Clinical Trials Register

Summary
EudraCT Number:	2005-006069-15
Sponsor's Protocol Code Number:	Gebro-III-28-2
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2006-02-21
Trial results	View 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

Austria - BASG

A.2

EudraCT number

2005-006069-15

A.3

Full title of the trial

Population pharmacokinetic/pharmacodynamic
and tolerability clinical trial in patients
suffering from acute post-operative pain

A.3.2

Name or abbreviated title of the trial where available

Dexibuprofen ready oral suspension

A.4.1

Sponsor's protocol code number

Gebro-III-28-2

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

n.a.

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Gebro Pharma GmbH
B.1.3.4	Country	Austria
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Dexibuprofen [S(+)-ibuprofen]
D.3.2	Product code	n.a.
D.3.4	Pharmaceutical form	Oral suspension
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	S(+)-ibuprofen, Dexibuprofen
D.3.9.1	CAS number	0051146-56-6
D.3.9.2	Current sponsor code	n.a.
D.3.9.3	Other descriptive name	n.a.
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/V) percent weight/volume
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
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)	Information not present in EudraCT
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	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	Information not present in EudraCT
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	Information not present in EudraCT
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	chemical active substance of class of NSAID, Dexibuprofen
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	Nureflex
D.2.1.1.2	Name of the Marketing Authorisation holder	Boots Healthcare Deutschland
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Ibuprofen
D.3.2	Product code	n.a.
D.3.4	Pharmaceutical form	Oral suspension
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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
D.3.9.1	CAS number	0015687-27-1
D.3.9.2	Current sponsor code	n.a
D.3.9.3	Other descriptive name	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)	Information not present in EudraCT
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	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	Information not present in EudraCT
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	Information not present in EudraCT
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	chemical active substance, class of NSAID, ibuprofen

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

pharmakodynamik: Acute post-operative pain after an operation (surgery) (acute is defined as within 4 hours after end of surgery).

pharmakokinetik: Acute post-operative pain is not necessary. Trial medication will be used after surgery as defined in Amendment III (Trial Protocol).

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	8.1
E.1.2	Level	LLT
E.1.2	Classification code	10054711

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Main objective is to test bioequivalence between adults and children according to CPMP/EWP/QWP/401/98 guideline.
Pharmacokinetic information may be used to extrapolate clinical efficacy and safety from adult to paediatric patients as well as between paediatric patients of different ages.
Provided that data from adults are considered relevant, pharmacokinetic information can be used to extrapolate efficacy and safety to the paediatric population.
Similar exposure (plasma concentration) in adult and paediatric patients is assumed to result in similar efficacy, therefore pharmacokinetic data alone can be used to extrapolate efficacy and safety.
In particular, the serum levels of dexibuprofen can be readily related to the pharmacological or therapeutic effects.
The present clinical trial was designed to investigate pharmacokinetic/pharmacodynamic profile of dexibuprofen ready oral suspension in adults and in children (population bioequivalence).

E.2.2

Secondary objectives of the trial

Second aim is to compare efficacy and tolerability of dexibuprofen ready oral suspension with ibuprofen liquid formulation, which is already exhaustive used in children.
Secondary objective is to test non-inferiority of the investigational medicial product (dexibuprofen) versus an active control (ibuprofen) concerning pain relieve according to CPMP/ICH/363/96 guideline.
According to international requirements about efficacy equivalence trials with an active control (accepted reference drug) the trial is designed as an one-sided equivalence or non-inferiority trial (Garbe E et al 1995) (Schmidt K 1995).
Starting from the assumption that dexibuprofen and ibuprofen are equally effective, a one-sided test is used to prove in a confirmatory way that the efficacy of the test preparation (dexibuprofen) in patients with acute post-operative pain is at least equal to or even superior to the reference preparation (ibuprofen).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Pharmakokinetik/ Pharmakodynamik: male or female patients; age between 2 and 11 years (children) and 18 and 55 years (adults), body weight between 12 kg and 121 kg (> 11 kg and < 122 kg), written informed consent/assent (parents and children, adults); operation (surgery).

pharmakodynamik only: acute post-operative pain (at least moderate).

E.4

Principal exclusion criteria

post-opertive i.v. analgesics during the intubation and after the extubation period when oral ingestion is not possible, post-operative emesis which makes an oral ingestion of the IMPDs four hours after surgery impossible, patients hypersensitive to dexibuprofen or ibuprofen, to any other NSAID, or to any excipient of the products; pregnancy; participation in an other clinical trial less than 30 days ago, simultaneous participation in an other clinical trial; patients already treated under this protocol, patients taken in custody by court or authorities, patients in whom substances with similar action (e.g. aspirin or other NSAIDs) precipitate attacks of asthma, bronchospasm, acute rhinitis, or causal nasal polyps, urticaria or anioneurotic oedema; patients with anemia, patients with active or suspected gastrointestinal ulcer or history of gastrointestinal ulcer (in the past 6 months); patients who have gastro-intestinal bleeding or other active bleedings or bleeding disorders; patients with Crohn´s disease or ulcerative colitis, with severe heart failure, with severe renal dysfunction (GFR < 30 ml/min), with severely impaired hepatic function, with haemorrhagic diathesis and other coagulation disorders, or patients receiving anticoagulant therapy; connective tissue diseases such as e.g. lupus erythematosus and other autoimmune diseases;

E.5 End points

E.5.1

Primary end point(s)

Pharmacokinetic part:
Primary efficacy criteria:
Population bioequivalence evaluation is based upon plasma concentration-time profiles for the pharmacologically active substance dexibuprofen, which is measured in plasma by HPLC, liquid-liquid extraction and fluorescence detection. Pharmacokinetic parameters are determined using a non-compartimental approach. Primary criteria are AUC0-t and Cmax.

Secondary efficacy criteria:
Second order criteria are Tmax and AUC0-inf.

Pharmacodynamic part:
Primary efficacy criteria:
SPID0-6 and TOTPAR0-6

Secondary efficacy criteria:
peak of PID, time to peak PID, time point by time point PID and pain relief assessment > 50% max TOTPAR0-6, global assessment by patients and by investigator.

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

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

Yes

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

Yes

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

Yes

E.8.1.7.1

Other trial design description

analyst-blinded

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.8.3

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

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

Last visit of the last patient undergoing the clinical trial

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.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2006-02-21.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

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

children

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

192

F.4.2

For a multinational trial

F.4.2.1

In the EEA

192

F.4.2.2

In the whole clinical trial

192

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)

n.a.

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

2006-05-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2006-05-19

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2010-10-08

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