A Study to Look at Tapentadol Oral Solution in Children and Adolescents in Pain
Condition: Acute Pain
MeSH terms: Acute Pain
Intervention: Tapentadol oral solution 4 mg/mL; Tapentadol oral solution 20 mg/mL; Placebo
Intervention description: Participants aged 6 months to less than 18 years old with a body weight below 20 kg received tapentadol oral solution 4 mg/mL by mouth every 4 hours for up to 72 hours.
Participants from birth to less than 6 months received tapentadol oral solution, diluted 4 fold.; Participants aged from 6 months to less than 18 years with a body weight greater than or equal to 20 kg received tapentadol oral solution 20 mg/mL by mouth every 4 hours for up to 72 hours.; Matching placebo oral solution was administered by mouth every 4 hours up to 72 hours.
Intervention MeSH terms: Tapentadol; Pharmaceutical Solutions
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: The trial was double-blinded to prevent bias. The blind was broken for the participants aged 2 years to <18 years (Pediatric Committee of the European Medicines Agency [EU PDCO] set) before recruitment of the <6 month-old subjects for the United Sates Food and Drug Administration (US FDA) set (which comprised participants from birth to <18 years) was completed. Participants not belonging to the EU PDCO set (<2 years old) remained blinded (as independent randomization lists were used for participants aged <2 years old) and were unblinded only after the data base was locked for all participants from birth to <2 years old who were included in the US FDA <2 years population.
Enrollment: 216.0
Sex: All
Minimum age: 1 Day
Maximum age: 18 Years
Healthy volunteers: No
Keywords: Acute Pain; Post-operative; Tapentadol; Opioid Treatment; Pediatric Participants

Summary:

      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.
    

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.