Clinical Trials Register

Summary
EudraCT Number:	2012-004359-35
Sponsor's Protocol Code Number:	R331333PAI3037
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-05-16
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

Germany - BfArM

A.2

EudraCT number

2012-004359-35

A.3

Full title of the trial

An evaluation of the efficacy and safety of tapentadol oral solution in the treatment of post-operative acute pain requiring opioid treatment in pediatric subjects aged from birth to less than 18 years old.

A.3.1

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

A study to look at Tapentadol Oral Solution in Children and Adolescents in pain after Surgery

A.4.1

Sponsor's protocol code number

R331333PAI3037

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02081391

A.5.4

Other Identifiers

Name:	IND	Number:	108134
Name:	Grünenthal	Number:	KF5503/65
Name:	Depomed	Number:	R331333PAI3037

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/090/2016

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.4.1	Name of organisation providing support	Depomed Inc.
B.4.2	Country	United States
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 Trial Information Desk
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 4 mg/mL oral solution
D.3.2	Product code	CG5503/R331333
D.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	No
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	Tapentadol hydrochloride
D.3.9.1	CAS number	175591-09-0
D.3.9.2	Current sponsor code	CG5503/R331333
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	4
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	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 20 mg/mL oral solution
D.3.2	Product code	CG5503/R331333
D.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	No
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	Tapentadol hydrochloride
D.3.9.1	CAS number	175591-09-0
D.3.9.2	Current sponsor code	CG5503/R331333
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	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	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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Oral solution
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

The management of acute postoperative pain in hospitalized paediatric patients.

E.1.1.1

Medical condition in easily understood language

A study to look at Tapentadol Oral Solution in Children and Adolescents in pain after Surgery

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10036236
E.1.2	Term	Postoperative pain relief
E.1.2	System Organ Class	100000004865

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	10054711
E.1.2	Term	Postoperative 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

Efficacy of tapentadol oral solution, based on the total amount of supplemental opioid analgesic medication (morphine equivalents in mg/kg body weight) used within the first 24 hours after first IMP intake.

E.2.2

Secondary objectives of the trial

To assess the efficacy of tapentadol oral solution using multiple subjective and objective measures of the subject’s response to treatment.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Informed consent, and if applicable assent, given according to local regulations.
2. Male or female subject aged from birth (greater than or equal to 37 weeks gestational Alge) to less than 18 years.
3. A female subject must be pre-menarchal, or surgically incapable of childbearing, or sexually abstinent, or if a female subject is sexually active, then she must be practicing an effective method of birth control (e.g., prescription hormonal contraceptives, intra-uterine devices used according to the product’s instruction, double-barrier methods) before trial entry and throughout the trial.
4. A female subject must have a negative pregnancy test if aged 12 years or older, or is post-menarchal, or is sexually active.
5. Subject has undergone surgery (other than brain surgery or gastrointestinal surgery expected to affect the absorption of tapentadol [in the investigator’s judgment]) that, in the investigator’s opinion, would reliably produce moderate to severe pain requiring opioid treatment for at least 24 hours after first dose of IMP. Subjects must remain hospitalized until the End of Treatment Visit.
6. Subject has received post-operative morphine or hydromorphone by NCA/PCA, with or without a background infusion of the same opioid, according to standard of care prior to allocation/randomization to IMP and subject is expected to require this morphine or hydromorphone by NCA/PCA after starting IMP.
7. Subject is able to tolerate liquids at the time of allocation/randomization to IMP.

E.4

Principal exclusion criteria

1. Subject, parent or the legal representative is an employee of the investigator or trial site, with direct involvement in the proposed trial or other trials under the direction of that investigator or trial site, or 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/randomization to IMP, or within a period less than 10 times the drug’s half-life,
whichever is longer.
4. Subject has a history or current condition of any one of the following:
• Non-febrile seizure disorder.
• Epilepsy.
• Serotonin syndrome.
• Traumatic or hypoxic brain injury, brain contusion, stroke, transient ischemic attack, intracranial hematoma, post-traumatic amnesia, brain neoplasm, or episode(s) of unconsciousness of more than 24 hours.
5. Subject has a history or current condition of any one of the following:
• Moderate to severe renal or hepatic impairment.
• Abnormal pulmonary function or clinically relevant respiratory disease (e.g., acute or severe bronchial asthma, hypercapnia).
6. Subject has a concomitant disease or disorder (e.g., endocrine, metabolic, neurological, psychiatric, infection, febrile seizure, paralytic ileus) that in the opinion of the investigator may affect or compromise subject safety during the trial participation.
7. Subject has history of suicidal ideation or behavior.
8. Subject is obese in the investigator´s judgment. Obesity can be determined based on appropriate BMI charts or tables; e.g., a BMI above the 97th percentile for children based on the World Health Organization growth Charts or Subject weight is less than 2500 gm.
9. Subject has a clinically relevant history of hypersensitivity, allergy, or contraindication to the supplemental opioid analgesic medication or tapentadol, or the excipients, or naloxone.
10. Subject is not able to understand and comply with the protocol as appropriate for the age of the subject or subject is cognitively impaired in the investigator’s judgment such that they cannot comply with the protocol.
11. Subject has a history of alcohol and/or substance abuse in the investigator’s judgment based on subject’s history and physical examination.
12. Subject is taking prohibited concomitant medication.
13. Subject has received a long-acting opioid for the treatment of pain following surgery within 6 hours of allocation/randomization to IMP.
14. Subject has clinically relevant (in the investigator’s judgment) abnormal values for clinical chemistry or hematology (local laboratory sample taken after surgery).
A subject aged 6 months to less than 18 years old is excluded if the:
• Aspartate transaminase or alanine transaminase is >3-times upper limit of normal.
• Total bilirubin is >2-times upper limit of normal (except if the cause is due to Gilbert’s syndrome).
• Glomerular filtration rate <60 mL/min (calculated according to Schwartz et al. 1984).
A subject aged from birth to less than 6 months old is excluded if:
• Aspartate transaminase or alanine transaminase is >3-times upper limit of normal.
• There is pathological jaundice in the opinion of the investigator.
• Glomerular filtration rate (calculated according to Schwartz et al. 1984) is:
<20 mL/min/1.73 m2 for subjects <1 week post-partum.
<30 mL/min/1.73 m2 for subjects 1 week to 8 weeks post-partum.
<50 mL/min/1.73 m2 for subjects >8 weeks post-partum to <6 months old.
15. Subject has:
• Clinically relevant abnormal ECG.
• Signs of pre-excitation syndrome.
• Brugada’s syndrome.
• QT or QTc interval >470 ms for children aged 6 years to less than 18 years old.
• QT or QTc interval >460 ms for children aged from birth to less than 6 years old.
16. Peri- or post-operative analgesia supplied by a continuous regional technique (e.g., nerve block, wound infiltration catheter) or subject controlled epidural analgesia that was terminated less than 6 hours before allocation/randomization to IMP.
17. 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), or a saturation of peripheral oxygen (SpO2) <92% at the time of randomization (allocation/randomization to IMP).
18. Female subject is breast-feeding a child.
19. Subject requires continuous positive airway pressure or mechanical ventilation, at the time of allocation to IMP.
20. The mother of a newborn subject or the breastfeeding mother of a subject was administered a prohibited medication.

E.5 End points

E.5.1

Primary end point(s)

The total amount of supplemental opioid analgesic medication (morphine equivalents in mg/kg body weight) used after first IMP intake.

E.5.1.1

Timepoint(s) of evaluation of this end point

EU: 24 hours
US: 12 hours

E.5.2

Secondary end point(s)

The total amount of supplemental opioid analgesic medication received assessed in 12 hour intervals from 24 hours to 96 hours after the first dose of IMP.
Palatability and acceptability of the IMP.
Changes from baseline in pain intensity.
Clinician Global Impression of Change.
Patient Global Impression of Change.
Time to first and time to second NCA/PCA after first dose of IMP.
Time to first dose of IMP until IMP treatment discontinuation due to lack of efficacy.
Safety
• Percentage of subjects with TEAEs.
• Percentages of subjects who develop abnormal:
− Vital signs.
− Laboratory parameters.
− 12-lead ECG parameters.
• Changes from baseline in vital signs parameters.
• Changes from baseline in safety laboratory parameters.
• Changes from baseline in 12-lead ECG parameters.
• Percentage of subjects discontinuing the trial due to TEAEs and drug-related adverse events.
• Suicidal ideation/behavior in subjects aged 6 years or older using the C-SSRS scores before IMP and at the end of the trial.
• Sedation scores.

E.5.2.1

Timepoint(s) of evaluation of this end point

Efficacy endpoints:
12 hours
24 hours
up to 96 hours
Safety endpoints:
up to Day 14

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

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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)

E.8.2.2

Placebo

Yes

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Austria

Croatia

France

Germany

Poland

Spain

United Kingdom

United States

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

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