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NCT02081391

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

Completed Phase 3 Results posted Last updated 18 January 2020
What this trial tests

Phase 3 trial testing Tapentadol oral solution 4 mg/mL in Acute Pain in 216 participants. Completed in 14 March 2019.

Timeline
19 February 2015
Primary endpoint
3 March 2019
14 March 2019

Quick facts

Lead sponsorGrünenthal GmbH
PhasePhase 3
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingquadruple
Primary purposetreatment
Enrollment216
Start date19 February 2015
Primary completion3 March 2019
Estimated completion14 March 2019
Sites43 locations across France, United Kingdom, Germany, Hungary, Poland, Bulgaria, Croatia, United States

Drugs / interventions tested

Conditions studied

Sponsor

Grünenthal GmbH — full company profile →

Who can join

Adults 1 Day to 18, any sex, with Acute Pain. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

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] Primary · 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.

GroupValue95% CI
Tapentadol (From 2 to <18 Years)0.08± 0.01
Placebo (From 2 to <18 Years)0.13± 0.02
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] Primary · 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.

GroupValue95% CI
Tapentadol (From 2 to <18 Years)0.14± 0.03
Placebo (From 2 to <18 Years)0.24± 0.03
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 Secondary · 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.

24 h to 36 h
GroupValue95% CI
Tapentadol (From 2 to <18 Years)0.080.0 – 0.4
Placebo (From 2 to <18 Years)0.140.0 – 0.7
Tapentadol (From Birth to <2 Years)0.0200.02 – 0.02
Placebo (From Birth to <2 Years)0.0030.003 – 0.003
36 h to 48 h
GroupValue95% CI
Tapentadol (From 2 to <18 Years)0.060.0 – 0.4
Placebo (From 2 to <18 Years)0.060.0 – 0.4
Tapentadol (From Birth to <2 Years)0.0000.00 – 0.00
Placebo (From Birth to <2 Years)0.0000.00 – 0.00
48 h to 60 h
GroupValue95% CI
Tapentadol (From 2 to <18 Years)0.050.0 – 0.4
Placebo (From 2 to <18 Years)0.060.0 – 0.4
60 h to 72 h
GroupValue95% CI
Tapentadol (From 2 to <18 Years)0.060.0 – 0.2
Placebo (From 2 to <18 Years)0.030.0 – 0.2
72 h to 84 h
GroupValue95% CI
Tapentadol (From 2 to <18 Years)0.00.0 – 0.0
Placebo (From 2 to <18 Years)0.00.0 – 0.0
Palatability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale Secondary · 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. Palatabilit

Really bad
GroupValue95% CI
Tapentadol (From 2 to <18 Years)13
Placebo (From 2 to <18 Years)2
Bad
GroupValue95% CI
Tapentadol (From 2 to <18 Years)28
Placebo (From 2 to <18 Years)2
A bit bad / a bit good
GroupValue95% CI
Tapentadol (From 2 to <18 Years)36
Placebo (From 2 to <18 Years)10
Good
GroupValue95% CI
Tapentadol (From 2 to <18 Years)24
Placebo (From 2 to <18 Years)24
Really good
GroupValue95% CI
Tapentadol (From 2 to <18 Years)6
Placebo (From 2 to <18 Years)11
Missing
GroupValue95% CI
Tapentadol (From 2 to <18 Years)1
Placebo (From 2 to <18 Years)3
Acceptability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale Secondary · 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. Acceptab

GroupValue95% CI
Tapentadol (From 2 to <18 Years)1
Placebo (From 2 to <18 Years)0
Tapentadol (From 2 to <18 Years)7
Placebo (From 2 to <18 Years)3
Tapentadol (From 2 to <18 Years)17
Placebo (From 2 to <18 Years)7
Tapentadol (From 2 to <18 Years)46
Placebo (From 2 to <18 Years)20
Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years Secondary · 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 en

30-60 mins after 1st IMP
GroupValue95% CI
Tapentadol (From 2 to <6 Years)1.1-5.0 – 4.0
Placebo (From 2 to <6 Years)1.90.0 – 6.0
Tapentadol (From Birth to <2 Years)1.4-4.0 – 6.0
Placebo (From Birth to <2 Years)2.80.0 – 5.0
Before 2nd dose of IMP
GroupValue95% CI
Tapentadol (From 2 to <6 Years)1.4-2.0 – 7.0
Placebo (From 2 to <6 Years)1.30.0 – 6.0
Tapentadol (From Birth to <2 Years)0.7-5.0 – 6.0
Placebo (From Birth to <2 Years)1.00.0 – 2.0
Before 3rd dose of IMP
GroupValue95% CI
Tapentadol (From 2 to <6 Years)1.7-2.0 – 7.0
Placebo (From 2 to <6 Years)1.6-1.0 – 6.0
Tapentadol (From Birth to <2 Years)2.00.0 – 6.0
Placebo (From Birth to <2 Years)-1.3-6.0 – 2.0
Before 4th dose of IMP
GroupValue95% CI
Tapentadol (From 2 to <6 Years)1.4-2.0 – 5.0
Placebo (From 2 to <6 Years)1.3-1.0 – 6.0
Tapentadol (From Birth to <2 Years)1.3-5.0 – 5.0
Placebo (From Birth to <2 Years)0.0-5.0 – 3.0
Before 5th dose of IMP
GroupValue95% CI
Tapentadol (From 2 to <6 Years)1.8-1.0 – 5.0
Placebo (From 2 to <6 Years)1.9-1.0 – 6.0
Tapentadol (From Birth to <2 Years)1.4-2.0 – 6.0
Placebo (From Birth to <2 Years)2.00.0 – 4.0
Before 6th dose of IMP
GroupValue95% CI
Tapentadol (From 2 to <6 Years)1.6-2.0 – 5.0
Placebo (From 2 to <6 Years)2.30 – 6.0
Tapentadol (From Birth to <2 Years)2.0-1.0 – 6.0
Placebo (From Birth to <2 Years)2.50.0 – 5.0
Before 7th dose of IMP
GroupValue95% CI
Tapentadol (From 2 to <6 Years)1.6-2.0 – 6.0
Placebo (From 2 to <6 Years)2.10.0 – 6.0
Tapentadol (From Birth to <2 Years)1.9-1.0 – 6.0
Placebo (From Birth to <2 Years)2.00.0 – 3.0
Before 8th dose of IMP
GroupValue95% CI
Tapentadol (From 2 to <6 Years)1.2-1.0 – 4.0
Placebo (From 2 to <6 Years)2.2-3.0 – 6.0
Tapentadol (From Birth to <2 Years)3.81.0 – 6.0
Placebo (From Birth to <2 Years)-0.5-5.0 – 4.0
Change From Baseline Pain Intensity Using the Faces Pain Scale-Revised (FPS-R) in Participants Aged 6 to Less Than 12 Years Secondary · 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 tim

30-60 mins after 1st IMP
GroupValue95% CI
Tapentadol (6 to <12 Years)1.0± 1.72
Placebo (6 to <12 Years)0.7± 1.86
Before 2nd dose of IMP
GroupValue95% CI
Tapentadol (6 to <12 Years)1.0± 2.5
Placebo (6 to <12 Years)0.5± 2.84
Before 3rd dose of IMP
GroupValue95% CI
Tapentadol (6 to <12 Years)1.0± 2.35
Placebo (6 to <12 Years)-0.2± 2.17
Before 4th dose of IMP
GroupValue95% CI
Tapentadol (6 to <12 Years)1.3± 2.33
Placebo (6 to <12 Years)-0.3± 3.7
Before 5th dose of IMP
GroupValue95% CI
Tapentadol (6 to <12 Years)0.8± 2.75
Placebo (6 to <12 Years)0± 2.19
Before 6th dose of IMP
GroupValue95% CI
Tapentadol (6 to <12 Years)0.5± 2.43
Placebo (6 to <12 Years)0.2± 2.2
Before 7th dose of IMP
GroupValue95% CI
Tapentadol (6 to <12 Years)2.0± 2.37
Placebo (6 to <12 Years)0.7± 2.24
Before 8th dose of IMP
GroupValue95% CI
Tapentadol (6 to <12 Years)1.3± 2.55
Placebo (6 to <12 Years)0.2± 2.73
Change From Baseline in the Visual Analog Scale (VAS) Pain Intensity Score in Participants Aged 12 to Less Than 18 Years Secondary · 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,

30-60 mins after 1st IMP
GroupValue95% CI
Tapentadol (12 to <18 Years)8.0± 18.67
Placebo (12 to <18 Years)6.4± 19.58
Before 2nd dose of IMP
GroupValue95% CI
Tapentadol (12 to <18 Years)6.5± 23.61
Placebo (12 to <18 Years)6.0± 19.36
Before 3rd dose of IMP
GroupValue95% CI
Tapentadol (12 to <18 Years)13.1± 25.09
Placebo (12 to <18 Years)5.9± 22.11
Before 4th dose of IMP
GroupValue95% CI
Tapentadol (12 to <18 Years)8.8± 29.01
Placebo (12 to <18 Years)5.1± 21.7
Before 5th dose of IMP
GroupValue95% CI
Tapentadol (12 to <18 Years)13.0± 22.92
Placebo (12 to <18 Years)-2.7± 34.4
Before 6th dose of IMP
GroupValue95% CI
Tapentadol (12 to <18 Years)13.0± 24.74
Placebo (12 to <18 Years)6.6± 28.4
Before 7th dose of IMP
GroupValue95% CI
Tapentadol (12 to <18 Years)10.7± 25.77
Placebo (12 to <18 Years)15.0± 20.27
Before 8th dose of IMP
GroupValue95% CI
Tapentadol (12 to <18 Years)12.2± 28.91
Placebo (12 to <18 Years)11.9± 14.6
Clinical Global Impression of Change (CGIC) Secondary · 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.

GroupValue95% CI
Tapentadol (From 2 to <18 Years)15
Placebo (From 2 to <18 Years)12
Tapentadol (From Birth to <2 Years)3
Placebo (From Birth to <2 Years)1
Tapentadol (From 2 to <18 Years)58
Placebo (From 2 to <18 Years)22
Tapentadol (From Birth to <2 Years)2
Placebo (From Birth to <2 Years)2
Tapentadol (From 2 to <18 Years)18
Placebo (From 2 to <18 Years)8
Tapentadol (From Birth to <2 Years)1
Placebo (From Birth to <2 Years)1
Tapentadol (From 2 to <18 Years)11
Placebo (From 2 to <18 Years)4
Tapentadol (From Birth to <2 Years)2
Placebo (From Birth to <2 Years)0
Patient Global Impression of Change (PGIC) Secondary · 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.

GroupValue95% CI
Tapentadol (From 2 to <18 Years)16
Placebo (From 2 to <18 Years)11
Tapentadol (From Birth to <2 Years)4
Placebo (From Birth to <2 Years)3
Tapentadol (From 2 to <18 Years)53
Placebo (From 2 to <18 Years)23
Tapentadol (From Birth to <2 Years)1
Placebo (From Birth to <2 Years)1
Tapentadol (From 2 to <18 Years)21
Placebo (From 2 to <18 Years)12
Tapentadol (From Birth to <2 Years)1
Placebo (From Birth to <2 Years)0
Tapentadol (From 2 to <18 Years)13
Placebo (From 2 to <18 Years)3
Tapentadol (From Birth to <2 Years)2
Placebo (From Birth to <2 Years)0
Time to Receive First and Second Patient- or Nurse-controlled Analgesia After the First Dose of IMP Secondary · 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 rema

Time to first NCA/PCA administration
GroupValue95% CI
Tapentadol (From 2 to <18 Years)183.090.0 – 446.0
Placebo (From 2 to <18 Years)131.574.0 – 216.0
Tapentadol (From Birth to <2 Years)960.080.0 – NA
Placebo (From Birth to <2 Years)155.0124.0 – NA
Time to second NCA/PCA administration
GroupValue95% CI
Tapentadol (From 2 to <18 Years)572.0321.0 – 1993.0
Placebo (From 2 to <18 Years)388.0194.0 – 820.0
Tapentadol (From Birth to <2 Years)NA210 – NA
Placebo (From Birth to <2 Years)NA500.0 – NA
Time From First Dose of IMP Until Treatment Discontinuation Due to Lack of Efficacy Secondary · 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 inter

GroupValue95% CI
Tapentadol (From 2 to <18 Years)104
Placebo (From 2 to <18 Years)48
Tapentadol (From Birth to <2 Years)11
Placebo (From Birth to <2 Years)4
Tapentadol (From 2 to <18 Years)4
Placebo (From 2 to <18 Years)4
Tapentadol (From Birth to <2 Years)0
Placebo (From Birth to <2 Years)0

Adverse events — posted to ClinicalTrials.gov

Time frame: Any adverse event (AE) is reported that started at or after the first dose of IMP or started before the first dose of IMP and worsened in intensity after the first dose of IMP up to the end of the therapeutic reach of the last dose of IMP. The therapeutic reach is the time after IMP intake that a participant is still considered to be potentially affected by the study drug. For tapentadol oral solution, the therapeutic reach is defined as 48 hours.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Overall (From 2 to <18 Years)
Serious: 2/160 (1%)
Deaths: 0/160
Tapentadol (From 2 to <18 Years)
Serious: 2/108 (2%)
Deaths: 0/108
Placebo (From 2 to <18 Years)
Serious: 0/52 (0%)
Deaths: 0/52
Overall (From Birth to <2 Years)
Serious: 0/15 (0%)
Deaths: 0/15
Tapentadol (From Birth to <2 Years)
Serious: 0/11 (0%)
Deaths: 0/11
Placebo (From Birth to <2 Years)
Serious: 0/4 (0%)
Deaths: 0/4

Serious adverse events (2 terms)

ReactionSystemOverall (From 2 to <18 Yea…Tapentadol (From 2 to <18 …Placebo (From 2 to <18 Yea…Overall (From Birth to <2 …Tapentadol (From Birth to …Placebo (From Birth to <2 …
Abdominal abscessInfections and infestations
SeizureNervous system disorders
Other adverse events (59 terms — click to expand)

ReactionSystemOverall (From 2 to <18 Yea…Tapentadol (From 2 to <18 …Placebo (From 2 to <18 Yea…Overall (From Birth to <2 …Tapentadol (From Birth to …Placebo (From Birth to <2 …
VomitingGastrointestinal disorders
NauseaGastrointestinal disorders
ConstipationGastrointestinal disorders
PyrexiaGeneral disorders
SomnolenceNervous system disorders
PruritusSkin and subcutaneous tissue disorders
HeadacheNervous system disorders
DizzinessNervous system disorders
Oxygen saturation decreasedInvestigations
Urinary retentionRenal and urinary disorders
Sinus TachycardiaCardiac disorders
HypoxiaRespiratory, thoracic and mediastinal disorders
InsomniaPsychiatric disorders
Anaemia postoperativeInjury, poisoning and procedural complications
Haemoglobin decreasedInvestigations
SedationNervous system disorders
Decreased AppetiteMetabolism and nutrition disorders
HypomagnesaemiaMetabolism and nutrition disorders
Chest painGeneral disorders
Face oedemaGeneral disorders
Infusion site pruritusGeneral disorders
AgitationPsychiatric disorders
AnxietyPsychiatric disorders
Hallucinations, mixedPsychiatric disorders
Initial insomniaPsychiatric disorders
Withdrawal syndromePsychiatric disorders
Transfusion reactionInjury, poisoning and procedural complications
Administration related reactionInjury, poisoning and procedural complications
Alanine aminotransferase increasedInvestigations
Aspartate aminotransferase increasedInvestigations
Blood urea decreasedInvestigations
Haematocrit decreasedInvestigations
Hepatic enzyme increasedInvestigations
Po2 decreasedInvestigations
Red blood cell count decreasedInvestigations
Respiratory rate decreasedInvestigations
AnaemiaCardiac disorders
Haemorrhagic anaemiaCardiac disorders
ThrombocytopeniaCardiac disorders
BradypnoeaRespiratory, thoracic and mediastinal disorders

Most-reported serious reactions: Abdominal abscess, Seizure.

Data from ClinicalTrials.gov NCT02081391 adverse events section.

Sponsor's own description

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.

Publications & conference data

2 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Tapentadol for the Treatment of Moderate-to-Severe Acute Pain in Children Under the Age of Two Years.
    Eissa A, Tarau E, Beuter C, Radic T, et al · · 2021 · cited 8× · PMID 33542653 · DOI 10.2147/jpr.s269530
  2. Population pharmacokinetic modeling to facilitate dose selection of tapentadol in the pediatric population.
    Watson E, Khandelwal A, Freijer J, van den Anker J, et al · · 2019 · cited 8× · PMID 31686902 · DOI 10.2147/jpr.s208454

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