobiële resistentie.

E.5.2.1

Timepoint(s) of evaluation of this end point

3 days, 2 weeks, 3 months

dag 3, 2 weken, 3 maanden

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

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

Yes

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)

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

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)

Yes

E.8.2.2

Placebo

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

Yes

E.8.4

The trial involves multiple sites in the 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

Due to a slow accrual rate, the subsidising party (ZonMw) has send a latter dated 23 August 2022 in which they informed us to prematurely end the project. To meet the final report deadline set by ZonMw, we will prematurely stop patient inclusion by 1 March 2023. The end date will depend on the date of inclusion of last patient, but be at latest 1 June 2023 (last patient last visit).

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:

350

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:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

300

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

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

350

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

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-06-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-08-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-05-25

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