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    The EU Clinical Trials Register currently displays   36348   clinical trials with a EudraCT protocol, of which   5989   are clinical trials conducted with subjects less than 18 years old.
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    EudraCT Number:2014-002259-24
    Sponsor's Protocol Code Number:KF5503-73
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-06-02
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2014-002259-24
    A.3Full 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.3.1Title 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.4.1Sponsor's protocol code numberKF5503-73
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1157-3228
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/236/2014
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorGrünenthal GmbH
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportGrünenthal GmbH
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGrünenthal GmbH
    B.5.2Functional name of contact pointGrünenthal Clinical Trial Helpdesk
    B.5.3 Address:
    B.5.3.1Street AddressZieglerstr. 6
    B.5.3.2Town/ cityAachen
    B.5.3.3Post code52078
    B.5.4Telephone number+49241569 3223
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTapentadol 1 mg/mL solution for injection
    D.3.2Product code CG5503
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTapentadol hydrochloride
    D.3.9.1CAS number 175591-09-0
    D.3.9.2Current sponsor codeCG5503
    D.3.9.3Other descriptive nameTAPENTADOL HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB32145
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another 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.1.1Medical condition(s) being investigated
    Severe post-operative pain
    E.1.1.1Medical condition in easily understood language
    Acute post-operative pain
    E.1.1.2Therapeutic area Diseases [C] - Symptoms and general pathology [C23]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level LLT
    E.1.2Classification code 10036286
    E.1.2Term Post-operative pain
    E.1.2System Organ Class 100000004863
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.2.2Secondary 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.2.3Trial contains a sub-study No
    E.3Principal 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.4Principal 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.5.1Primary end point(s)
    • Pharmacokinetic evaluation based on serum concentrations of tapentadol, and
    • Pharmacokinetic evaluation based on serum concentrations of tapentadol-O-glucuronide.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Blood samples taken within 10 hours of IMP intake at 3 time points per subject.
    E.5.2Secondary end point(s)
    No secondary endpoints
    E.5.2.1Timepoint(s) of evaluation of this end point
    No secondary endpoints
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other 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.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months7
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 32
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Yes
    F. of subjects for this age range: 8
    F.1.1.3Newborns (0-27 days) Yes
    F. of subjects for this age range: 8
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F. of subjects for this age range: 16
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F. of subjects incapable of giving consent
    Minors incapable of giving consent.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 32
    F.4.2.2In the whole clinical trial 32
    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
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-01-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-11-17
    P. End of Trial
    P.End of Trial StatusCompleted
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