Acute PainPhase 3NCT02081391
A Study to Look at Tapentadol Oral Solution in Children and Adolescents in Pain
A Phase 3 study testing Tapentadol oral solution 4 mg/mL and Tapentadol oral solution 20 mg/mL in people with Acute Pain, run by Grünenthal GmbH at 43 sites in 10 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 1 day to 18 years
- Conditions the study is for
- Acute Pain
- What is being tested?
- Tapentadol oral solution 4 mg/mL and Tapentadol oral solution 20 mg/mL
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 216 participants
- Where
- 43 sitesin 10 countries
- Study dates
- 19 Feb 2015to 14 Mar 2019
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 day to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Informed consent, and if applicable assent, given according to local regulations.
- Male or female participant aged from birth (at least 37 weeks gestational age) to less than 18 years.
- 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.
- A female participant must have a negative pregnancy test if aged 12 years or older, or is post-menarchal, or is sexually active.
- 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.
- 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.
- Participant is able to tolerate liquids at the time of allocation/randomization to IMP.
Who cannot join
- 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.
- Participant has been previously exposed to tapentadol.
- 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.
- Participant has a history or current condition of any one of the following:
- Non-febrile seizure disorder.
- Epilepsy.
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- 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.
- 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).
- 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.
- Participant has history of suicidal ideation or behavior.
- 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.
- Participant has a clinically relevant history of hypersensitivity, allergy, or contraindication to the supplemental opioid analgesic medication or tapentadol, or the excipients, or naloxone.
- 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
- Participant has a history of alcohol and/or substance abuse in the investigator's judgment based on participant's history and physical examination.
- Participant is taking prohibited concomitant medication.
- Participant has received a long-acting opioid for the treatment of pain following surgery within 6 hours of allocation/randomization to IMP.
- 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.
- 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.
- 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.
- 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).
- Female participant is breast-feeding a child.
- Participant requires continuous positive airway pressure or mechanical ventilation, at the time of allocation to IMP.
- The mother of a newborn participant or the breastfeeding mother of a participant was administered a prohibited medication.
Trial locations and contacts
43 sites in 10 countries.
43 sites in 10 countries
United States13 sites
US016
Cincinnati, Ohio, 45229
US003
Dallas, Texas, 75235
US006
Durham, North Carolina, 27710
US005
Houston, Texas, 77030
US008
Little Rock, Arkansas, 72202
US012
Louisville, Kentucky, 40202
US011
Miami, Florida, 33136
US007
Milwaukee, Wisconsin, 53226
US015
Philadelphia, Pennsylvania, 19104
US014
Pittsburgh, Pennsylvania, 15224
US004
Stanford, California, 94305
US001
The Bronx, New York, 10461
US018
The Bronx, New York, 10467
Poland9 sites
PL011
Bydgoszcz, 85-094
PL010
Gdansk, 80-803
PL005
Lodz, 93-338
PL002
Lublin, 20-093
PL009
Olsztyn, 10-561
PL014
Rzeszów, 35-301
PL007
Torun, 87-100
PL004
Warsaw, 04-730
PL008
Warsaw, 04-730
Spain5 sites
ES002
Barcelona, 8950
ES005
Madrid, 28040
ES007
Madrid, 28046
ES009
Santiago de Compostela, 15706
ES006
Valladolid, 47003
Czechia3 sites
CZ004
Fryštát, 73506
CZ003
Olomouc, 77900
CZ001
Praha 4 - Krč, 14059
About this study
Official title: An Evaluation of the Efficacy and Safety of Tapentadol Oral Solution in the Treatment of Post-operative Acute Pain Requiring Opioid Treatment in Pediatric Subjects Aged From Birth to Less Than 18 Years Old
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.
Read the 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.
- Conditions
- Acute Pain
- Being tested
- Tapentadol oral solution 4 mg/mL, Tapentadol oral solution 20 mg/mL, Placebo
- Keywords
- Acute Pain, Post-operative, Tapentadol, Opioid Treatment, Pediatric Participants
- Medical subject headings
- Acute Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Tapentadol oral solution 4 mg/mLDrug
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.
Tapentadol oral solution 20 mg/mLDrug
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.
PlaceboOther
Matching placebo oral solution was administered by mouth every 4 hours up to 72 hours.
| Study group | Role | What they receive |
|---|---|---|
| Tapentadol immediate-release (IR) | Experimental | In the first 24 hours, tapentadol oral solution at a dose of 1.25 mg/kg body weight was given every 4 hours (±15 min) to participants aged 6 months to less than 18 years (maximum individual dose of tapentadol was 100 mg). Participants from 30 days to less than 6 months were dosed with 0.5 mg/kg body weight every 4 hours. Participants from birth to less than 30 days of age were dosed with 0.1 mg/kg body weight every 4 hours.
After 24 hours and up to 72 hours, the dose could be reduced based on the investigator's judgment. Receives: Drug: Tapentadol oral solution 4 mg/mL; Drug: Tapentadol oral solution 20 mg/mL |
| Placebo | Placebo comparator | Matching placebo oral solution was administered every 4 hours (±15 min) up to 72 hours. Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Up to 12 hours
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.
Measured: Up to 24 hours
Secondary outcomes (12)
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.
Measured: Up to 96 hours
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.
Measured: Up to 96 hours
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.
Measured: Up to 96 hours
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.
Measured: Up to 96 hours
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).
Measured: Up to 96 hours
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.
Measured: Up to 96 hours
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.
Measured: Day 4
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.
Measured: Day 4
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).
Measured: Up to 96 hours
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.
Measured: Up to 72 hours
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.
Measured: Up to 96 hours
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.
Measured: Up to 96 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Mar 2014 (estimated)
- Study start19 Feb 2015
- Primary completion3 Mar 2019
- Study completion14 Mar 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Acute PainStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 216 participants (actual)
Sponsor and investigators
- Lead sponsor
- Grünenthal GmbH
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Depomed
- Responsible party
- Sponsor
- Investigators
- Grünenthal Study Director, Study director, Grünenthal GmbH
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02081391
- Sponsor's protocol ID
- KF5503/65
- Other IDs
- 2012-004359-35
- Status last verified
- Jan 2020
- First submitted
- 5 Mar 2014
- Last updated
- 18 Jan 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Information available on the Grünenthal Web Site
Publications
Schwartz GJ, Feld LG, Langford DJ. A simple estimate of glomerular filtration rate in full-term infants during the first year of life. J Pediatr. 1984 Jun;104(6):849-54. doi: 10.1016/s0022-3476(84)80479-5.
PubMed 6726515
Study at a glance
From the registry record, last updated by the sponsor on 18 Jan 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Evaluation of the Efficacy and Safety of Tapentadol Oral Solution in the Treatment of Post-operative Acute Pain Requiring Opioid Treatment in Pediatric Subjects Aged From Birth to Less Than 18 Years Old
- ClinicalTrials.gov ID
- NCT02081391
- Acronym / sponsor ID
- KF5503/65
- Conditions
- Acute Pain
- Keywords
- Acute Pain, Post-operative, Tapentadol, Opioid Treatment, Pediatric Participants
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 216 participants (actual)
- Lead sponsor
- Grünenthal GmbHIndustry (pharma, biotech, devices)
- Collaborators
- Depomed
- Study start
- 19 Feb 2015 (actual)
- Primary completion
- 3 Mar 2019 (actual)
- Study completion
- 14 Mar 2019 (actual)
- First posted
- 7 Mar 2014 (estimated)
- Results
- Posted 18 Jan 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Tapentadol immediate-release (IR) | Experimental | Drug: Tapentadol oral solution 4 mg/mL, Drug: Tapentadol oral solution 20 mg/mLIn the first 24 hours, tapentadol oral solution at a dose of 1.25 mg/kg body weight was given every 4 hours (±15 min) to participants aged 6 months to less than 18 years (maximum individual dose of tapentadol was 100 mg). Participants from 30 days to less than 6 months were dosed with 0.5 mg/kg body weight every 4 hours. Participants from birth to less than 30 days of age were dosed with 0.1 mg/kg body weight every 4 hours. After 24 hours and up to 72 hours, the dose could be reduced based on the investigator's judgment. |
| Placebo | Placebo comparator | Other: PlaceboMatching placebo oral solution was administered every 4 hours (±15 min) up to 72 hours. |
Who may qualify
- Ages
- 1 day to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (7 listed)
- Informed consent, and if applicable assent, given according to local regulations.
- Male or female participant aged from birth (at least 37 weeks gestational age) to less than 18 years.
- 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.
- A female participant must have a negative pregnancy test if aged 12 years or older, or is post-menarchal, or is sexually active.
- 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.
Key exclusion criteria (42 listed)
- 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.
- Participant has been previously exposed to tapentadol.
- 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.
- Participant has a history or current condition of any one of the following:
- Participant has a history or current condition of any one of the following:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Tapentadol oral solution 4 mg/mLParticipants 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. | Drug | Tapentadol immediate-release (IR) |
| Tapentadol oral solution 20 mg/mLParticipants 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. | Drug | Tapentadol immediate-release (IR) |
| PlaceboMatching placebo oral solution was administered by mouth every 4 hours up to 72 hours. | Other | Placebo |
Primary outcome
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]
Time frame: 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]
Time frame: 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.
12 secondary outcomes
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
Time frame: Up to 96 hours
Palatability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale
Time frame: Up to 96 hours
Acceptability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale
Time frame: Up to 96 hours
Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years
Time frame: Up to 96 hours
Change From Baseline Pain Intensity Using the Faces Pain Scale-Revised (FPS-R) in Participants Aged 6 to Less Than 12 Years
Time frame: Up to 96 hours
Change From Baseline in the Visual Analog Scale (VAS) Pain Intensity Score in Participants Aged 12 to Less Than 18 Years
Time frame: Up to 96 hours
Clinical Global Impression of Change (CGIC)
Time frame: Day 4
Patient Global Impression of Change (PGIC)
Time frame: Day 4
Time to Receive First and Second Patient- or Nurse-controlled Analgesia After the First Dose of IMP
Time frame: Up to 96 hours
Time From First Dose of IMP Until Treatment Discontinuation Due to Lack of Efficacy
Time frame: Up to 72 hours
Palatability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale
Time frame: Up to 96 hours
Acceptability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale
Time frame: Up to 96 hours
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jan 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 6726515Schwartz GJ, Feld LG, Langford DJ. A simple estimate of glomerular filtration rate in full-term infants during the first year of life. J Pediatr. 1984 Jun;104(6):849-54. doi: 10.1016/s0022-3476(84)80479-5.
- Individual participant dataSharing planned: Yes. Information available on the Grünenthal Web Site
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Grünenthal Study Director study director
Grünenthal GmbH
43 sites in 10 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Tapentadol oral solution 4 mg/mL and Tapentadol oral solution 20 mg/mL in people with Acute Pain, run by Grünenthal GmbH at 43 sites in 10 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 42 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Jan 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 43 sites in United States, Poland, Spain, Bulgaria, Czechia and 5 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 18 Jan 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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] (time frame: Up to 12 hours). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02081391, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jan 2020.