Clinical Trials Register

Summary
EudraCT Number:	2016-002119-16
Sponsor's Protocol Code Number:	NORM2016-IQ
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-07-26
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

Poland - Office for Medicinal Products

A.2

EudraCT number

2016-002119-16

A.3

Full title of the trial

Multi-center phase 3 clinical study of fever reduction effectiveness in children age 24-72 months using combined therapy (ibuprofen plus paracetamol) compared to monotherapy with paracetamol and/or ibuprofen

Wieloośrodkowe badanie kliniczne III fazy dotyczące skuteczności obniżenia gorączki u dzieci w wieku powyżej 24 miesiąca do ukończenia 72 miesiąca życia z zastosowaniem terapii złożonej (ibuprofen plus paracetamol) w porównaniu do monoterapii paracetamolem lub ibuprofenem

A.3.1

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

Multi-center clinical study of fever reduction effectiveness in children age 2-6 years using ibuprofen with paracetamol compared to paracetamol and/or ibuprofen alone

Wieloośrodkowe badanie kliniczne dotyczące skuteczności obniżenia gorączki u dzieci w wieku 2-6 lat z zastosowaniem ibuprofenu z paracetamolem w porównaniu do zastosowania samego paracetamolu lub ibuprofenu

A.3.2

Name or abbreviated title of the trial where available

NORMOTHERMIA

NORMOTERMIA

A.4.1

Sponsor's protocol code number

NORM2016-IQ

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	Aflofarm Farmacja Polska Sp. z o.o.
B.1.3.4	Country	Poland
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	Aflofarm Farmacja Polska Sp. z o.o.
B.4.2	Country	Poland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Aflofarm Farmacja Polska Sp. z o.o.
B.5.2	Functional name of contact point	Clinical Trial Information
B.5.3	Address:
B.5.3.1	Street Address	ul. Partyzancka 133/151
B.5.3.2	Town/ city	Pabianice
B.5.3.3	Post code	95-200
B.5.3.4	Country	Poland
B.5.4	Telephone number	4842225 31 05
B.5.5	Fax number	4842225 31 05
B.5.6	E-mail	aflofarm@aflofarm.pl

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	Kidofen Duo
D.2.1.1.2	Name of the Marketing Authorisation holder	Aflofarm Farmacja Polska Sp. z o.o.
D.2.1.2	Country which granted the Marketing Authorisation	Poland
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	Kidofen Duo
D.3.4	Pharmaceutical form	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.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	Kidofen
D.2.1.1.2	Name of the Marketing Authorisation holder	Aflofarm Farmacja Polska Sp. z o.o.
D.2.1.2	Country which granted the Marketing Authorisation	Poland
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	Kidofen
D.3.4	Pharmaceutical form	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.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	Paracetamol Aflofarm
D.2.1.1.2	Name of the Marketing Authorisation holder	Aflofarm Farmacja Polska Sp. z o.o.
D.2.1.2	Country which granted the Marketing Authorisation	Poland
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	Paracetamol Aflofarm
D.3.4	Pharmaceutical form	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

Fever due to viral infection

Gorączka spowodowana infekcją wirusową

E.1.1.1

Medical condition in easily understood language

Fever due to viral infection

Gorączka spowodowana infekcją wirusową

E.1.1.2

Therapeutic area

Diseases [C] - Symptoms and general pathology [C23]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10051998
E.1.2	Term	Febrile infection
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Efficacy assessment of combined therapy with Kidofen Duo (paracetamol plus ibuprofen) compared to monotherapy with Paracetamol Aflofarm and/or Kidofen (ibuprofen) based on average body temperature reduction

Ocena skuteczności terapii złożonej preparatem Kidofen Duo (paracetamol plus ibuprofen) w porównaniu do monoterapii preparatami Paracetamol Aflofarm lub Kidofen (ibuprofen) na podstawie średniego spadku temperature ciała

E.2.2

Secondary objectives of the trial

1. Assessment of average normothermia (<37,2°C) reached in combined therapy group (paracetamol plus ibuprofen) compared to monotherapy groups with ibuprofen and/or paracetamol
2. Assessment of average change in body temperature during treatment in combined therapy group (paracetamol plus ibuprofen) compared to monotherapy groups with ibuprofen and/or paracetamol

1. Ocena średniej częstości uzyskiwania normotermii (<37,2°C) w grupie terapii złożonej (paracetamol plus ibuprofen) w stosunku do grup monoterapii ibuprofenem lub paracetamolem
2. Ocena zmian średniej temperatury w czasie w grupie terrapin złożonej (paracetamol plus ibuprofen) w stosunku do grup monoterapii ibuprofenem lub paracetamolem

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Children age over 24 months to the end of 72 months
2) Fever defined as tympanic body temperature ≥ 38,3°C
3) Viral infection based on clinical assessment
4) C-reactive protein rapid test showing viral infection (<40 mg/l).

1) Dzieci w wieku powyżej 24 miesiąca do ukończenia 72 miesiąca życia;
2) Gorączka definiowana jako temperatura ciała ≥ 38,3°C mierzona w uchu;
3) Infekcja wirusowa na podstawie oceny klinicznej;
4) Wynik testu paskowego CRP wskazujący na infekcję wirusową (<40 mg/l).

E.4

Principal exclusion criteria

1) Hypersensitivity to ibuprofen, paracetamol, other NSAiDs or other constituents of tested products
2) History of hypersensitivity reactions (bronchospasm, angioedema, asthma, rhinitis, urticaria) following aspirin ingestion or other NSAiDs, history of aspirin-induced asthma in parents
3) Current or past ulceration, perforation or bleeding from gastrointestinal tract
4) Severe renal insufficiency
5) Severe hepatic insufficiency
6) Any coagulation disorders
7) Hereditary disorders of carbohydrate metabolism (fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency)
8) Naproxen or any other NSAiDs except ibuprofen use < 7 days before inclusion
9) Concomitant use of any physical methods or supplements affecting body temperature
10) Concomitant antimicrobials
11) Contraindications to oral route of medicine administration
12) Viral hepatitis

1) Nadwrażliwość na ibuprofen, paracetamol, inne niesteroidowe leki przeciwzapalne (NLPZ) lub którąkolwiek z substancji pomocniczych stosowanych preparatów;
2) Reakcje nadwrażliwości w wywiadzie (skurcz oskrzeli, obrzęk naczynioruchowy, astma, zapalenie błony śluzowej nosa, pokrzywka) po przyjęciu kwasu acetylosalicylowego lub innych NLPZ, astma aspirynowa w wywiadzie u rodziców;
3) Owrzodzenie, perforacja lub krwawienie z przewodu pokarmowego, czynne lub w wywiadzie;
4) Ciężka niewydolność nerek;
5) Ciężka niewydolność wątroby;
6) Zaburzenia krzepnięcia - jakiekolwiek;
7) Dziedziczne zaburzenia przemiany węglowodanów (nietolerancja fruktozy, zespół złego wchłaniania glukozy/galaktozy, niedobór sacharazy/izomaltazy);
8) Stosowanie naproksenu lub innych poza ibuprofenem NLPZ w ciągu tygodnia przed włączeniem do badania;
9) Równoległe stosowanie jakichkolwiek fizykalnych metod obniżających temperaturę ciała lub produktów spożywczych/suplementów mogących wpływać na temperaturę ciała;
10) Stosowanie antybiotyków i innych leków przeciwdrobnoustrojowych;
11) Przeciwwskazania do przyjmowania leków doustnie;
12) Wirusowe zapalenie wątroby.

E.5 End points

E.5.1

Primary end point(s)

Average body temperature differences in combined therapy group with Kidofen Duo (paracetamol+ibuprofen) compared to monotherapy groups with Paracetamol Aflofarm (paracetamol) and/or Kidofen (ibuprofen)

Różnice średniej temperatury w grupie terapii złożonej preparatem Kidofen Duo (paracetamol+ibuprofen) w porównaniu do monoterapii preparatami Paracetamol Aflofarm (paracetamol) lub Kidofen (ibuprofen)

E.5.1.1

Timepoint(s) of evaluation of this end point

30 min, 1 h, 1,5 h, 2 h, 3 h, and 4 h, 5 h, 6 h and/or before next dose of Paracetamol Aflofarm, 30 min, 1 h, 1,5 h, 2 h, 3 h ,4 h, 5 h, and 6 h, 7 h, 8 h and/or before next dose of Kidofen and Kidofen Duo

30 min, 1 h, 1,5 h, 2 h, 3 h, oraz 4 h, 5 h, 6 h lub przed podaniem kolejnej dawki Paracetamol Aflofarm, 30 min, 1 h, 1,5 h, 2 h, 3 h ,4 h, 5 h, oraz 6 h, 7 h, 8 h lub przed podaniem kolejnej dawki dla preparatów Kidofen i Kidofen Duo

E.5.2

Secondary end point(s)

1. Average normothermia (<37,2°C) reached in combined therapy group (paracetamol plus ibuprofen) compared to monotherapy groups with ibuprofen and/or paracetamol
2. Average change in body temperature during treatment in combined therapy group (paracetamol plus ibuprofen) compared to monotherapy groups with ibuprofen and/or paracetamol

1. Średnia częstość uzyskiwania normotermii (<37,2°C) w grupie terapii złożonej preparatem Kidofen Duo w stosunku do monoterapii preparatami Paracetamol Aflofarm lub Kidofen
2. Zmiany średniej temperatury w czasie w grupie terapii złożonej preparatem Kidofen Duo w stosunku do monoterapii preparatami Paracetamol Aflofarm lub Kidofen

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

Yes

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)

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

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

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

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

Ostatnia wizyta ostatniego włączonego pacjenta

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:

300

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)

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

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

Under age of consent to treatment

Niemożność udzielenia zgody ze względu na wiek

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

300

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

Brak

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

2016-11-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-08-18

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-10-31

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