A Study to Look at Tapentadol Oral Solution in Children and Adolescents in Pain

The purpose of the study was to evaluate the efficacy of tapentadol oral solution, based on the total amount of supplemental opioid analgesic used over 12 hours or 24 hours after initiation of investigational medicinal product (IMP) in children and adolescents who had undergone surgery that would produce moderate to severe pain during opioid treatment.

The supplemental opioid medication reflecting the standard of care was available as patient- or nurse-controlled intravenous (i.v.) morphine or hydromorphone. This supplemental opioid analgesic medication (SOAM) was given to control pain, as needed, in both the treatment and placebo groups.

Children and adolescents 6 months and older were dosed with a dose regimen of 1.25 mg/kg body weight for the first 24 hours of treatment. 24 hours after the start of study medication (and based on clinical judgment), a dose reduction to 1.0 mg/kg was allowed.

Participants 30 days to less than 6 months old were dosed with a regimen of 0.5 mg/kg for the first 24 hours of treatment. The dose of IMP could be reduced after 24 hours to 0.3 mg/kg (if there was a reduced need for analgesia according to the investigator's judgment).

Participants aged from birth to less than 30 days old were dosed with a regimen of 0.1 mg/kg for the first 24 hours of treatment. The dose of the IMP could be reduced after 24 hours to 0.075 mg/kg (if there was a reduced need for analgesia according to the investigator's judgment).

The decision to maintain or alter the dose based on the effectiveness of the analgesia (pain killer) and the adverse event profile observed in each participant over the first 24-hour dosing period was made based on the investigator's judgment.

In exceptional cases, if a participant had unbearable pain despite using nurse-controlled analgesia (NCA) or patient-controlled analgesia (PCA), an additional bolus (defined as a clinician bolus) of morphine or hydromorphone could have been administered. The clinician bolus could have been given either using the NCA/PCA pump system or by an intravenous bolus injection. The opioid given as a clinician bolus or if the NCA/PCA intravenous line failed, had to be the same opioid used in the NCA/PCA pump system.

Dosing with IMP was stopped if:

* A switch to exclusively oral opioid analgesic medication was indicated according to the local standard of care.
* Opioid analgesic medication was no longer needed.
* IMP had been administered for 72 hours.

Safety evaluations included assessment of adverse events, physical examination, vital signs, laboratory parameters, electrocardiogram, oxygen saturation, and, only for children older than 6 years of age, a scale to assess suicidal ideation (Columbia Suicide Severity Rating Scale \[C-SSRS\]). The maximum study duration for each participant was 42 days.

The evaluation of the safety and efficacy data was performed by age groups as aligned with European and United States agencies. Within the tapentadol treatment group, no analysis by tapentadol dose was conducted. Results for participants aged 2 years to \<18 years were provided to the Pediatric Committee of the European Medicines Agency (EU PDCO) before recruitment of the children less than 6-month old required for the US Food and Drug Administration \[FDA\] analysis was completed. Participants from birth to \<2 years old were analyzed separately for the US FDA only and not included in the analysis of the population aged from 2 years to \<18 years.

Eligibility Criteria:
Inclusion Criteria:

1. Informed consent, and if applicable assent, given according to local regulations.
2. Male or female participant aged from birth (at least 37 weeks gestational age) to less than 18 years.
3. A female participant must be pre-menarchal, or surgically incapable of childbearing, or sexually abstinent, or if a female participant 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 participant must have a negative pregnancy test if aged 12 years or older, or is post-menarchal, or is sexually active.
5. Participant 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. Participants must remain hospitalized until the End of Treatment Visit.
6. Participant 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 participant is expected to require this morphine or hydromorphone by NCA/PCA after starting IMP.
7. Participant is able to tolerate liquids at the time of allocation/randomization to IMP.

Exclusion Criteria:

1. Participant, 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. Participant has been previously exposed to tapentadol.
3. Participant 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. Participant 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. Participant 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. Participant 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 participant safety during the study participation.
7. Participant has history of suicidal ideation or behavior.
8. Participant is obese in the investigator's judgment. Obesity can be determined based on appropriate body mass index (BMI) charts or tables; e.g., a BMI above the 97th percentile for children based on the World Health Organization growth charts or the participant's weight is less than 2500 grams.
9. Participant has a clinically relevant history of hypersensitivity, allergy, or contraindication to the supplemental opioid analgesic medication or tapentadol, or the excipients, or naloxone.
10. Participant is not able to understand and comply with the protocol as appropriate for the age of the participant or participant is cognitively impaired in the investigator's judgment such that they cannot comply with the protocol
11. Participant has a history of alcohol and/or substance abuse in the investigator's judgment based on participant's history and physical examination.
12. Participant is taking prohibited concomitant medication.
13. Participant has received a long-acting opioid for the treatment of pain following surgery within 6 hours of allocation/randomization to IMP.
14. Participant has clinically relevant (in the investigator's judgment) abnormal values for clinical chemistry or hematology (local laboratory sample taken after surgery).

    A participant aged 6 months to less than 18 years old is excluded if the:
    * Aspartate transaminase or alanine transaminase is greater 3-times upper limit of normal.
    * Total bilirubin is greater 2-times upper limit of normal (except if the cause is due to Gilbert's syndrome).
    * Glomerular filtration rate less than 60 mL/min.

    A participant 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 participants \<1 week post-partum.
      * \<30 mL/min/1.73 m2 for participants 1 week to 8 weeks post-partum.
      * \<50 mL/min/1.73 m2 for participants \>8 weeks postpartum to \<6 months old.
15. Participant has:

    * Clinically relevant abnormal electrocardiogram (ECG).
    * Signs of pre-excitation syndrome.
    * Brugada's syndrome.
    * QT or corrected QT interval (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 participant-controlled epidural analgesia that was terminated less than 6 hours before allocation/randomization to IMP.
17. Participant 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 participant is breast-feeding a child.
19. Participant requires continuous positive airway pressure or mechanical ventilation, at the time of allocation to IMP.
20. The mother of a newborn participant or the breastfeeding mother of a participant was administered a prohibited medication.