Clinical Trials Register

Summary
EudraCT Number:	2014-002259-24
Sponsor's Protocol Code Number:	KF5503-73
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2014-11-12
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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2014-002259-24

A.3

Full title of the trial

Open-label evaluation of the population pharmacokinetic profile, safety, tolerability, and efficacy of intravenous tapentadol solution for injection for the treatment of post-surgical pain in children aged from birth to less than 2 years, including preterm neonates.

A.3.1

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

Use of intravenous tapentadol solution for injection for pain after surgery in children from newborn to less than 2 years old, including preterm babies.

A.4.1

Sponsor's protocol code number

KF5503-73

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1157-3228

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/279/2013

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Grünenthal GmbH
B.1.3.4	Country	Germany
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	Grünenthal GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Grünenthal GmbH
B.5.2	Functional name of contact point	Grünenthal Clinical Trial Helpdesk
B.5.3	Address:
B.5.3.1	Street Address	Zieglerstr. 6
B.5.3.2	Town/ city	Aachen
B.5.3.3	Post code	52078
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49241569 3223
B.5.6	E-mail	Clinical-Trials@grunenthal.com

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	Tapentadol 1 mg/mL solution for injection
D.3.2	Product code	CG5503
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tapentadol hydrochloride
D.3.9.1	CAS number	175591-09-0
D.3.9.2	Current sponsor code	CG5503
D.3.9.3	Other descriptive name	TAPENTADOL HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB32145
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	1
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

Severe post-operative pain

E.1.1.1

Medical condition in easily understood language

Acute post-operative pain

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	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10036286
E.1.2	Term	Post-operative pain
E.1.2	System Organ Class	100000004863

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of the trial is to collect serum concentration data of tapentadol and its major metabolite tapentadol-O-glucuronide after the administration of a single dose of intravenous tapentadol solution for injection in children aged from birth to less than 2 years, including preterm neonates, after a surgical procedure that routinely produces moderate to severe acute pain requiring opioid treatment. The concentration data will be used to characterize the pharmacokinetic parameters of tapentadol using population and physiologically-based pharmacokinetic approaches.
This will enable data based recommendations for the use of tapentadol in children of different ages.

E.2.2

Secondary objectives of the trial

To evaluate the safety and tolerability of a single dose of tapentadol intravenous solution in the population studied.
To explore the effect of intravenous tapentadol solution for injection on moderate to severe pain that, in the opinion of the investigator, requires treatment with an opioid, using validated age appropriate scales.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. The subject’s parent(s) or legal guardian(s) have given written informed consent to participate.
2. Male or female subject aged from birth to less than 2 years, including preterm neonates.
3. Gestational age at least 32 weeks.
4. Postnatal age at least 1 week (age subgroup 3 and age subgroup 4).
5. A body weight below the 97th percentile range according to World Health Organization standards, with a minimum body weight of 1.5 kg.
6. Physical status rated not higher than P3 on the American Society of Anesthesiologists physical status classification.
7. Subject has undergone surgery that, in the investigator’s opinion, would reliably produce moderate to severe pain requiring opioid treatment.
8. Preterm neonatal and neonatal subjects must be on an intensive care unit.
9. At the time of allocation to Investigational Medicinal Product, subject has a sedation score that is not higher than 2 (moderately sedated) on the University of Michigan Sedation Scale.
10. Subject has a reliable venous vascular access for pharmacokinetic blood sampling.

E.4

Principal exclusion criteria

1. The subject’s parent(s) or legal guardian(s) is an employee of the investigator or trial site, with direct involvement in this trial or other trials under the direction of that investigator or trial site, or the subject, or subject’s parent(s), or legal guardian(s) is a family member of the employees or the investigator.
2. Subject has been previously exposed to tapentadol.
3. Subject has received an experimental drug or used an experimental medical device within 28 days before allocation to Investigational Medicinal Product (IMP), or within a period less than 10 times the drug’s half-life, whichever is longer.
4. Concomitant participation in another interventional clinical trial for the duration of this trial.
5. Subject has undergone brain surgery.
6. Subject requires prolonged mechanical ventilation (more than 48 hours after surgery) or, the subject is mechanically ventilated at the time of allocation to Investigational Medicinal Product.
7. Subject has a history or current condition of any one of the following:
• Seizure disorder.
• Traumatic or hypoxic brain injury, brain contusion, intracranial
hematoma/hemorrhage, post-traumatic recovery, brain neoplasm, or episode(s) of unconsciousness of more than 24 hours.
8. Subject has a history or current condition of any one of the following:
• Moderate to severe renal impairment.
• Moderate to severe hepatic impairment.
• Clinically relevant abnormal pulmonary function or clinically relevant
respiratory disease that in the opinion of the investigator would put the subject at risk for developing respiratory depression.
9. Subject has signs or symptoms of congestive heart failure (e.g., requiring more
than minimal inotropic support, an abnormal lactic acid value >2-times upper
limit of normal), or hemorrhagic disorder following surgery.
• Minimal inotropic medication is defined as:
− - Dopamine 3 or more microgram/kg per minute (but not together with epinephrine).
− - Epinephrine 0.03 or more microgram/kg per minute (but not together with dopamine).
− - Milrinone 0.5 or more microgram/kg per minute or less.
10. Subject has a concomitant disease or disorder (e.g., endocrine, metabolic, neurological, or psychiatric disorder, or a febrile seizure or is at risk of, or has, paralytic ileus) that in the opinion of the investigator can affect or compromise subject’s safety during the trial participation.
11. Subject has cognitive or developmental impairment such that trial participation can affect or compromise the subject’s safety, or the subject’s ability to comply with the protocol requirements (as appropriate for the subject’s age), in the investigator’s judgment. Otherwise, subjects with cognitive or developmental impairment can be enrolled in the trial.
12. Subject has a clinically relevant history of hypersensitivity, allergy, or contraindication to tapentadol (or ingredients).
13. Subject has:
• Clinically relevant abnormal ECG in the investigator’s judgment.
• QT or corrected QT (QTc) interval >460 ms.
14. Subject has clinically relevant abnormal lab values from a sample obtained postoperatively
and prior to allocation to IMP. The following specifications apply:
• Aspartate transaminase or alanine transaminase is greater than 2.5-times upper limit of normal.
• For age subgroup 1 and age subgroup 2, total bilirubin is greater than 2-times upper limit of normal and direct bilirubin greater than 20% of the total bilirubin.
• For age subgroup 3 and age subgroup 4, total bilirubin is outside of the normal range for the age of the subject.
• Glomerular filtration rate (calculated according to Schwartz et al. 1984):
− - less than 30 mL/min/1.73 m2 for subjects 1 week to 8 weeks post-partum.
− - less than 50 mL/min/1.73 m2 for subjects >8 weeks post-partum.
• Other parameters (in the investigator’s judgment).
15. Sepsis that requires treatment with catecholamines.
16. Subject has been administered a prohibited medication.
17. The mother of a newborn subject or the breastfeeding mother of a subject was administered a prohibited medication.
18. Subject has post-operative, clinically unstable systolic and diastolic blood pressure, heart rate, respiratory depression, or clinically unstable upper or lower airway conditions (in the investigator’s judgment).
19. A peripheral oxygen saturation (SpO2) less than 92% for acyanotic subjects, or less than 75% for cyanotic subjects, with or without supplemental oxygen via nasal cannula, at the time of allocation to IMP.
20. Subject requires positive airway pressure, e.g., in form of a high flow nasal cannula or continuous positive airway pressure.

E.5 End points

E.5.1

Primary end point(s)

• Pharmacokinetic evaluation based on serum concentrations of tapentadol, and
• Pharmacokinetic evaluation based on serum concentrations of tapentadol-O-glucuronide.

E.5.1.1

Timepoint(s) of evaluation of this end point

Blood samples taken within 10 hours of IMP intake at 3 time points per subject.

E.5.2

Secondary end point(s)

No secondary endpoints

E.5.2.1

Timepoint(s) of evaluation of this end point

No secondary endpoints

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

Yes

E.6.6

Pharmacokinetic

Yes

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

Staggered recruitment by age starting with the recruitment of subjects in age group 1.
At least 4 subjects must be enrolled and dosed in an older age subgroup to assess targeted exposure and safety before enrollment of subjects in the next younger age subgroup.

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

E.8.1.1

Randomised

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

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

Yes

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

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:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

Yes

F.1.1.2.1

Number of subjects for this age range:

F.1.1.3

Newborns (0-27 days)

Yes

F.1.1.3.1

Number of subjects for this age range:

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)

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

Minors incapable of giving consent.

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)

Standard of care.

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

2015-03-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-02-19

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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