E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Moderate to severe acute post-operative pain. |
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E.1.1.1 | Medical condition in easily understood language |
Acute post-operative pain |
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E.1.1.2 | Therapeutic area | Diseases [C] - Symptoms and general pathology [C23] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
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 tapentadol oral solution in children aged from birth to less than 2 years after a surgical procedure that routinely produces moderate to severe acute post-surgical pain requiring opioid treatment. The concentration data will be used to characterize the pharmacokinetic parameters of tapentadol using a population and physiologically-based pharmacokinetic approach. This will enable data based recommendations for the use of tapentadol in children of different ages (birth to less than 1 month, 1 month to less than 6 months, and 6 months to less than 2 years) in subsequent safety and efficacy trials. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of tapentadol oral solution in the population studied. To explore the effect of tapentadol oral solution on moderate to severe pain that, in the opinion of the investigator, requires treatment with an opioid. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• The participant's parent(s) or legal guardian(s) have given written informed consent to participate. • Male or female subject aged from birth (≥37 weeks gestational age) to less than 2 years. • Participant is not obese (e.g., a body weight above the 97th percentile for children based on the World Health Organization weight charts) with a minimum body weight of 2.5 kg. • Physical status rated not higher than P3 on the American Society of Anesthesiologists physical status classification in subjects aged from 1 month to less than 2 years. • Participant has undergone surgery that, in the investigator's opinion, would reliably produce moderate to severe pain requiring opioid treatment. • At the time of allocation to IMP, subject has a sedation score that is not higher than 2 (moderately sedated) on the University of Michigan Sedation Scale with the exception of subjects who are mechanically ventilated in age subgroup 3 , has a functioning gastrointestinal tract after surgery, and can tolerate medication administered orally or via a feeding tube at the time of allocation to IMP. • Participant has a reliable venous vascular access for pharmacokinetic blood sampling.
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E.4 | Principal exclusion criteria |
• The participant's parent(s)/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/trial site/the subject/subject's parent(s)/or legal guardian(s) is a family member of the employees or the investigator. • Participant has been previously exposed to tapentadol. • Participant has received an experimental drug or used an experimental medical device within 28 days before allocation to study medication, or within a period less than 10 times the drug's half-life, whichever is longer. • Concomitant participation in another clinical trial with an experimental drug or experimental device for the duration of this trial. • Participant has undergone brain surgery. • Participant has undergone a surgery that is expected to affect the absorption of tapentadol (e.g., to the gastrointestinal tract). • Subject has a history or current condition of any one of the following: • Seizure disorder. • Traumatic or hypoxic brain injury, i.e., brain contusion, stroke, transient ischemic attack, intracranial bleeding or hematoma, brain neoplasm. • Subject has a history or current condition of any one of the following: • Moderate to severe renal impairment. • Moderate to severe hepatic impairment, congestive hepatopathy, or hepatic portosystemic shunting. • 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, unless the subject is mechanically ventilated in age subgroup 3. • Participant has signs or symptoms of congestive heart failure (e.g., requiring more than minimal inotropic support, an abnormal lactic acid value greater than 2-times upper limit of normal), or hemorrhagic disorder following surgery. • Minimal inotropic medication is defined as: - Dopamine less or equal to 5 microgram/kg per minute. - Epinephrine less or equal to 0.03 microgram/kg per minute (but not both dopamine and epinephrine). - Milrinone less or equal to 0.5 microgram/kg per minute or less. • Participant has a concomitant disease or disorder that in the opinion of the investigator may affect or compromise participant's safety during the trial participation. • Participant has cognitive or developmental impairment such that trial participation may affect or compromise the participant's safety, or the participant's ability to comply with the protocol requirements (as appropriate for the subject's age), in the investigator's judgment. Otherwise, participant's with cognitive or developmental impairment may be enrolled in the trial. • Participant has a clinically relevant history of hypersensitivity, allergy, or contraindication to tapentadol (or ingredients). Participant has: • Clinically relevant abnormal 12-lead ECG. • Signs of pre-excitation syndrome. • Corrected QT (QTcF) interval >460 ms. Subjects may be allocated to IMP with values >460 ms if, in the investigator’s opinion, the value is a consequence of cardiac surgery and is not considered clinically significant. • Subject has clinically relevant abnormal laboratory values from a sample obtained post-operatively and prior to allocation to IMP. The following specifications will apply: • Aspartate transaminase or alanine transaminase is >2.5-times upper limit of normal. • Total bilirubin is >2-times upper limit of normal and direct bilirubin >20% of the total bilirubin, and for subjects in age subgroup 3, the presence of pathological jaundice in the opinion of the investigator. • Glomerular filtration rate: − <20 mL/min/1.73 m2 for subjects <1 week old. − <30 mL/min/1.73 m2 for subjects 1 week to 8 weeks old. − <50 mL/min/1.73 m2 for subjects >8 weeks old. • Other parameters (in the investigator’s judgment). • Signs or symptoms indicative of a systemic infection within 24 hours prior to allocation to IMP, in the investigator’s judgment. • Participant has been administered a prohibited medication. • The mother of a newborn participant or the breastfeeding mother of a participant was administered a prohibited medication (see Restrictions for the mother of a newborn or breastfeeding mother). • At the time of dosing, in the investigator’s judgment, the subject has either of the following: Clinically unstable upper or lower airway conditions or respiratory depression (unless the subject is mechanically ventilated in age subgroup 3). Clinically unstable systolic or diastolic blood pressure, heart rate, or respiratory rate. • Participant has a peripheral oxygen saturation (SpO2) <92% for acyanotic subjects, or <75% for cyanotic subjects, with or without supplemental oxygen via nasal cannula or high flow nasal cannula, at the time of allocation to IMP. • For age subgroup 1 and age subgroup 2, subject requires continuous positive airway pressure or mechanical ventilation, at the time of allocation to IMP. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Pharmacokinetic evaluation based on serum concentrations of tapentadol and tapentadol-O-glucuronide obtained from blood samples. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Within 8 hours of study medication intake at 2 time points per participant. |
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
staggered sequential dosing by participant age. |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
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 | No |
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 |
Poland |
United Kingdom |
United States |
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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
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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 | 8 |
E.8.9.1 | In the Member State concerned days | 15 |
E.8.9.2 | In all countries concerned by the trial months | 12 |