Acute Pain
Conditions
Keywords
Acute Pain, Post-operative, Tapentadol, Opioid Treatment, Pediatric Participants
Brief 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.
Detailed description
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.
Interventions
DRUGTapentadol oral solution 4 mg/mL
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.
DRUGTapentadol oral solution 20 mg/mL
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.
OTHERPlacebo
Matching placebo oral solution was administered by mouth every 4 hours up to 72 hours.
Sponsors
Depomed
Grünenthal GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, 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.
Eligibility
Sex/Gender
ALL
Age
1 Days to 18 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| For the US FDA: The Total Amount of Supplemental Opioid Analgesic Medication Used Within the First 12 Hours After First Intake of Investigational Medicinal Product (IMP) [Tapentadol Oral Solution or Placebo] | Up to 12 hours | The primary endpoint for the United States Food and Drug Administration (US FDA) (and secondary endpoint for the Pediatric Committee of the European Medicines Agency \[EU PDCO\]) was the total amount of supplemental opioid analgesic medication (SOAM) used in the Full Analysis Set (from 2 years to \<18 years old) within 12 hours after first intake of IMP. SOAM use is expressed in mg/kg of morphine i.v. equivalents. |
| For the EU PDCO: The Total Amount of Supplemental Opioid Analgesic Medication Used Within the First 24 Hours After First Intake of IMP [Tapentadol Oral Solution or Placebo] | Up to 24 hours | The primary endpoint for the EU PDCO (and secondary endpoint for the US FDA) was the total amount of supplemental opioid analgesic medication (SOAM) used in the Full Analysis Set (from 2 years to \<18 years old) within 24 hours after first intake of IMP. SOAM use is expressed in mg/kg of morphine i.v. equivalents. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Palatability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale | Up to 96 hours | Palatability of IMP after the first dose was assessed in participants aged 2 years to less than 18 years using 5-point hedonic scales in combination with verbal rating. A question How does the medication taste was asked and the verbal rating was from really good, good, a bit good/a bit bad, bad, and really bad. The pictorial scale of facial expressions was co-related with verbal rating range where 5 = really good, 4 = good, 3 = a bit good/a bit bad, 2 = bad, and 1 = really bad. Higher scores represent good palatability. Responses were summarized. Missing values were not imputed. Palatability data was not collected for participants \<2 years old. |
| Acceptability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale | Up to 96 hours | Acceptability of IMP in participants aged 2 years to less than 18 years was assessed using 5-point hedonic scales in combination with verbal rating. A question Swallowing the medication is... was asked and the verbal rating was from really good, good, a bit good/a bit bad, bad, and really bad. The pictorial scale of facial expressions was co-related with verbal rating range, with 5 = really easy, 4 = easy, 3 = a bit easy/a bit difficult, 2 = difficult, and 1 = really difficult. Higher scores represent better acceptability. Responses were summarized. Missing values were not imputed. Acceptability data was not collected in participants \<2 years old. |
| Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Up to 96 hours | The FLACC scale was used for children from birth to less than 6 years, or in older children who were not able to report their pain using the other scales. This tool includes 5 categories of pain behaviors: facial expression (F), leg movement (L), activity (A), cry (C), and consolability (C). Each of the 5 categories is scored 0, 1 or 2. The total score between 0 and 10 is the sum of the 5 individual categories. Higher scores represent worse condition. The Pain intensity scores were obtained before and after first dose of IMP, and before each subsequent dose of IMP, whenever possible, up to end of treatment (96 hours). Changes from baseline values were summarized descriptively for each time point. |
| Change From Baseline Pain Intensity Using the Faces Pain Scale-Revised (FPS-R) in Participants Aged 6 to Less Than 12 Years | Up to 96 hours | For children aged 6 years (if possible) to less than 12 years, pain intensity was assessed by the use of the Faces Pain Scale-Revised (FPS-R). The FPS-R is a validated self-reported 6-point scale (0, 2, 4, 6, 8, 10) with 0 representing no pain and 10 representing very much pain. Facial representations were used to indicate how much the pain hurts. Higher scores represent worse condition. Pain intensity scores were obtained before and after first dose of IMP, and before each subsequent dose of IMP, whenever possible. Changes from baseline pain values were summarized descriptively for each time point up to end of treatment (96 hours). |
| Change From Baseline in the Visual Analog Scale (VAS) Pain Intensity Score in Participants Aged 12 to Less Than 18 Years | Up to 96 hours | For children and adolescents aged 12 years to less than 18 years, pain intensity was assessed by the use of a Visual analog scale (VAS). The participant was asked to draw a single line to indicate the current level of pain intensity on a 100 mm long scale by marking a point on the line in response to: My pain right now is. The mark was scored between no pain and pain as bad as it could be. A value of 0 indicates no pain. A value of 100 indicates pain as bad as it could be. Pain intensity scores were obtained before and after first dose of IMP, and before each subsequent dose of IMP, whenever possible. Changes from baseline values were summarized descriptively for each time point. |
| Patient Global Impression of Change (PGIC) | Day 4 | The PGIC was assessed at the End of Treatment Visit (Day 4). Participants rated their impression of overall status on a 7-point scale with 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. Higher scores indicate worsening. If participants were not capable of completing the questionnaire, the parent/legal guardian could completed the questionnaire on behalf of the participant. Results were summarized descriptively. |
| Time to Receive First and Second Patient- or Nurse-controlled Analgesia After the First Dose of IMP | Up to 96 hours | The time to first and time to second patient-controlled analgesia (PCA) or nurse-controlled analgesia (NCA) after the first dose of IMP were summarized descriptively using time-to-event methods and are displayed by relevant treatment groups. Participants who completed the End of Treatment Visit (scheduled for 96 hours after first IMP) before their first/second use of NCA/PCA or participants who terminated treatment before their first/second use of NCA/PCA were censored at the End of Treatment Visit. Time-to-event variables are reported using Kaplan-Meier analyses. Therefore, values might remain missing if the survival function does not reach a respective threshold. This is indicated by not applicable (NA). |
| Time From First Dose of IMP Until Treatment Discontinuation Due to Lack of Efficacy | Up to 72 hours | The distributions of the time from the first dose of IMP to treatment discontinuation due to lack of efficacy were summarized descriptively using time-to-event methods. Participants who reached the maximum duration of treatment (72 hours) were censored at 72 hours after first IMP intake. Participants who discontinued during the Treatment Period for reasons other than lack of efficacy were censored at the time of the decision to discontinue treatment. Due to the low number of participants with events in the age group from 2 to \<18 years, the median time and the corresponding confidence interval could not be calculated. The number of participants who discontinued early due to lack of efficacy is presented instead. |
| Palatability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale | Up to 96 hours | Palatability of IMP after the last dose in participants aged 2 years to less than 18 years was assessed using 5-point hedonic scales in combination with verbal rating. A question How does the medication taste was asked and the verbal rating was from really good, good, a bit good/a bit bad, bad, and really bad. The pictorial scale of facial expressions was co-related with verbal rating range with 5 = really good, 4 = good, 3 = a bit good/a bit bad, 2 = bad, and 1 = really bad. Higher scores represent good palatability. Responses were summarized. Missing values were not imputed. Palatability data was not collected in participants \<2 years old. |
| Acceptability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale | Up to 96 hours | Acceptability of IMP in participants aged 2 years to less than 18 years was assessed using 5-point hedonic scales in combination with verbal rating. A question Swallowing the medication is... was asked and the verbal rating was from really good, good, a bit good/a bit bad, bad, and really bad. The pictorial scale of facial expressions was co-related with verbal rating range, with 5 = really easy, 4 = easy, 3 = a bit easy/a bit difficult, 2 = difficult, and 1 = really difficult. Higher scores represent better acceptability. Responses were summarized. Missing values were not imputed. Acceptability data was not collected in participants \<2 years old. |
| Clinical Global Impression of Change (CGIC) | Day 4 | The CGIC was assessed at the End of Treatment Visit (Day 4). The investigator rated the participant's global improvement and satisfaction with the treatment on a 7-point scale with 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. Higher scores indicate worsening. Results were summarized descriptively. |
| Total Amount of Supplemental Opioid Analgesic Medication Received, Assessed in 12-hour Intervals From 24 Hours to 96 Hours After the First Dose of IMP | Up to 96 hours | The total amount of supplemental opioid analgesic medication (SOAM) received was assessed in 12-hour intervals from 24 hours to 96 hours after the first dose of IMP for participants who were administered SOAM. SOAM use was expressed in mg/kg of morphine i.v. equivalents. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Mean Amount of Supplemental Opioid Analgesic Medication Use After First Intake of Investigational Medicinal Product in Children Aged From Birth to Less Than 2 Years | Up to 24 hours | The mean amount of supplemental opioid analgesic medication (SOAM) used in the Full Analysis Set subset aged from birth to less than 2 years old was determined from 0 to 12 hours and from 0 to 24 hours after first intake of IMP. SOAM use is expressed in mg/kg of morphine i.v. equivalents. |
| Median Amount of Supplemental Opioid Analgesic Medication Use After First Intake of Investigational Medicinal Product in Children Aged From Birth to Less Than 2 Years | Up to 24 hours | The median amount of supplemental opioid analgesic medication (SOAM) used in the Full Analysis Set subset aged from birth to less than 2 years old was determined from 0 to 12 hours and from 0 to 24 hours after first intake of IMP. SOAM use is expressed in mg/kg of morphine i.v. equivalents. |
Countries
Bulgaria, Croatia, Czechia, France, Germany, Hungary, Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
The trial started on 19 Feb 2015 with the enrollment of the first participant. Recruitment of participants aged 2 to \<18 years old was completed on 05 Dec 2016 with the last participant out. Recruitment of the remaining participants aged from birth to \<2 years old was completed on 14 Mar 2019.
Pre-assignment details
A total of 216 participants (or parents/caregivers) gave informed consent to participate in the trial, 180 of these participants were allocated to study drug (investigational medicinal product = IMP) and 175 participants received IMP (56 participants received placebo oral solution and 119 participants received tapentadol oral solution).
Participants by arm
| Arm | Count |
|---|---|
| Tapentadol (From 2 to <18 Years) - 12-h Treatm. Completion Participants had undergone surgery that, in the investigator's opinion, would reliably produce moderate to severe pain requiring opioid treatment via NCA or PCA.
This arm includes all participants aged 2 years to less than 18 years who received at least 1 dose of tapentadol oral solution.
12-hour treatment period completers were defined as participants who did not discontinue the treatment period before 12 hours. | 108 |
| Placebo (From 2 to <18 Years) - 12-h Treatm. Completion Participants had undergone surgery that, in the investigator's opinion, would reliably produce moderate to severe pain requiring opioid treatment via NCA or PCA.
This arm includes all participants aged 2 years to less than 18 years who received at least 1 dose of placebo.
12-hour treatment period completers were defined as participants who did not discontinue the treatment period before 12 hours. | 52 |
| Tapentadol (From Birth to <2 Years) - 12-h Treatm. Completion Participants had undergone surgery that, in the investigator's opinion, would reliably produce moderate to severe pain requiring opioid treatment via NCA.
This arm includes all participants aged from birth (at least 37 weeks gestational age) to less than 2 years who received at least 1 dose of tapentadol oral solution.
12-hour treatment period completers were defined as participants who did not discontinue the treatment period before 12 hours. | 11 |
| Placebo (From Birth to <2 Years) - 12-h Treatm. Completion Participants had undergone surgery that, in the investigator's opinion, would reliably produce moderate to severe pain requiring opioid treatment via NCA.
This arm includes all participants aged from birth (at least 37 weeks gestational age) to less than 2 years who received at least 1 dose of placebo.
12-hour treatment period completers were defined as participants who did not discontinue the treatment period before 12 hours. | 4 |
| Total | 175 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| 12-hour Treatment | Adverse Event | 4 | 2 | 0 | 0 |
| 12-hour Treatment | Further reasons | 2 | 1 | 0 | 0 |
| 12-hour Treatment | Lack of Efficacy | 3 | 0 | 0 | 0 |
| 12-hour Treatment | Physician Decision | 4 | 1 | 0 | 0 |
| 12-hour Treatment | Recovery (opioid no longer needed) | 2 | 0 | 1 | 0 |
| 12-hour Treatment | Withdrawal by Subject | 3 | 2 | 0 | 0 |
| 24-hour Treatment and Trial Completion | Adverse Event | 1 | 0 | 0 | 0 |
| 24-hour Treatment and Trial Completion | Further reasons | 3 | 4 | 0 | 0 |
| 24-hour Treatment and Trial Completion | Lack of Efficacy | 1 | 3 | 0 | 0 |
| 24-hour Treatment and Trial Completion | Physician Decision | 10 | 5 | 0 | 0 |
| 24-hour Treatment and Trial Completion | Recovery (opioid no longer needed) | 11 | 5 | 1 | 0 |
| 24-hour Treatment and Trial Completion | Technical Problems | 1 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo (From 2 to <18 Years) - 12-h Treatm. Completion | Tapentadol (From Birth to <2 Years) - 12-h Treatm. Completion | Tapentadol (From 2 to <18 Years) - 12-h Treatm. Completion | Placebo (From Birth to <2 Years) - 12-h Treatm. Completion | Total |
|---|---|---|---|---|---|
| Age, Continuous | 10.4 years | 0.74 years | 10.8 years | 0.48 years | 9.81 years |
| Age, Customized 28 days to less than 2 years | 0 Participants | 9 Participants | 0 Participants | 3 Participants | 12 Participants |
| Age, Customized Adolescents (12 to <18 years) | 25 Participants | 0 Participants | 53 Participants | 0 Participants | 78 Participants |
| Age, Customized Birth to less than 28 days | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| Age, Customized Children (2 to <12 years) | 27 Participants | 0 Participants | 55 Participants | 0 Participants | 82 Participants |
| Amount of morphine or hydromorphone taken prior to IMP | 0.45 mg/kg | 0.26 mg/kg | 0.59 mg/kg | 0.3 mg/kg | 0.52 mg/kg |
| Body Mass Index | 19.12 kg per square meter | 14.95 kg per square meter | 18.83 kg per square meter | 14.73 kg per square meter | 18.58 kg per square meter |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 0 Participants | 21 Participants | 0 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 38 Participants | 10 Participants | 80 Participants | 3 Participants | 131 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 1 Participants | 7 Participants | 1 Participants | 14 Participants |
| Height | 143.3 centimeter | 71.8 centimeter | 145 centimeter | 65.3 centimeter | 138.1 centimeter |
| Region of Enrollment Bulgaria | 5 participants | 0 participants | 10 participants | 0 participants | 15 participants |
| Region of Enrollment Croatia | 2 participants | 0 participants | 8 participants | 1 participants | 11 participants |
| Region of Enrollment Czechia | 3 participants | 0 participants | 7 participants | 0 participants | 10 participants |
| Region of Enrollment France | 3 participants | 0 participants | 3 participants | 0 participants | 6 participants |
| Region of Enrollment Germany | 2 participants | 0 participants | 4 participants | 0 participants | 6 participants |
| Region of Enrollment Hungary | 3 participants | 1 participants | 4 participants | 1 participants | 9 participants |
| Region of Enrollment Poland | 5 participants | 9 participants | 20 participants | 2 participants | 36 participants |
| Region of Enrollment Spain | 3 participants | 0 participants | 6 participants | 0 participants | 9 participants |
| Region of Enrollment United Kingdom | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants |
| Region of Enrollment United States | 26 participants | 1 participants | 45 participants | 0 participants | 72 participants |
| Sex: Female, Male Female | 23 Participants | 5 Participants | 53 Participants | 2 Participants | 83 Participants |
| Sex: Female, Male Male | 29 Participants | 6 Participants | 55 Participants | 2 Participants | 92 Participants |
| Type of opioid analgesia used Hydromorphone | 18 Participants | 1 Participants | 33 Participants | 0 Participants | 52 Participants |
| Type of opioid analgesia used Morphine | 34 Participants | 10 Participants | 75 Participants | 4 Participants | 123 Participants |
| Weight | 42.22 kg | 7.97 kg | 43.09 kg | 6.63 kg | 39.79 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 160 | 0 / 108 | 0 / 52 | 0 / 15 | 0 / 11 | 0 / 4 |
| other Total, other adverse events | 87 / 160 | 61 / 108 | 26 / 52 | 9 / 15 | 6 / 11 | 3 / 4 |
| serious Total, serious adverse events | 2 / 160 | 2 / 108 | 0 / 52 | 0 / 15 | 0 / 11 | 0 / 4 |
Outcome results
Primary
For the EU PDCO: The Total Amount of Supplemental Opioid Analgesic Medication Used Within the First 24 Hours After First Intake of IMP [Tapentadol Oral Solution or Placebo]
The primary endpoint for the EU PDCO (and secondary endpoint for the US FDA) was the total amount of supplemental opioid analgesic medication (SOAM) used in the Full Analysis Set (from 2 years to \<18 years old) within 24 hours after first intake of IMP. SOAM use is expressed in mg/kg of morphine i.v. equivalents.
Time frame: Up to 24 hours
Population: Full Analysis Set; subset of 160 participants from 2 to less than 18 years included in the analysis; if by error a participant did not receive the allocated medication, the participant was evaluated as allocated following the intention-to-treat principle.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tapentadol (From 2 to <18 Years) | For the EU PDCO: The Total Amount of Supplemental Opioid Analgesic Medication Used Within the First 24 Hours After First Intake of IMP [Tapentadol Oral Solution or Placebo] | 0.14 mg/kg | Standard Error 0.03 |
| Placebo (From 2 to <18 Years) | For the EU PDCO: The Total Amount of Supplemental Opioid Analgesic Medication Used Within the First 24 Hours After First Intake of IMP [Tapentadol Oral Solution or Placebo] | 0.24 mg/kg | Standard Error 0.03 |
Comparison: The endpoint was analyzed using an analysis of variance model. This included treatment, baseline age group, and the used supplemental opioid analgesic medication (SOAM) as factors. For participants discontinuing treatment before 24 hours for any other reason than no further need of SOAM or switch to exclusively oral opioid analgesics, cumulative SOAM use over the respective time period was based on the observed SOAM use up to the time of the participant's discontinuation.p-value: 0.015495% CI: [-0.18, -0.02]ANOVA
Primary
For the US FDA: The Total Amount of Supplemental Opioid Analgesic Medication Used Within the First 12 Hours After First Intake of Investigational Medicinal Product (IMP) [Tapentadol Oral Solution or Placebo]
The primary endpoint for the United States Food and Drug Administration (US FDA) (and secondary endpoint for the Pediatric Committee of the European Medicines Agency \[EU PDCO\]) was the total amount of supplemental opioid analgesic medication (SOAM) used in the Full Analysis Set (from 2 years to \<18 years old) within 12 hours after first intake of IMP. SOAM use is expressed in mg/kg of morphine i.v. equivalents.
Time frame: Up to 12 hours
Population: Full Analysis Set; subset of 160 participants from 2 to less than 18 years included in the analysis. If by error a participant did not receive the allocated medication, the participant was evaluated as allocated following the intention-to-treat principle.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tapentadol (From 2 to <18 Years) | For the US FDA: The Total Amount of Supplemental Opioid Analgesic Medication Used Within the First 12 Hours After First Intake of Investigational Medicinal Product (IMP) [Tapentadol Oral Solution or Placebo] | 0.08 mg/kg | Standard Error 0.01 |
| Placebo (From 2 to <18 Years) | For the US FDA: The Total Amount of Supplemental Opioid Analgesic Medication Used Within the First 12 Hours After First Intake of Investigational Medicinal Product (IMP) [Tapentadol Oral Solution or Placebo] | 0.13 mg/kg | Standard Error 0.02 |
Comparison: The endpoint was analyzed using an analysis of variance model. This included treatment, baseline age group, and the used SOAM as factors. For participants discontinuing treatment before 12 hours for any other reason than no further need of opioid analgesics or switch to exclusively oral opioid analgesics, cumulative SOAM use over the respective time period was based on the observed SOAM use up to the time of the participant's discontinuation.p-value: 0.040495% CI: [-0.09, 0]ANOVA
Secondary
Acceptability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale
Acceptability of IMP in participants aged 2 years to less than 18 years was assessed using 5-point hedonic scales in combination with verbal rating. A question Swallowing the medication is... was asked and the verbal rating was from really good, good, a bit good/a bit bad, bad, and really bad. The pictorial scale of facial expressions was co-related with verbal rating range, with 5 = really easy, 4 = easy, 3 = a bit easy/a bit difficult, 2 = difficult, and 1 = really difficult. Higher scores represent better acceptability. Responses were summarized. Missing values were not imputed. Acceptability data was not collected in participants \<2 years old.
Time frame: Up to 96 hours
Population: Full Analysis Set: subset of 160 participants aged from 2 years to \<18 years included in the analysis. If by error a participant did not receive the allocated medication, the participant was evaluated as allocated following the intention-to-treat principle.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tapentadol (From 2 to <18 Years) | Acceptability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale | Really difficult | 1 Participants |
| Tapentadol (From 2 to <18 Years) | Acceptability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale | Difficult | 7 Participants |
| Tapentadol (From 2 to <18 Years) | Acceptability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale | A bit difficult/a bit easy | 17 Participants |
| Tapentadol (From 2 to <18 Years) | Acceptability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale | Easy | 46 Participants |
| Tapentadol (From 2 to <18 Years) | Acceptability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale | Really easy | 35 Participants |
| Tapentadol (From 2 to <18 Years) | Acceptability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale | Missing | 2 Participants |
| Placebo (From 2 to <18 Years) | Acceptability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale | Really easy | 19 Participants |
| Placebo (From 2 to <18 Years) | Acceptability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale | Really difficult | 0 Participants |
| Placebo (From 2 to <18 Years) | Acceptability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale | Easy | 20 Participants |
| Placebo (From 2 to <18 Years) | Acceptability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale | Difficult | 3 Participants |
| Placebo (From 2 to <18 Years) | Acceptability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale | Missing | 3 Participants |
| Placebo (From 2 to <18 Years) | Acceptability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale | A bit difficult/a bit easy | 7 Participants |
Secondary
Acceptability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale
Acceptability of IMP in participants aged 2 years to less than 18 years was assessed using 5-point hedonic scales in combination with verbal rating. A question Swallowing the medication is... was asked and the verbal rating was from really good, good, a bit good/a bit bad, bad, and really bad. The pictorial scale of facial expressions was co-related with verbal rating range, with 5 = really easy, 4 = easy, 3 = a bit easy/a bit difficult, 2 = difficult, and 1 = really difficult. Higher scores represent better acceptability. Responses were summarized. Missing values were not imputed. Acceptability data was not collected in participants \<2 years old.
Time frame: Up to 96 hours
Population: Full Analysis Set; 160 participants aged 2 to less than 18 years were included in the analysis. If by error a participant did not receive the allocated medication, the participant was evaluated as allocated following the intention-to-treat principle.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tapentadol (From 2 to <18 Years) | Acceptability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale | Really difficult | 3 Participants |
| Tapentadol (From 2 to <18 Years) | Acceptability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale | Difficult | 6 Participants |
| Tapentadol (From 2 to <18 Years) | Acceptability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale | A bit difficult/a bit easy | 9 Participants |
| Tapentadol (From 2 to <18 Years) | Acceptability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale | Easy | 43 Participants |
| Tapentadol (From 2 to <18 Years) | Acceptability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale | Really easy | 39 Participants |
| Tapentadol (From 2 to <18 Years) | Acceptability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale | Missing | 8 Participants |
| Placebo (From 2 to <18 Years) | Acceptability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale | Really easy | 20 Participants |
| Placebo (From 2 to <18 Years) | Acceptability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale | Really difficult | 0 Participants |
| Placebo (From 2 to <18 Years) | Acceptability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale | Easy | 18 Participants |
| Placebo (From 2 to <18 Years) | Acceptability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale | Difficult | 2 Participants |
| Placebo (From 2 to <18 Years) | Acceptability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale | Missing | 6 Participants |
| Placebo (From 2 to <18 Years) | Acceptability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale | A bit difficult/a bit easy | 6 Participants |
Secondary
Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years
The FLACC scale was used for children from birth to less than 6 years, or in older children who were not able to report their pain using the other scales. This tool includes 5 categories of pain behaviors: facial expression (F), leg movement (L), activity (A), cry (C), and consolability (C). Each of the 5 categories is scored 0, 1 or 2. The total score between 0 and 10 is the sum of the 5 individual categories. Higher scores represent worse condition. The Pain intensity scores were obtained before and after first dose of IMP, and before each subsequent dose of IMP, whenever possible, up to end of treatment (96 hours). Changes from baseline values were summarized descriptively for each time point.
Time frame: Up to 96 hours
Population: Full Analysis Set: subset of 51 participants aged from birth to \<6 years included in the analysis; participants with missing data were excluded from calculations. No standard deviations were derived for less than 5 participants.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Tapentadol (From 2 to <18 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 8th dose of IMP | 1.2 score on a scale |
| Tapentadol (From 2 to <18 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 3rd dose of IMP | 1.7 score on a scale |
| Tapentadol (From 2 to <18 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | 30-60 mins after 1st IMP | 1.1 score on a scale |
| Tapentadol (From 2 to <18 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 4th dose of IMP | 1.4 score on a scale |
| Tapentadol (From 2 to <18 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 7th dose of IMP | 1.6 score on a scale |
| Tapentadol (From 2 to <18 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 5th dose of IMP | 1.8 score on a scale |
| Tapentadol (From 2 to <18 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | At End of Treatment | 2.4 score on a scale |
| Tapentadol (From 2 to <18 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 6th dose of IMP | 1.6 score on a scale |
| Tapentadol (From 2 to <18 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 2nd dose of IMP | 1.4 score on a scale |
| Placebo (From 2 to <18 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 7th dose of IMP | 2.1 score on a scale |
| Placebo (From 2 to <18 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 3rd dose of IMP | 1.6 score on a scale |
| Placebo (From 2 to <18 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 8th dose of IMP | 2.2 score on a scale |
| Placebo (From 2 to <18 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | At End of Treatment | 2.0 score on a scale |
| Placebo (From 2 to <18 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | 30-60 mins after 1st IMP | 1.9 score on a scale |
| Placebo (From 2 to <18 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 2nd dose of IMP | 1.3 score on a scale |
| Placebo (From 2 to <18 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 4th dose of IMP | 1.3 score on a scale |
| Placebo (From 2 to <18 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 5th dose of IMP | 1.9 score on a scale |
| Placebo (From 2 to <18 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 6th dose of IMP | 2.3 score on a scale |
| Tapentadol (From Birth to <2 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 6th dose of IMP | 2.0 score on a scale |
| Tapentadol (From Birth to <2 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 5th dose of IMP | 1.4 score on a scale |
| Tapentadol (From Birth to <2 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 3rd dose of IMP | 2.0 score on a scale |
| Tapentadol (From Birth to <2 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 2nd dose of IMP | 0.7 score on a scale |
| Tapentadol (From Birth to <2 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 7th dose of IMP | 1.9 score on a scale |
| Tapentadol (From Birth to <2 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | At End of Treatment | 2.1 score on a scale |
| Tapentadol (From Birth to <2 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 4th dose of IMP | 1.3 score on a scale |
| Tapentadol (From Birth to <2 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 8th dose of IMP | 3.8 score on a scale |
| Tapentadol (From Birth to <2 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | 30-60 mins after 1st IMP | 1.4 score on a scale |
| Placebo (From Birth to <2 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 3rd dose of IMP | -1.3 score on a scale |
| Placebo (From Birth to <2 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | 30-60 mins after 1st IMP | 2.8 score on a scale |
| Placebo (From Birth to <2 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 7th dose of IMP | 2.0 score on a scale |
| Placebo (From Birth to <2 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 2nd dose of IMP | 1.0 score on a scale |
| Placebo (From Birth to <2 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 6th dose of IMP | 2.5 score on a scale |
| Placebo (From Birth to <2 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 4th dose of IMP | 0.0 score on a scale |
| Placebo (From Birth to <2 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 5th dose of IMP | 2.0 score on a scale |
| Placebo (From Birth to <2 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | Before 8th dose of IMP | -0.5 score on a scale |
| Placebo (From Birth to <2 Years) | Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years | At End of Treatment | 3.5 score on a scale |
Secondary
Change From Baseline in the Visual Analog Scale (VAS) Pain Intensity Score in Participants Aged 12 to Less Than 18 Years
For children and adolescents aged 12 years to less than 18 years, pain intensity was assessed by the use of a Visual analog scale (VAS). The participant was asked to draw a single line to indicate the current level of pain intensity on a 100 mm long scale by marking a point on the line in response to: My pain right now is. The mark was scored between no pain and pain as bad as it could be. A value of 0 indicates no pain. A value of 100 indicates pain as bad as it could be. Pain intensity scores were obtained before and after first dose of IMP, and before each subsequent dose of IMP, whenever possible. Changes from baseline values were summarized descriptively for each time point.
Time frame: Up to 96 hours
Population: Full Analysis Set: subset of 78 participants aged from 12 to less than 18 years included in the analysis; participants with missing data are not included in the analysis. If by error a participant did not receive the allocated medication, the participant was evaluated as allocated following the intention-to-treat principle.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tapentadol (From 2 to <18 Years) | Change From Baseline in the Visual Analog Scale (VAS) Pain Intensity Score in Participants Aged 12 to Less Than 18 Years | 30-60 mins after 1st IMP | 8.0 units on a scale | Standard Deviation 18.67 |
| Tapentadol (From 2 to <18 Years) | Change From Baseline in the Visual Analog Scale (VAS) Pain Intensity Score in Participants Aged 12 to Less Than 18 Years | Before 6th dose of IMP | 13.0 units on a scale | Standard Deviation 24.74 |
| Tapentadol (From 2 to <18 Years) | Change From Baseline in the Visual Analog Scale (VAS) Pain Intensity Score in Participants Aged 12 to Less Than 18 Years | Before 3rd dose of IMP | 13.1 units on a scale | Standard Deviation 25.09 |
| Tapentadol (From 2 to <18 Years) | Change From Baseline in the Visual Analog Scale (VAS) Pain Intensity Score in Participants Aged 12 to Less Than 18 Years | Before 7th dose of IMP | 10.7 units on a scale | Standard Deviation 25.77 |
| Tapentadol (From 2 to <18 Years) | Change From Baseline in the Visual Analog Scale (VAS) Pain Intensity Score in Participants Aged 12 to Less Than 18 Years | Before 2nd dose of IMP | 6.5 units on a scale | Standard Deviation 23.61 |
| Tapentadol (From 2 to <18 Years) | Change From Baseline in the Visual Analog Scale (VAS) Pain Intensity Score in Participants Aged 12 to Less Than 18 Years | Before 8th dose of IMP | 12.2 units on a scale | Standard Deviation 28.91 |
| Tapentadol (From 2 to <18 Years) | Change From Baseline in the Visual Analog Scale (VAS) Pain Intensity Score in Participants Aged 12 to Less Than 18 Years | Before 4th dose of IMP | 8.8 units on a scale | Standard Deviation 29.01 |
| Tapentadol (From 2 to <18 Years) | Change From Baseline in the Visual Analog Scale (VAS) Pain Intensity Score in Participants Aged 12 to Less Than 18 Years | At End of Treatment | 11.0 units on a scale | Standard Deviation 27.87 |
| Tapentadol (From 2 to <18 Years) | Change From Baseline in the Visual Analog Scale (VAS) Pain Intensity Score in Participants Aged 12 to Less Than 18 Years | Before 5th dose of IMP | 13.0 units on a scale | Standard Deviation 22.92 |
| Placebo (From 2 to <18 Years) | Change From Baseline in the Visual Analog Scale (VAS) Pain Intensity Score in Participants Aged 12 to Less Than 18 Years | At End of Treatment | 11.4 units on a scale | Standard Deviation 28.47 |
| Placebo (From 2 to <18 Years) | Change From Baseline in the Visual Analog Scale (VAS) Pain Intensity Score in Participants Aged 12 to Less Than 18 Years | Before 4th dose of IMP | 5.1 units on a scale | Standard Deviation 21.7 |
| Placebo (From 2 to <18 Years) | Change From Baseline in the Visual Analog Scale (VAS) Pain Intensity Score in Participants Aged 12 to Less Than 18 Years | Before 2nd dose of IMP | 6.0 units on a scale | Standard Deviation 19.36 |
| Placebo (From 2 to <18 Years) | Change From Baseline in the Visual Analog Scale (VAS) Pain Intensity Score in Participants Aged 12 to Less Than 18 Years | Before 3rd dose of IMP | 5.9 units on a scale | Standard Deviation 22.11 |
| Placebo (From 2 to <18 Years) | Change From Baseline in the Visual Analog Scale (VAS) Pain Intensity Score in Participants Aged 12 to Less Than 18 Years | Before 5th dose of IMP | -2.7 units on a scale | Standard Deviation 34.4 |
| Placebo (From 2 to <18 Years) | Change From Baseline in the Visual Analog Scale (VAS) Pain Intensity Score in Participants Aged 12 to Less Than 18 Years | Before 6th dose of IMP | 6.6 units on a scale | Standard Deviation 28.4 |
| Placebo (From 2 to <18 Years) | Change From Baseline in the Visual Analog Scale (VAS) Pain Intensity Score in Participants Aged 12 to Less Than 18 Years | Before 7th dose of IMP | 15.0 units on a scale | Standard Deviation 20.27 |
| Placebo (From 2 to <18 Years) | Change From Baseline in the Visual Analog Scale (VAS) Pain Intensity Score in Participants Aged 12 to Less Than 18 Years | Before 8th dose of IMP | 11.9 units on a scale | Standard Deviation 14.6 |
| Placebo (From 2 to <18 Years) | Change From Baseline in the Visual Analog Scale (VAS) Pain Intensity Score in Participants Aged 12 to Less Than 18 Years | 30-60 mins after 1st IMP | 6.4 units on a scale | Standard Deviation 19.58 |
Secondary
Change From Baseline Pain Intensity Using the Faces Pain Scale-Revised (FPS-R) in Participants Aged 6 to Less Than 12 Years
For children aged 6 years (if possible) to less than 12 years, pain intensity was assessed by the use of the Faces Pain Scale-Revised (FPS-R). The FPS-R is a validated self-reported 6-point scale (0, 2, 4, 6, 8, 10) with 0 representing no pain and 10 representing very much pain. Facial representations were used to indicate how much the pain hurts. Higher scores represent worse condition. Pain intensity scores were obtained before and after first dose of IMP, and before each subsequent dose of IMP, whenever possible. Changes from baseline pain values were summarized descriptively for each time point up to end of treatment (96 hours).
Time frame: Up to 96 hours
Population: Full Analysis Set: subset of 46 participants aged from 6 to less than 12 years included in the analysis; participants with missing data are not included in the analysis. If by error a participant did not receive the allocated medication, the participant was evaluated as allocated following the intention-to-treat principle.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tapentadol (From 2 to <18 Years) | Change From Baseline Pain Intensity Using the Faces Pain Scale-Revised (FPS-R) in Participants Aged 6 to Less Than 12 Years | Before 2nd dose of IMP | 1.0 units on a scale | Standard Deviation 2.5 |
| Tapentadol (From 2 to <18 Years) | Change From Baseline Pain Intensity Using the Faces Pain Scale-Revised (FPS-R) in Participants Aged 6 to Less Than 12 Years | Before 6th dose of IMP | 0.5 units on a scale | Standard Deviation 2.43 |
| Tapentadol (From 2 to <18 Years) | Change From Baseline Pain Intensity Using the Faces Pain Scale-Revised (FPS-R) in Participants Aged 6 to Less Than 12 Years | Before 4th dose of IMP | 1.3 units on a scale | Standard Deviation 2.33 |
| Tapentadol (From 2 to <18 Years) | Change From Baseline Pain Intensity Using the Faces Pain Scale-Revised (FPS-R) in Participants Aged 6 to Less Than 12 Years | Before 7th dose of IMP | 2.0 units on a scale | Standard Deviation 2.37 |
| Tapentadol (From 2 to <18 Years) | Change From Baseline Pain Intensity Using the Faces Pain Scale-Revised (FPS-R) in Participants Aged 6 to Less Than 12 Years | Before 3rd dose of IMP | 1.0 units on a scale | Standard Deviation 2.35 |
| Tapentadol (From 2 to <18 Years) | Change From Baseline Pain Intensity Using the Faces Pain Scale-Revised (FPS-R) in Participants Aged 6 to Less Than 12 Years | Before 8th dose of IMP | 1.3 units on a scale | Standard Deviation 2.55 |
| Tapentadol (From 2 to <18 Years) | Change From Baseline Pain Intensity Using the Faces Pain Scale-Revised (FPS-R) in Participants Aged 6 to Less Than 12 Years | Before 5th dose of IMP | 0.8 units on a scale | Standard Deviation 2.75 |
| Tapentadol (From 2 to <18 Years) | Change From Baseline Pain Intensity Using the Faces Pain Scale-Revised (FPS-R) in Participants Aged 6 to Less Than 12 Years | At End of Treatment | 2.8 units on a scale | Standard Deviation 2.93 |
| Tapentadol (From 2 to <18 Years) | Change From Baseline Pain Intensity Using the Faces Pain Scale-Revised (FPS-R) in Participants Aged 6 to Less Than 12 Years | 30-60 mins after 1st IMP | 1.0 units on a scale | Standard Deviation 1.72 |
| Placebo (From 2 to <18 Years) | Change From Baseline Pain Intensity Using the Faces Pain Scale-Revised (FPS-R) in Participants Aged 6 to Less Than 12 Years | At End of Treatment | 3.4 units on a scale | Standard Deviation 3.56 |
| Placebo (From 2 to <18 Years) | Change From Baseline Pain Intensity Using the Faces Pain Scale-Revised (FPS-R) in Participants Aged 6 to Less Than 12 Years | 30-60 mins after 1st IMP | 0.7 units on a scale | Standard Deviation 1.86 |
| Placebo (From 2 to <18 Years) | Change From Baseline Pain Intensity Using the Faces Pain Scale-Revised (FPS-R) in Participants Aged 6 to Less Than 12 Years | Before 2nd dose of IMP | 0.5 units on a scale | Standard Deviation 2.84 |
| Placebo (From 2 to <18 Years) | Change From Baseline Pain Intensity Using the Faces Pain Scale-Revised (FPS-R) in Participants Aged 6 to Less Than 12 Years | Before 3rd dose of IMP | -0.2 units on a scale | Standard Deviation 2.17 |
| Placebo (From 2 to <18 Years) | Change From Baseline Pain Intensity Using the Faces Pain Scale-Revised (FPS-R) in Participants Aged 6 to Less Than 12 Years | Before 4th dose of IMP | -0.3 units on a scale | Standard Deviation 3.7 |
| Placebo (From 2 to <18 Years) | Change From Baseline Pain Intensity Using the Faces Pain Scale-Revised (FPS-R) in Participants Aged 6 to Less Than 12 Years | Before 5th dose of IMP | 0 units on a scale | Standard Deviation 2.19 |
| Placebo (From 2 to <18 Years) | Change From Baseline Pain Intensity Using the Faces Pain Scale-Revised (FPS-R) in Participants Aged 6 to Less Than 12 Years | Before 6th dose of IMP | 0.2 units on a scale | Standard Deviation 2.2 |
| Placebo (From 2 to <18 Years) | Change From Baseline Pain Intensity Using the Faces Pain Scale-Revised (FPS-R) in Participants Aged 6 to Less Than 12 Years | Before 7th dose of IMP | 0.7 units on a scale | Standard Deviation 2.24 |
| Placebo (From 2 to <18 Years) | Change From Baseline Pain Intensity Using the Faces Pain Scale-Revised (FPS-R) in Participants Aged 6 to Less Than 12 Years | Before 8th dose of IMP | 0.2 units on a scale | Standard Deviation 2.73 |
Secondary
Clinical Global Impression of Change (CGIC)
The CGIC was assessed at the End of Treatment Visit (Day 4). The investigator rated the participant's global improvement and satisfaction with the treatment on a 7-point scale with 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. Higher scores indicate worsening. Results were summarized descriptively.
Time frame: Day 4
Population: Full Analysis Set; 175 participants from birth to less than 18 years are included. If by error a participant did not receive the allocated medication, the participant was evaluated as allocated following the intention-to-treat principle.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tapentadol (From 2 to <18 Years) | Clinical Global Impression of Change (CGIC) | Missing | 2 Participants |
| Tapentadol (From 2 to <18 Years) | Clinical Global Impression of Change (CGIC) | Minimally worse | 3 Participants |
| Tapentadol (From 2 to <18 Years) | Clinical Global Impression of Change (CGIC) | Very much improved | 15 Participants |
| Tapentadol (From 2 to <18 Years) | Clinical Global Impression of Change (CGIC) | Much worse | 1 Participants |
| Tapentadol (From 2 to <18 Years) | Clinical Global Impression of Change (CGIC) | Much improved | 58 Participants |
| Tapentadol (From 2 to <18 Years) | Clinical Global Impression of Change (CGIC) | Minimally improved | 18 Participants |
| Tapentadol (From 2 to <18 Years) | Clinical Global Impression of Change (CGIC) | No change | 11 Participants |
| Tapentadol (From 2 to <18 Years) | Clinical Global Impression of Change (CGIC) | Very much worse | 0 Participants |
| Placebo (From 2 to <18 Years) | Clinical Global Impression of Change (CGIC) | Minimally improved | 8 Participants |
| Placebo (From 2 to <18 Years) | Clinical Global Impression of Change (CGIC) | Missing | 3 Participants |
| Placebo (From 2 to <18 Years) | Clinical Global Impression of Change (CGIC) | Minimally worse | 2 Participants |
| Placebo (From 2 to <18 Years) | Clinical Global Impression of Change (CGIC) | Very much worse | 0 Participants |
| Placebo (From 2 to <18 Years) | Clinical Global Impression of Change (CGIC) | Much improved | 22 Participants |
| Placebo (From 2 to <18 Years) | Clinical Global Impression of Change (CGIC) | No change | 4 Participants |
| Placebo (From 2 to <18 Years) | Clinical Global Impression of Change (CGIC) | Much worse | 1 Participants |
| Placebo (From 2 to <18 Years) | Clinical Global Impression of Change (CGIC) | Very much improved | 12 Participants |
| Tapentadol (From Birth to <2 Years) | Clinical Global Impression of Change (CGIC) | Much worse | 0 Participants |
| Tapentadol (From Birth to <2 Years) | Clinical Global Impression of Change (CGIC) | Very much worse | 0 Participants |
| Tapentadol (From Birth to <2 Years) | Clinical Global Impression of Change (CGIC) | Very much improved | 3 Participants |
| Tapentadol (From Birth to <2 Years) | Clinical Global Impression of Change (CGIC) | Missing | 2 Participants |
| Tapentadol (From Birth to <2 Years) | Clinical Global Impression of Change (CGIC) | Much improved | 2 Participants |
| Tapentadol (From Birth to <2 Years) | Clinical Global Impression of Change (CGIC) | Minimally improved | 1 Participants |
| Tapentadol (From Birth to <2 Years) | Clinical Global Impression of Change (CGIC) | No change | 2 Participants |
| Tapentadol (From Birth to <2 Years) | Clinical Global Impression of Change (CGIC) | Minimally worse | 1 Participants |
| Placebo (From Birth to <2 Years) | Clinical Global Impression of Change (CGIC) | Missing | 0 Participants |
| Placebo (From Birth to <2 Years) | Clinical Global Impression of Change (CGIC) | Much improved | 2 Participants |
| Placebo (From Birth to <2 Years) | Clinical Global Impression of Change (CGIC) | Very much improved | 1 Participants |
| Placebo (From Birth to <2 Years) | Clinical Global Impression of Change (CGIC) | Minimally improved | 1 Participants |
| Placebo (From Birth to <2 Years) | Clinical Global Impression of Change (CGIC) | No change | 0 Participants |
| Placebo (From Birth to <2 Years) | Clinical Global Impression of Change (CGIC) | Minimally worse | 0 Participants |
| Placebo (From Birth to <2 Years) | Clinical Global Impression of Change (CGIC) | Much worse | 0 Participants |
| Placebo (From Birth to <2 Years) | Clinical Global Impression of Change (CGIC) | Very much worse | 0 Participants |
Secondary
Palatability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale
Palatability of IMP after the first dose was assessed in participants aged 2 years to less than 18 years using 5-point hedonic scales in combination with verbal rating. A question How does the medication taste was asked and the verbal rating was from really good, good, a bit good/a bit bad, bad, and really bad. The pictorial scale of facial expressions was co-related with verbal rating range where 5 = really good, 4 = good, 3 = a bit good/a bit bad, 2 = bad, and 1 = really bad. Higher scores represent good palatability. Responses were summarized. Missing values were not imputed. Palatability data was not collected for participants \<2 years old.
Time frame: Up to 96 hours
Population: Full Analysis Set; subset of 160 participants aged from 2 years to less than 18 years included in the analysis. If by error a participant did not receive the allocated medication, the participant was evaluated as allocated following the intention-to-treat principle.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tapentadol (From 2 to <18 Years) | Palatability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale | Really good | 6 Participants |
| Tapentadol (From 2 to <18 Years) | Palatability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale | Missing | 1 Participants |
| Tapentadol (From 2 to <18 Years) | Palatability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale | Really bad | 13 Participants |
| Tapentadol (From 2 to <18 Years) | Palatability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale | Bad | 28 Participants |
| Tapentadol (From 2 to <18 Years) | Palatability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale | A bit bad / a bit good | 36 Participants |
| Tapentadol (From 2 to <18 Years) | Palatability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale | Good | 24 Participants |
| Placebo (From 2 to <18 Years) | Palatability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale | A bit bad / a bit good | 10 Participants |
| Placebo (From 2 to <18 Years) | Palatability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale | Really good | 11 Participants |
| Placebo (From 2 to <18 Years) | Palatability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale | Bad | 2 Participants |
| Placebo (From 2 to <18 Years) | Palatability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale | Missing | 3 Participants |
| Placebo (From 2 to <18 Years) | Palatability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale | Good | 24 Participants |
| Placebo (From 2 to <18 Years) | Palatability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale | Really bad | 2 Participants |
Secondary
Palatability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale
Palatability of IMP after the last dose in participants aged 2 years to less than 18 years was assessed using 5-point hedonic scales in combination with verbal rating. A question How does the medication taste was asked and the verbal rating was from really good, good, a bit good/a bit bad, bad, and really bad. The pictorial scale of facial expressions was co-related with verbal rating range with 5 = really good, 4 = good, 3 = a bit good/a bit bad, 2 = bad, and 1 = really bad. Higher scores represent good palatability. Responses were summarized. Missing values were not imputed. Palatability data was not collected in participants \<2 years old.
Time frame: Up to 96 hours
Population: Full Analysis Set; participants aged 2 to less than 18 years were included in the analysis. If by error a participant did not receive the allocated medication, the participant was evaluated as allocated following the intention-to-treat principle.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tapentadol (From 2 to <18 Years) | Palatability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale | Really bad | 14 Participants |
| Tapentadol (From 2 to <18 Years) | Palatability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale | Bad | 15 Participants |
| Tapentadol (From 2 to <18 Years) | Palatability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale | A bit bad / a bit good | 38 Participants |
| Tapentadol (From 2 to <18 Years) | Palatability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale | Good | 28 Participants |
| Tapentadol (From 2 to <18 Years) | Palatability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale | Really good | 5 Participants |
| Tapentadol (From 2 to <18 Years) | Palatability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale | Missing | 8 Participants |
| Placebo (From 2 to <18 Years) | Palatability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale | Really good | 12 Participants |
| Placebo (From 2 to <18 Years) | Palatability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale | Really bad | 1 Participants |
| Placebo (From 2 to <18 Years) | Palatability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale | Good | 16 Participants |
| Placebo (From 2 to <18 Years) | Palatability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale | Bad | 3 Participants |
| Placebo (From 2 to <18 Years) | Palatability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale | Missing | 6 Participants |
| Placebo (From 2 to <18 Years) | Palatability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale | A bit bad / a bit good | 14 Participants |
Secondary
Patient Global Impression of Change (PGIC)
The PGIC was assessed at the End of Treatment Visit (Day 4). Participants rated their impression of overall status on a 7-point scale with 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. Higher scores indicate worsening. If participants were not capable of completing the questionnaire, the parent/legal guardian could completed the questionnaire on behalf of the participant. Results were summarized descriptively.
Time frame: Day 4
Population: Full Analysis Set; 175 participants from birth to less than 18 years are included. If by error a participant did not receive the allocated medication, the participant was evaluated as allocated following the intention-to-treat principle.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tapentadol (From 2 to <18 Years) | Patient Global Impression of Change (PGIC) | Minimally worse | 1 Participants |
| Tapentadol (From 2 to <18 Years) | Patient Global Impression of Change (PGIC) | Much improved | 53 Participants |
| Tapentadol (From 2 to <18 Years) | Patient Global Impression of Change (PGIC) | Much worse | 1 Participants |
| Tapentadol (From 2 to <18 Years) | Patient Global Impression of Change (PGIC) | Minimally improved | 21 Participants |
| Tapentadol (From 2 to <18 Years) | Patient Global Impression of Change (PGIC) | Missing | 3 Participants |
| Tapentadol (From 2 to <18 Years) | Patient Global Impression of Change (PGIC) | Very much worse | 0 Participants |
| Tapentadol (From 2 to <18 Years) | Patient Global Impression of Change (PGIC) | Very much improved | 16 Participants |
| Tapentadol (From 2 to <18 Years) | Patient Global Impression of Change (PGIC) | No change | 13 Participants |
| Placebo (From 2 to <18 Years) | Patient Global Impression of Change (PGIC) | Very much improved | 11 Participants |
| Placebo (From 2 to <18 Years) | Patient Global Impression of Change (PGIC) | Very much worse | 0 Participants |
| Placebo (From 2 to <18 Years) | Patient Global Impression of Change (PGIC) | Missing | 3 Participants |
| Placebo (From 2 to <18 Years) | Patient Global Impression of Change (PGIC) | Much improved | 23 Participants |
| Placebo (From 2 to <18 Years) | Patient Global Impression of Change (PGIC) | Minimally worse | 0 Participants |
| Placebo (From 2 to <18 Years) | Patient Global Impression of Change (PGIC) | Minimally improved | 12 Participants |
| Placebo (From 2 to <18 Years) | Patient Global Impression of Change (PGIC) | No change | 3 Participants |
| Placebo (From 2 to <18 Years) | Patient Global Impression of Change (PGIC) | Much worse | 0 Participants |
| Tapentadol (From Birth to <2 Years) | Patient Global Impression of Change (PGIC) | Minimally worse | 0 Participants |
| Tapentadol (From Birth to <2 Years) | Patient Global Impression of Change (PGIC) | No change | 2 Participants |
| Tapentadol (From Birth to <2 Years) | Patient Global Impression of Change (PGIC) | Much worse | 0 Participants |
| Tapentadol (From Birth to <2 Years) | Patient Global Impression of Change (PGIC) | Missing | 3 Participants |
| Tapentadol (From Birth to <2 Years) | Patient Global Impression of Change (PGIC) | Very much improved | 4 Participants |
| Tapentadol (From Birth to <2 Years) | Patient Global Impression of Change (PGIC) | Much improved | 1 Participants |
| Tapentadol (From Birth to <2 Years) | Patient Global Impression of Change (PGIC) | Very much worse | 0 Participants |
| Tapentadol (From Birth to <2 Years) | Patient Global Impression of Change (PGIC) | Minimally improved | 1 Participants |
| Placebo (From Birth to <2 Years) | Patient Global Impression of Change (PGIC) | Missing | 0 Participants |
| Placebo (From Birth to <2 Years) | Patient Global Impression of Change (PGIC) | No change | 0 Participants |
| Placebo (From Birth to <2 Years) | Patient Global Impression of Change (PGIC) | Very much improved | 3 Participants |
| Placebo (From Birth to <2 Years) | Patient Global Impression of Change (PGIC) | Much improved | 1 Participants |
| Placebo (From Birth to <2 Years) | Patient Global Impression of Change (PGIC) | Minimally improved | 0 Participants |
| Placebo (From Birth to <2 Years) | Patient Global Impression of Change (PGIC) | Minimally worse | 0 Participants |
| Placebo (From Birth to <2 Years) | Patient Global Impression of Change (PGIC) | Much worse | 0 Participants |
| Placebo (From Birth to <2 Years) | Patient Global Impression of Change (PGIC) | Very much worse | 0 Participants |
Secondary
Time From First Dose of IMP Until Treatment Discontinuation Due to Lack of Efficacy
The distributions of the time from the first dose of IMP to treatment discontinuation due to lack of efficacy were summarized descriptively using time-to-event methods. Participants who reached the maximum duration of treatment (72 hours) were censored at 72 hours after first IMP intake. Participants who discontinued during the Treatment Period for reasons other than lack of efficacy were censored at the time of the decision to discontinue treatment. Due to the low number of participants with events in the age group from 2 to \<18 years, the median time and the corresponding confidence interval could not be calculated. The number of participants who discontinued early due to lack of efficacy is presented instead.
Time frame: Up to 72 hours
Population: Full Analysis Set; 160 participants from 2 to less than 18 years were included in the analysis. If by error a participant did not receive the allocated medication, he/she was evaluated as allocated following the intention-to-treat principle. No participant \<2 years was discontinued from treatment due to lack of efficacy; no analysis was performed.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tapentadol (From 2 to <18 Years) | Time From First Dose of IMP Until Treatment Discontinuation Due to Lack of Efficacy | Number of censored participants | 104 Participants |
| Tapentadol (From 2 to <18 Years) | Time From First Dose of IMP Until Treatment Discontinuation Due to Lack of Efficacy | Number of participants with event | 4 Participants |
| Placebo (From 2 to <18 Years) | Time From First Dose of IMP Until Treatment Discontinuation Due to Lack of Efficacy | Number of censored participants | 48 Participants |
| Placebo (From 2 to <18 Years) | Time From First Dose of IMP Until Treatment Discontinuation Due to Lack of Efficacy | Number of participants with event | 4 Participants |
| Tapentadol (From Birth to <2 Years) | Time From First Dose of IMP Until Treatment Discontinuation Due to Lack of Efficacy | Number of participants with event | 0 Participants |
| Tapentadol (From Birth to <2 Years) | Time From First Dose of IMP Until Treatment Discontinuation Due to Lack of Efficacy | Number of censored participants | 11 Participants |
| Placebo (From Birth to <2 Years) | Time From First Dose of IMP Until Treatment Discontinuation Due to Lack of Efficacy | Number of participants with event | 0 Participants |
| Placebo (From Birth to <2 Years) | Time From First Dose of IMP Until Treatment Discontinuation Due to Lack of Efficacy | Number of censored participants | 4 Participants |
Secondary
Time to Receive First and Second Patient- or Nurse-controlled Analgesia After the First Dose of IMP
The time to first and time to second patient-controlled analgesia (PCA) or nurse-controlled analgesia (NCA) after the first dose of IMP were summarized descriptively using time-to-event methods and are displayed by relevant treatment groups. Participants who completed the End of Treatment Visit (scheduled for 96 hours after first IMP) before their first/second use of NCA/PCA or participants who terminated treatment before their first/second use of NCA/PCA were censored at the End of Treatment Visit. Time-to-event variables are reported using Kaplan-Meier analyses. Therefore, values might remain missing if the survival function does not reach a respective threshold. This is indicated by not applicable (NA).
Time frame: Up to 96 hours
Population: Full Analysis Set; 175 participants from birth to less than 18 years are included, censored participants are not displayed. If by error a participant did not receive the allocated medication, the participant was evaluated as allocated following the intention-to-treat principle.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Tapentadol (From 2 to <18 Years) | Time to Receive First and Second Patient- or Nurse-controlled Analgesia After the First Dose of IMP | Time to first NCA/PCA administration | 183.0 minutes |
| Tapentadol (From 2 to <18 Years) | Time to Receive First and Second Patient- or Nurse-controlled Analgesia After the First Dose of IMP | Time to second NCA/PCA administration | 572.0 minutes |
| Placebo (From 2 to <18 Years) | Time to Receive First and Second Patient- or Nurse-controlled Analgesia After the First Dose of IMP | Time to second NCA/PCA administration | 388.0 minutes |
| Placebo (From 2 to <18 Years) | Time to Receive First and Second Patient- or Nurse-controlled Analgesia After the First Dose of IMP | Time to first NCA/PCA administration | 131.5 minutes |
| Tapentadol (From Birth to <2 Years) | Time to Receive First and Second Patient- or Nurse-controlled Analgesia After the First Dose of IMP | Time to first NCA/PCA administration | 960.0 minutes |
| Tapentadol (From Birth to <2 Years) | Time to Receive First and Second Patient- or Nurse-controlled Analgesia After the First Dose of IMP | Time to second NCA/PCA administration | NA minutes |
| Placebo (From Birth to <2 Years) | Time to Receive First and Second Patient- or Nurse-controlled Analgesia After the First Dose of IMP | Time to first NCA/PCA administration | 155.0 minutes |
| Placebo (From Birth to <2 Years) | Time to Receive First and Second Patient- or Nurse-controlled Analgesia After the First Dose of IMP | Time to second NCA/PCA administration | NA minutes |
Secondary
Total Amount of Supplemental Opioid Analgesic Medication Received, Assessed in 12-hour Intervals From 24 Hours to 96 Hours After the First Dose of IMP
The total amount of supplemental opioid analgesic medication (SOAM) received was assessed in 12-hour intervals from 24 hours to 96 hours after the first dose of IMP for participants who were administered SOAM. SOAM use was expressed in mg/kg of morphine i.v. equivalents.
Time frame: Up to 96 hours
Population: Full Analysis Set; 175 participants aged from birth to \<18 years; participants with no documented SOAM use in the respective time period are excluded from calculations. When 0 participants are indicated in the Row Analyzed that means no data was collected.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Tapentadol (From 2 to <18 Years) | Total Amount of Supplemental Opioid Analgesic Medication Received, Assessed in 12-hour Intervals From 24 Hours to 96 Hours After the First Dose of IMP | 24 h to 36 h | 0.08 mg/kg |
| Tapentadol (From 2 to <18 Years) | Total Amount of Supplemental Opioid Analgesic Medication Received, Assessed in 12-hour Intervals From 24 Hours to 96 Hours After the First Dose of IMP | 60 h to 72 h | 0.06 mg/kg |
| Tapentadol (From 2 to <18 Years) | Total Amount of Supplemental Opioid Analgesic Medication Received, Assessed in 12-hour Intervals From 24 Hours to 96 Hours After the First Dose of IMP | 48 h to 60 h | 0.05 mg/kg |
| Tapentadol (From 2 to <18 Years) | Total Amount of Supplemental Opioid Analgesic Medication Received, Assessed in 12-hour Intervals From 24 Hours to 96 Hours After the First Dose of IMP | 72 h to 84 h | 0.0 mg/kg |
| Tapentadol (From 2 to <18 Years) | Total Amount of Supplemental Opioid Analgesic Medication Received, Assessed in 12-hour Intervals From 24 Hours to 96 Hours After the First Dose of IMP | 36 h to 48 h | 0.06 mg/kg |
| Placebo (From 2 to <18 Years) | Total Amount of Supplemental Opioid Analgesic Medication Received, Assessed in 12-hour Intervals From 24 Hours to 96 Hours After the First Dose of IMP | 72 h to 84 h | 0.0 mg/kg |
| Placebo (From 2 to <18 Years) | Total Amount of Supplemental Opioid Analgesic Medication Received, Assessed in 12-hour Intervals From 24 Hours to 96 Hours After the First Dose of IMP | 24 h to 36 h | 0.14 mg/kg |
| Placebo (From 2 to <18 Years) | Total Amount of Supplemental Opioid Analgesic Medication Received, Assessed in 12-hour Intervals From 24 Hours to 96 Hours After the First Dose of IMP | 36 h to 48 h | 0.06 mg/kg |
| Placebo (From 2 to <18 Years) | Total Amount of Supplemental Opioid Analgesic Medication Received, Assessed in 12-hour Intervals From 24 Hours to 96 Hours After the First Dose of IMP | 48 h to 60 h | 0.06 mg/kg |
| Placebo (From 2 to <18 Years) | Total Amount of Supplemental Opioid Analgesic Medication Received, Assessed in 12-hour Intervals From 24 Hours to 96 Hours After the First Dose of IMP | 60 h to 72 h | 0.03 mg/kg |
| Tapentadol (From Birth to <2 Years) | Total Amount of Supplemental Opioid Analgesic Medication Received, Assessed in 12-hour Intervals From 24 Hours to 96 Hours After the First Dose of IMP | 36 h to 48 h | 0.000 mg/kg |
| Tapentadol (From Birth to <2 Years) | Total Amount of Supplemental Opioid Analgesic Medication Received, Assessed in 12-hour Intervals From 24 Hours to 96 Hours After the First Dose of IMP | 24 h to 36 h | 0.020 mg/kg |
| Placebo (From Birth to <2 Years) | Total Amount of Supplemental Opioid Analgesic Medication Received, Assessed in 12-hour Intervals From 24 Hours to 96 Hours After the First Dose of IMP | 36 h to 48 h | 0.000 mg/kg |
| Placebo (From Birth to <2 Years) | Total Amount of Supplemental Opioid Analgesic Medication Received, Assessed in 12-hour Intervals From 24 Hours to 96 Hours After the First Dose of IMP | 24 h to 36 h | 0.003 mg/kg |
Other Pre-specified
Mean Amount of Supplemental Opioid Analgesic Medication Use After First Intake of Investigational Medicinal Product in Children Aged From Birth to Less Than 2 Years
The mean amount of supplemental opioid analgesic medication (SOAM) used in the Full Analysis Set subset aged from birth to less than 2 years old was determined from 0 to 12 hours and from 0 to 24 hours after first intake of IMP. SOAM use is expressed in mg/kg of morphine i.v. equivalents.
Time frame: Up to 24 hours
Population: Full Analysis Set: subset of 15 participants from birth to less than 2 years included in the analysis; participants with missing data were excluded from calculations. If by error a participant did not receive the allocated medication, the participant was evaluated as allocated following the intention-to-treat principle.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Tapentadol (From 2 to <18 Years) | Mean Amount of Supplemental Opioid Analgesic Medication Use After First Intake of Investigational Medicinal Product in Children Aged From Birth to Less Than 2 Years | 0-12 hours | 0.03 mg/kg |
| Tapentadol (From 2 to <18 Years) | Mean Amount of Supplemental Opioid Analgesic Medication Use After First Intake of Investigational Medicinal Product in Children Aged From Birth to Less Than 2 Years | 0-24 hours | 0.054 mg/kg |
| Placebo (From 2 to <18 Years) | Mean Amount of Supplemental Opioid Analgesic Medication Use After First Intake of Investigational Medicinal Product in Children Aged From Birth to Less Than 2 Years | 0-12 hours | 0.01 mg/kg |
| Placebo (From 2 to <18 Years) | Mean Amount of Supplemental Opioid Analgesic Medication Use After First Intake of Investigational Medicinal Product in Children Aged From Birth to Less Than 2 Years | 0-24 hours | 0.016 mg/kg |
Other Pre-specified
Median Amount of Supplemental Opioid Analgesic Medication Use After First Intake of Investigational Medicinal Product in Children Aged From Birth to Less Than 2 Years
The median amount of supplemental opioid analgesic medication (SOAM) used in the Full Analysis Set subset aged from birth to less than 2 years old was determined from 0 to 12 hours and from 0 to 24 hours after first intake of IMP. SOAM use is expressed in mg/kg of morphine i.v. equivalents.
Time frame: Up to 24 hours
Population: Full Analysis Set: subset of 15 participants from birth to less than 2 years included in the analysis; participants with missing data were excluded from calculations. If by error a participant did not receive the allocated medication, the participant was evaluated as allocated following the intention-to-treat principle.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Tapentadol (From 2 to <18 Years) | Median Amount of Supplemental Opioid Analgesic Medication Use After First Intake of Investigational Medicinal Product in Children Aged From Birth to Less Than 2 Years | 0-12 hours | 0.00 mg/kg |
| Tapentadol (From 2 to <18 Years) | Median Amount of Supplemental Opioid Analgesic Medication Use After First Intake of Investigational Medicinal Product in Children Aged From Birth to Less Than 2 Years | 0-24 hours | 0.016 mg/kg |
| Placebo (From 2 to <18 Years) | Median Amount of Supplemental Opioid Analgesic Medication Use After First Intake of Investigational Medicinal Product in Children Aged From Birth to Less Than 2 Years | 0-12 hours | 0.01 mg/kg |
| Placebo (From 2 to <18 Years) | Median Amount of Supplemental Opioid Analgesic Medication Use After First Intake of Investigational Medicinal Product in Children Aged From Birth to Less Than 2 Years | 0-24 hours | 0.013 mg/kg |