| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033371 |
| E.1.2 | Term | Pain |
| E.1.2 | System Organ Class | 10018065 - General disorders and administration site conditions |
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| 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 evaluate the pharmacokinetic profile of Tapentadol and its major metabolite Tapentadol-O-glucuronide after administration of a single dose of Tapentadol oral solution (OS) 1 mg/kg in children and adolescents aged from 6 to less than 18 years after scheduled surgical procedures that routinely produce acute, moderate to severe post-surgical pain. |
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| E.2.2 | Secondary objectives of the trial |
| Safety and tolerability will be evaluated and the measurement of pain intensity will be explored. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must satisfy the following criteria to be enrolled in the study:
1. Male or female subject from 12 to less than 18 years of age (Part 1 only) or male or female subject from 6 to less than 18 years of age (Part 2 only). Age is determined on the day of dosing of study medication.
2. BMI below the 95th percentile for children, based on CDC growth charts
3. A maximum body weight of 85 kg.
4. Having completed scheduled surgery per investigator’s judgment such as examples provided here but not limited to tonsillectomy, minor orthopedic procedure, corrective spinal or thoracic orthopedic surgeries, peripheral soft tissue procedure, uncomplicated inguinal hernia repair, minor urogenital procedure, ear surgery, eye surgery, peripheral plastic, or cosmetic surgery. Other surgical procedures may be allowed, based on investigator’s judgment, that will not result in heavy blood loss and/or a long and difficult recovery period.
5. Having a postoperative pain intensity score ≥ 4 on the McGrath CAS as a result of the scheduled surgical procedure.
6. If applicable, has signed an Assent Form as per local regulations.
7. Parent(s) or the legal guardian(s) of the subject signed an informed consent
document indicating that they understand the purpose of the study, the risks and benefits of the procedures required for the study and give permission for their child’s participation in the study.
8. If a female, is premenarchal, surgically incapable of childbearing, abstinent, or, if sexually active, is practicing an effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, double-barrier method, contraceptive patch, male partner sterilization)
before study entry and throughout the study.
9. If a female and postmenarchal or older than 12 years, has a negative urine pregnancy test on the day before or on the day of study drug administration.
10. If a male and sexually active, agrees to use an approved method of birth control to prevent pregnancy and, as applicable to relevant local regulations and medical practices, not to donate sperm from the day of study drug administration until 3 months afterwards.
11. Physical status rated as I or II as per the American Society of Anesthesiologists
(ASA) classification.
12. Is alert, oriented, able to follow commands, able to understand the study
requirements and procedures, and able to communicate intelligibly with the health care provider (taking into account his/her age).
13. As per investigator’s medical evaluation, is able to drink and tolerate oral fluids
and medication. |
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| E.4 | Principal exclusion criteria |
1. Has been previously enrolled in this study (ie, subjects enrolled in part 1 may not be enrolled in part 2 or vice versa).
2. The qualifying surgery involves a large body cavity (e.g. opening the abdominal, cardiac, or thoracic cavities and intervention of the organs therein).
3. The qualifying surgery required prolonged ventilation and/or intensive care.
4. The qualifying surgery is upper or lower airway surgery.
5. The qualifying surgery is brain surgery.
6. Has significant pulmonary, gastrointestinal, endocrine, metabolic, neurological, psychiatric disorders or any other clinically significant disease that in the Investigator's opinion may affect or compromise subject safety during the trial participation.
7. Paralytic ileus.
8. Fever within 1 week prior to tapentadol administration.
9. Mentally retarded, cognitively impaired or unable to comprehensively understand or follow the study instructions, as per investigator’s judgment or based on medical history
10. Subjects currently taking medications that may be associated with the occurrence of serotonin syndrome or seizures.
11. Subjects with conditions that may be associated with the occurrence of serotonin syndrome or seizures.
12. History of any one of the following:
a. seizure disorder or epilepsy
b. serotonin syndrome
c. mild or moderate traumatic brain injury, stroke, transient ischemic attack,or brain neoplasm within 1 year of screening
d. severe traumatic brain injury (consisting of 1 or more of the following: brain contusion; intracranial hematoma; or episode(s) of more than 24 hours duration of unconsciousness or posttraumatic amnesia) within 15 years of screening
e. Any traumatic or hypoxic brain injury resulting in ongoing sequelae suggesting transient changes in consciousness or symptoms suggestive thereof
f. moderate to severe renal or hepatic impairment
g. abnormal pulmonary function or respiratory disease (e.g., clinically relevant respiratory depression, acute or severe bronchial asthma, hypercapnia)
13. Has clinically relevant abnormal values for chemistry, hematology, or urinalysis
laboratory results at screening. The following specifications will apply:
a. >2 x ULN for AST or ALT,
b. >1.5 x ULN for total bilirubin,
c. >2 x ULN for creatinine,
d. other parameters as per the investigator’s judgment.
14. Has clinically relevant abnormal ECG as per the investigator’s judgment.
15. Requires concomitant use of sedatives, other than those used during surgery (diphenhydramine administered for itching is exempted from this requirement).
16. Has had postoperative analgesia supplied by a continuous regional technique (ie. “nerve block”)or
subject-controlled epidural analgesia.
17. Has a history of alcohol and/or drug abuse in the investigator’s judgment, based
on subject’s history and physical examination. 18. Has received an experimental drug or used an experimental medical device within 30 days prior to study drug administration, or within a period less than 10 timesthe drug’s half-life, whichever is longer.
19. Has received a potent inducer of hepatic drug-metabolizing enzyme activity (eg, phenobarbital and rifampin) or neuroleptics, MAOIs, SSRIs, SNRIs,
TCAs, triptans, anticonvulsants, antiparkinsonian drugs, and any drug that impairs metabolism of serotonin within 14 days before the scheduled study drug administration.
20. Has received dextromethorphan within 2 days before the scheduled study drug administration.
21. Has had previous exposure to tapentadol.
22. Has a clinically relevant history of hypersensitivity, allergy, or contraindication to heparin, morphine, paracetamol/acetaminophen (or ingredients) or Tapentadol ingredients (see IB).
23. Has clinically unstable vital signs and/or clinically unstable upper or lower airway conditions and/or an arterial oxygen saturation (SaO2) lower than 93%.
24. Is an employee of the investigator or study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center, or family member of the employees or the investigator. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary objective is to evaluate the PK profile of Tapentadol and its major metabolite Tapentadol-O-glucuronide after administration of a single dose of Tapentadol oral solution 1 mg/kg in children and adolescents aged from 6 to less than 18 years after scheduled surgical procedures that routinely produce acute, moderate to severe postsurgical pain. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| PK samples will be taken post-dose at +15m, +30m, +1h, +2h, +4h, +6h, +11h, and +15h |
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| E.5.2 | Secondary end point(s) |
| Safety and tolerability will be evaluated and the measurement of pain intensity will be explored. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Safety and tolerability will be evaluated continuously. Pain Intensity measurement will be performed as follows: immediately before PK blood sampling (+15m, +30m, +1h, +2h, +4h, +6h, +11h, and +15h) and prior to any supplemental analgesic medication. |
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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 | 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.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
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| 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
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| 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.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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