Clinical trial NCT02081391: A Study to Look at Tapentadol Oral Solution in Children and Adolescents in Pain
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Pain
Keywords: Acute Pain
Post-operative
Tapentadol
Opioid Treatment
Pediatric Participants
Lead sponsor: Grünenthal GmbH
Sponsor class: INDUSTRY
Collaborators: name: Depomed
First posted: 2014-03-07
Enrollment: 216
Sex: ALL
Minimum age (years): 1
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. Informed consent, and if applicable assent, given according to local regulations.
2. Male or female participant aged from birth (at least 37 weeks gestational age) to less than 18 years.
3. A female participant must be pre-menarchal, or surgically incapable of childbearing, or sexually abstinent, or if a female participant is sexually active, then she must be practicing an effective method of birth control (e.g., prescription hormonal contraceptives, intra-uterine devices used according to the product's instruction, double-barrier methods) before trial entry and throughout the trial.
4. A female participant must have a negative pregnancy test if aged 12 years or older, or is post-menarchal, or is sexually active.
5. Participant has undergone surgery (other than brain surgery or gastrointestinal surgery expected to affect the absorption of tapentadol \[in the investigator's judgment\]) that, in the investigator's opinion, would reliably produce moderate to severe pain requiring opioid treatment for at least 24 hours after first dose of IMP. Participants must remain hospitalized until the End of Treatment Visit.
6. Participant has received post-operative morphine or hydromorphone by NCA/PCA, with or without a background infusion of the same opioid, according to standard of care prior to allocation/randomization to IMP and participant is expected to require this morphine or hydromorphone by NCA/PCA after starting IMP.
7. Participant is able to tolerate liquids at the time of allocation/randomization to IMP.

Exclusion Criteria:

1. Participant, parent or the legal representative is an employee of the investigator or trial site, with direct involvement in the proposed trial or other trials under the direction of that investigator or trial site, or family member of the employees or the investigator.
2. Participant has been previously exposed to tapentadol.
3. Participant has received an experimental drug or used an experimental medical device within 28 days before allocation/randomization to IMP, or within a period less than 10 times the drug's half-life, whichever is longer.
4. Participant has a history or current condition of any one of the following:

   * Non-febrile seizure disorder.
   * Epilepsy.
   * Serotonin syndrome.
   * Traumatic or hypoxic brain injury, brain contusion, stroke, transient ischemic attack, intracranial hematoma, post-traumatic amnesia, brain neoplasm, or episode(s) of unconsciousness of more than 24 hours.
5. Participant has a history or current condition of any one of the following:

   * Moderate to severe renal or hepatic impairment.
   * Abnormal pulmonary function or clinically relevant respiratory disease (e.g., acute or severe bronchial asthma, hypercapnia).
6. Participant has a concomitant disease or disorder (e.g., endocrine, metabolic, neurological, psychiatric, infection, febrile seizure, paralytic ileus) that in the opinion of the investigator may affect or compromise participant safety during the study participation.
7. Participant has history of suicidal ideation or behavior.
8. Participant is obese in the investigator's judgment. Obesity can be determined based on appropriate body mass index (BMI) charts or tables; e.g., a BMI above the 97th percentile for children based on the World Health Organization growth charts or the participant's weight is less than 2500 grams.
9. Participant has a clinically relevant history of hypersensitivity, allergy, or contraindication to the supplemental opioid analgesic medication or tapentadol, or the excipients, or naloxone.
10. Participant is not able to understand and comply with the protocol as appropriate for the age of the participant or participant is cognitively impaired in the investigator's judgment such that they cannot comply with the protocol
11. Participant has a history of alcohol and/or substance abuse in the investigator's judgment based on participant's history and physical examination.
12. Participant is taking prohibited concomitant medication.
13. Participant has received a long-acting opioid for the treatment of pain following surgery within 6 hours of allocation/randomization to IMP.
14. Participant has clinically relevant (in the investigator's judgment) abnormal values for clinical chemistry or hematology (local laboratory sample taken after surgery).

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

    A participant aged from birth to less than 6 months old is excluded if:
    * Aspartate transaminase or alanine transaminase is \>3-times upper limit of normal.
    * There is pathological jaundice in the opinion of the investigator.
    * Glomerular filtration rate (calculated according to Schwartz et al. 1984) is:

      * \<20 mL/min/1.73 m2 for participants \<1 week post-partum.
      * \<30 mL/min/1.73 m2 for participants 1 week to 8 weeks post-partum.
      * \<50 mL/min/1.73 m2 for participants \>8 weeks postpartum to \<6 months old.
15. Participant has:

    * Clinically relevant abnormal electrocardiogram (ECG).
    * Signs of pre-excitation syndrome.
    * Brugada's syndrome.
    * QT or corrected QT interval (QTc) interval \>470 ms for children aged 6 years to less than 18 years old.
    * QT or QTc interval \>460 ms for children aged from birth to less than 6 years old.
16. Peri- or post-operative analgesia supplied by a continuous regional technique (e.g., nerve block, wound infiltration catheter) or participant-controlled epidural analgesia that was terminated less than 6 hours before allocation/randomization to IMP.
17. Participant has post-operative clinically unstable systolic and diastolic blood pressure, heart rate, respiratory depression, or clinically unstable upper or lower airway conditions (in the investigator's judgment), or a saturation of peripheral oxygen (SpO2) \<92% at the time of randomization (allocation/randomization to IMP).
18. Female participant is breast-feeding a child.
19. Participant requires continuous positive airway pressure or mechanical ventilation, at the time of allocation to IMP.
20. The mother of a newborn participant or the breastfeeding mother of a participant was administered a prohibited medication.

Primary outcomes:
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]
timeFrame: Up to 12 hours
measure: 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]
timeFrame: Up to 24 hours
Secondary outcomes:
measure: 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
timeFrame: Up to 96 hours
measure: Palatability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale
timeFrame: Up to 96 hours
measure: Acceptability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale
timeFrame: Up to 96 hours
measure: Change From Baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) Total Score in Participants Aged Less Than 6 Years
timeFrame: Up to 96 hours
measure: Change From Baseline Pain Intensity Using the Faces Pain Scale-Revised (FPS-R) in Participants Aged 6 to Less Than 12 Years
timeFrame: Up to 96 hours
measure: Change From Baseline in the Visual Analog Scale (VAS) Pain Intensity Score in Participants Aged 12 to Less Than 18 Years
timeFrame: Up to 96 hours
measure: Clinical Global Impression of Change (CGIC)
timeFrame: Day 4
measure: Patient Global Impression of Change (PGIC)
timeFrame: Day 4
measure: Time to Receive First and Second Patient- or Nurse-controlled Analgesia After the First Dose of IMP
timeFrame: Up to 96 hours
measure: Time From First Dose of IMP Until Treatment Discontinuation Due to Lack of Efficacy
timeFrame: Up to 72 hours
measure: Palatability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale
timeFrame: Up to 96 hours
measure: Acceptability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale
timeFrame: Up to 96 hours
Other outcomes:
measure: 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
timeFrame: Up to 24 hours
measure: 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
timeFrame: Up to 24 hours
Locations:
city: Little Rock
country: United States
facility: US008
state: Arkansas
city: Stanford
country: United States
facility: US004
state: California
city: Miami
country: United States
facility: US011
state: Florida
city: Louisville
country: United States
facility: US012
state: Kentucky
city: Bronx
country: United States
facility: US001
state: New York
city: Bronx
country: United States
facility: US018
state: New York
city: Durham
country: United States
facility: US006
state: North Carolina
city: Cincinnati
country: United States
facility: US016
state: Ohio
city: Philadelphia
country: United States
facility: US015
state: Pennsylvania
city: Pittsburgh
country: United States
facility: US014
state: Pennsylvania
city: Dallas
country: United States
facility: US003
state: Texas
city: Houston
country: United States
facility: US005
state: Texas
city: Milwaukee
country: United States
facility: US007
state: Wisconsin
city: Pleven
country: Bulgaria
facility: BG003
city: Sofia
country: Bulgaria
facility: BG005
city: Stara Zagora
country: Bulgaria
facility: BG002
city: Split
country: Croatia
facility: HR003
city: Zagreb
country: Croatia
facility: HR001
city: Karviná
country: Czechia
facility: CZ004
city: Olomouc
country: Czechia
facility: CZ003
city: Praha 4 - Krč
country: Czechia
facility: CZ001
city: La Tronche
country: France
facility: FR002
city: Lille
country: France
facility: FR001
city: Limoges
country: France
facility: FR004
city: Freiburg
country: Germany
facility: DE001
city: Budapest
country: Hungary
facility: HU004
city: Debrecen
country: Hungary
facility: HU003
city: Bydgoszcz
country: Poland
facility: PL011
city: Gdansk
country: Poland
facility: PL010
city: Lodz
country: Poland
facility: PL005
city: Lublin
country: Poland
facility: PL002
city: Olsztyn
country: Poland
facility: PL009
city: Rzeszow
country: Poland
facility: PL014
city: Torun
country: Poland
facility: PL007
city: Warszawa
country: Poland
facility: PL004
city: Warszawa
country: Poland
facility: PL008
city: Barcelona
country: Spain
facility: ES002
city: Madrid
country: Spain
facility: ES005
city: Madrid
country: Spain
facility: ES007
city: Santiago de Compostela
country: Spain
facility: ES009
city: Valladolid
country: Spain
facility: ES006
city: Bristol
country: United Kingdom
facility: GB003
city: Sheffield
country: United Kingdom
facility: GB001
Study officials:
affiliation: Grünenthal GmbH
name: Grünenthal Study Director
role: STUDY_DIRECTOR
References:
citation: 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.