| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Moderate to severe acute pain | |
| E.1.1.1 | Medical condition in easily understood language | | Moderate to severe acute pain following a painful event e.g. an operation | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| 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 | 10066714 | | E.1.2 | Term | Acute pain | | E.1.2 | System Organ Class | 100000004867 | |
| 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 | To investigate the pharmacokinetic profile of tapentadol after the administration of multiple doses of tapentadol oral solution to
children aged 2 years to less than 7 years after a painful event that routinely produces acute pain requiring treatment with a strong
analgesic medication (e.g., opioids or metamizole). | |
| E.2.2 | Secondary objectives of the trial | To investigate the pharmacokinetic profile of tapentadol-O-glucuronide after the administration of multiple doses of tapentadol oral solution to children aged 2 years to less than 7 years after a painful event that routinely produces acute pain requiring treatment with a strong analgesic medication (e.g., opioids or metamizole).
To investigate the pharmacokinetic profile of tapentadol-O-sulphate after the administration of multiple doses of tapentadol oral solution to children aged 2 years to less than 7 years after a painful event that routinely produces acute pain requiring treatment with a strong analgesic medication (e.g., opioids or metamizole). | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | - Informed consent, and if applicable assent, given according to local regulations.
- The subject is male or female and aged 2 years to less than 7 years from the time of allocation to investigational medicinal product (IMP) until End of Treatment and Evaluation Visit (Visit 3).
- The subject experienced a painful event (e.g., a painful intervention or surgery) that, in the investigator’s opinion, would reliably produce acute pain requiring treatment with a strong analgesic (e.g., opioids or metamizole) for at least 24 hours after Dose 1. The subject is expected to remain hospitalized until Visit 3.
- The subject is able to tolerate liquids at the time of allocation to IMP.
- The subject has a reliable venous vascular access or can be venipunctured repeatedly for pharmacokinetic blood sampling, depending on which is less burdensome for the individual subject.
| |
| E.4 | Principal exclusion criteria | - The subject, their parent, or their 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 is a family member of the employees or the investigator.
- The subject has been exposed to tapentadol 28 days or less before enrollment.
- The subject has received an experimental drug 28 days or less before allocation to IMP or, if 10 half-lives of the drug are longer than 28 days, 10 half-lives of the drug or less before allocation to IMP.
- The subject participates concurrently in another clinical trial with an experimental drug.
- The subject has undergone brain surgery.
- The subject has undergone an intervention or surgery that will, in the opinion of the investigator, affect the absorption of tapentadol (e.g., surgery of the gastrointestinal tract).
- The subject has signs or symptoms of congestive heart failure (e.g., requiring more than minimal inotropic support), or hemorrhagic disorder following surgery.
- The subject has (a history of) any of the following:
• Seizure disorder or epilepsy.
• Renal or hepatic impairment.
• Acute or severe bronchial asthma or hypercapnia.
• Brain tumors, clinically relevant history or a current condition of head injury, or increased intracranial pressure including traumatic and hypoxic brain injuries such as stroke, transient ischemic attack, brain contusion, intracranial hematoma, episode(s) of more than 24 hours duration of unconsciousness, or posttraumatic amnesia.
- The subject has biliary tract disease or has or is suspected of having paralytic ileus.
- The subject has a disease or disorder (e.g., impaired respiratory function or clinically relevant respiratory disease, endocrine, metabolic, neurological, psychiatric, infection, febrile seizure, clinically relevant abnormal electrocardiogram [ECG]) that, in the opinion of the investigator, may affect or compromise the subject’s safety during participation in the trial.
- The subject is obese, i.e., has a body mass index (BMI) equal to or above the 95th percentile for children based on the World Health Organization (WHO) BMI charts.
- The subject has a body weight below 9.0 kg.
- The subject has a clinically relevant history of hypersensitivity, allergy, or contraindication to tapentadol, or the excipients (see the summary of product characteristics [SmPC]), or naloxone.
- The subject is mentally retarded, cognitively impaired, or unable to comprehensively understand or follow the trial instructions as appropriate for the age of the subject, based on medical history and/or in the judgment of the investigator.
- The subject is taking prohibited concomitant medication.
- The subject will be excluded if any of the following criteria applies for local safety laboratory results:
• Aspartate transaminase and/or alanine transaminase is above 3 times upper limit of normal.
• Total bilirubin is above 2 times upper limit of normal.
• Glomerular filtration rate (GFR) is below 60 mL/min (calculated according to Schwartz et al. 1984).
• Lactic acid value is above 2 times upper limit of normal (only if the painful event was cardiac surgery).
• Any other parameter is, in the judgment of the investigator, clinically significant and would put the subject at undue risk if they were to take part in the trial.
- The subject will be excluded if any of the following criteria is met at the time of allocation to IMP:
• The subject has, in the judgment of the investigator, clinically unstable systolic and diastolic blood pressure, heart rate, respiratory depression, or clinically unstable upper or lower airway conditions, or a clinically significant decreased/unstable saturation of peripheral oxygen (SpO2).
• The subject requires continuous positive airway pressure or mechanical ventilation. | |
| E.5 End points |
| E.5.1 | Primary end point(s) | | Area under the concentration-time curve at steady state for the dosing interval (AUCtau,SS) for tapentadol | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | | From 1.5 hours after Dose 1 (Day 1) until 10 hours after the final dose (Day 4) | |
| E.5.2 | Secondary end point(s) | Area under the concentration-time curve at steady state for the dosing interval (AUCtau,SS) for tapentadol-O-glucuronide
Area under the concentration-time curve at steady state for the dosing interval (AUCtau,SS) for tapentadol-O-sulphate | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | | From 1.5 hours after Dose 1 (Day 1) until 10 hours after the final dose (Day 4) | |
| 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 | No |
| 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 | No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 8 |
