Clinical Trials Register

Summary
EudraCT Number:	2019-000647-27
Sponsor's Protocol Code Number:	Ibu19
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2020-10-07
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2019-000647-27

A.3

Full title of the trial

Evaluation of efficacy and bioavailability of a new pediatric formulation based on ibuprofen lysinate vs ibuprofen in the management of pain in children

Valutazione dell'efficacia e della biodisponibilità di una nuova formulazione pediatrica di ibuprofene lisinato vs ibuprofene nella gestione del dolore nel bambino

A.3.1

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

Evaluation of efficacy and bioavailability of ibuprofen lysinate

Valutazione dell'efficacia e della biodisponibilità dell'ibuprofene lisinato

A.3.2

Name or abbreviated title of the trial where available

Efficacy and bioavailability of ibuprofen lysinate

Efficacia e biodisponibilità dell'ibuprofene lisinato

A.4.1

Sponsor's protocol code number

Ibu19

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	Dicofarm S.p.A.
B.1.3.4	Country	Italy
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	Dicofarm S.p.A.
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Dicofarm S.p.A.
B.5.2	Functional name of contact point	Ufficio Ricerca & Sviluppo
B.5.3	Address:
B.5.3.1	Street Address	Via del Casale della Marcigliana, 29
B.5.3.2	Town/ city	Roma
B.5.3.3	Post code	00138
B.5.3.4	Country	Italy
B.5.4	Telephone number	068856131
B.5.5	Fax number	068889334
B.5.6	E-mail	regolatorio@dicofarm.it

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	Algidrin pediatrico
D.2.1.1.2	Name of the Marketing Authorisation holder	LABORATORIO DE APLICACIONES FARMACODINÁMICAS, S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	N/A
D.3.2	Product code	[N/A]
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	Ibuprofen lysine salt
D.3.9.1	CAS number	57469-76-8
D.3.9.2	Current sponsor code	N/A
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	FrobenKids febbre e dolore
D.2.1.1.2	Name of the Marketing Authorisation holder	Mylan Italia S.r.l
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	FrobenKids Febbre e Dolore
D.3.2	Product code	[NA]
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	IBUPROFENE
D.3.9.2	Current sponsor code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

Pain on an inflammatory basis (otitis and otomastoiditis, adenite, cellulite, arthritis) and post-operative pain

Dolore su base infiammatoria (otite e otomastoidite, adenite, cellulite, artrite) e post-operatorio

E.1.1.1

Medical condition in easily understood language

Pain on an inflammatory basis and post-operative pain

Dolore su base infiammatoria e post-operatorio

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	21.0
E.1.2	Level	PT
E.1.2	Classification code	10050533
E.1.2	Term	Pain assessment
E.1.2	System Organ Class	10022891 - Investigations

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	10063374
E.1.2	Term	Pain scale
E.1.2	System Organ Class	10022891 - Investigations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Compare the analgesic efficacy of ibuprofen lysinate compared to ibuprofen, by filling in the pain pain scale Faces pain scale e Faces pain scale – revised (FPS-R).

Confrontare l’efficacia analgesica di ibuprofene lisinato rispetto a ibuprofene, verificato attraverso la compilazione della scala di rilevazione del dolore Faces pain scale e Faces pain scale – revised (FPS-R).

E.2.2

Secondary objectives of the trial

Compare the bioavailability and the pharmacokinetic profile of ibuprofen lysinate compared to ibuprofen, through the evaluation of the main pharmacokinetic parameters (AUC, Tmax, Cmax)

Confrontare la biodisponibilità e il profilo farmacocinetico di ibuprofene lisinato rispetto a ibuprofene, attraverso la valutazione dei principali parametri farmacocinetici (AUC, Tmax, Cmax)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age between 4-12 years
• Post-operative pain and pain on an inflammatory basis: mild (FPS-R: 2) or mild-moderate (FPS-R: from 4 to 6)
• Understanding of the Italian language by parents or legal guardian
• Written informed consent, signed by the parents or legal guardian
• Consent of the child with age between 8-12 years

• Età compresa tra 4-12 anni
• Dolore post-operatorio o dolore di origine infiammatoria lieve (punteggio FPS-R:2) o lieve moderato (punteggio FPS-R: da 4 a 6)
• Comprensione della lingua italiana da parte dei genitori o del tutore legale
• Consenso informato scritto, firmato dai genitori o dal tutore legale
• Assenso del minore di età compresa tra 8 e 12 anni

E.4

Principal exclusion criteria

• Hypersensitivity to ibuprofen, to any other NSAID or to any of the excipients of the product: Purified water, Microcrystalline cellulose, Sodium carboxymethyl cellulose, Sorbitol (E-420), Maltitol (E-965), Beta-cyclodextrin, Sodium saccharin,
Sucralose (E-955), Aroma of wild berries, Allura Red AC dye (E-129), Methyl para-hydroxybenzoate (E-218), Ethyl para-hydroxybenzoate (E-214), Propyl para-hydroxybenzoate (E-216)
• Verified allergy to ibuprofen or or acetylsalicylic acid or other NSAIDs (attacks of asthma, acute rhinitis, urticaria or angioneurotic oedema)
• Gastrointestinal haemorrhage or perforation related to previous treatments with NSAIDs
• Peptic ulcer, active or recurrent gastrointestinal haemorrhage (two or more separate episodes)
• Crohn's disease or active ulcerative colitis
• Severe heart failure (NYHA class IV)
• Renal failure (GFR <35mL / min, calculated with Schwartz formula, according to pRIFLE-Pediatric Risk, Injury, Failure, Loss, End Stage Renal Disease)
• Acute liver failure (Pediatric Acute Liver Failure Registry, PALF):
- Acute onset liver failure (8 weeks from the onset of liver disease)
- Biochemical evidence of liver damage (elevation of ALT, AST and / or total and conjugated bilirubin)
- Incorrect coagulopathy from vitamin K (INR> = 1.5)
- Clinical evidence of encephalopathy
• Chronic hepatic failure (starting with Pugh-Child Score Class A)
• Haemorrhagic diathesis or coagulation disorders
• Pregnancy
• Cognitive delay
• Lack of understanding of the Italian language by parents or legal guardian

• Ipersensibilità a ibuprofene o altri FANS o agli eccipienti del prodotto: Acqua purificata - Cellulosa microcristallina Sodio carbossimetilcellulosa - Sorbitolo (E-420) - Maltitolo (E-965) - Beta-ciclodestrina - Saccarina sodica - Sucralosio (E-955) -
Aroma di frutti di bosco - Colorante Rosso Allura-AC (E-129) - Para-idrossibenzoato di metile (E-218) - Para-idrossibenzoato di etile (E-214) - Para-idrossibenzoato di propile (E-216)
• Accertata allergia a ibuprofene o acido acetil salicilico o altri FANS (attacchi d'asma, rinite acuta, orticaria, edema angioneurotico)
• Emorragia gastrointestinale o perforazione gastrointestinale correlata a precedenti trattamenti con FANS
• Ulcera peptica, emorragia gastrointestinale attiva o ricorrente ( 2 o più episodi)
• Crohn’s o colite ulcerosa attiva
• Insufficienza cardiaca severa (classe IV secondo NYHA)
• Insufficienza renale (GFR< 35mL/min, calcolato con formula di Schwartz, secondo pRIFLE-Pediatric Risk, Injury, Failure, Loss, End Stage Renal Disease)
• Insufficienza epatica acuta (Pediatric Acute Liver Failure Registry, PALF):
-Insufficienza epatica ad esordio acuto (8 settimane dall'esordio di patologia epatica)
- Evidenza biochimica di danno epatico (elevazione di ALT, AST e/o bilirubina totale e coniugata)
- Coagulopatia non corretta dalla vitamina K (INR >= 1.5)
- Evidenza clinica di encefalopatia
• Insufficienza epatica cronica (a partire da Pugh-Child Score Classe A)
• Diatesi emorragica o patologie della coagulazione
• Gravidanza
• Ritardo cognitivo
• Mancanza di comprensione della lingua italiana da parte dei genitori o del tutore legale

E.5 End points

E.5.1

Primary end point(s)

The analgesic efficacy of the two formulations will be studied by verifying the reduction in pain reported by the child, through the compilation of the pain detection scale Faces pain scale - revised (FPS-R).

L’efficacia analgesica delle due formulazioni verrà studiata verificando la riduzione del dolore, riferita dal bambino, attraverso la compilazione della scala di rilevazione del dolore Faces pain scale – revised (FPS-R).

E.5.1.1

Timepoint(s) of evaluation of this end point

The filling of the pain detection scale will be at the following timepoints:
- T0 (enrollment)
- T1 (5 minutes from drug administration)
- T2 (10 minutes from drug administration)
- T3 (20 minutes from drug administration)
- T4 (48 ± 6 hours after administration) of the drug)

La compilazione della scala di rilevazione del dolore verrà effettuata ai seguenti tempi:
- T0 (arruolamento)
- T1 (5 minuti dalla somministrazione del farmaco)
- T2 (10 minuti dalla somministrazione del farmaco)
- T3 (20 minuti dalla somministrazione del farmaco),
-T4 (48 ± 6 ore dalla somministrazione del farmaco)

E.5.2

Secondary end point(s)

The bioavailability and the pharmacokinetic profile of the 2 formulations are evaluated by measuring:
- Area under the curve from time 0 to 20 minutes post-dose (AUC0-480min) estimated with the trapezoid method
- Systemic clearance of the two formulations (ratio between the dose of drug administered and the AUC)
- Cmax and Tmax (measured directly in the daily pharmacokinetic profile)

La biodisponibilità e il profilo farmacocinetico delle 2 formulazioni vengono valutati attraverso la misurazione di:
- Area sotto la curva dal tempo 0 a 20 minuti post-dose (AUC0-480min) stimata con il metodo dei trapezoidi
- Clearance sistemica delle due formulazioni (rapporto tra la dose di farmaco somministrato e l’AUC)
- Cmax e Tmax (misurati direttamente nel profilo farmacocinetico giornaliero)

E.5.2.1

Timepoint(s) of evaluation of this end point

Pharmacokinetic evaluations will be performed 2 days after starting therapy with one of the two ibuprofen formulations. Specifically, blood samples will be collected:
- at time 0 (immediately before the administration of the fourth dose)
- 5 minutes after administration of the fourth dose
- 10 minutes after administration of the fourth dose
- 20 minutes after administration of the fourth dose

Le valutazioni di farmacocinetica verranno eseguite 2 giorni dopo aver iniziato la terapia con una delle due formulazioni di ibuprofene. Nello specifico i prelievi ematici verranno raccolti:
- al tempo 0 (immediatamente prima della somministrazione della quarta dose)
- 5 minuti dopo la somministrazione della quarta dose
- 10 minuti dopo la somministrazione della quarta dose
- 20 minuti dopo la somministrazione della quarta dose

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

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)

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.8.4.1

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

Information not present in EudraCT

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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

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:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

Any withdrawal of patient from the study will not in any way compromise the quality of assistance and care provided to the patient. In case of failure of ibuprofen therapy due to a patient's failure to respond to persistent pain, paracetamol will be used as a painkiller rescue

L’eventuale ritiro del paziente dallo studio non comprometterà in alcun modo la qualità dell’assistenza e delle cure erogate al paziente. Nel caso di fallimento della terapia con ibuprofene determinato da una mancata risposta del paziente al trattamento con persistenza del dolore, sarà utilizzato come antidolorico ‘rescue’ il paracetamolo.

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

2019-12-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-12-18

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2022-03-31

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