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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 216
- 试验地点
- 43
- 主要终点
- 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]
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 1 Day 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
- •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.
研究组 & 干预措施
Tapentadol immediate-release (IR)
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.
干预措施: Tapentadol oral solution 4 mg/mL (Drug)
Tapentadol immediate-release (IR)
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.
干预措施: Tapentadol oral solution 20 mg/mL (Drug)
Placebo
Matching placebo oral solution was administered every 4 hours (±15 min) up to 72 hours.
干预措施: Placebo (Other)
结局指标
主要结局
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]
时间窗: 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]
时间窗: 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.
次要结局
- Acceptability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale(Up to 96 hours)
- Clinical Global Impression of Change (CGIC)(Day 4)
- Acceptability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale(Up to 96 hours)
- 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)
- Palatability of IMP After First Dose Assessed Using Facial 5-point Hedonic Scale(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(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(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(Up to 96 hours)
- Time to Receive First and Second Patient- or Nurse-controlled Analgesia After the First Dose of IMP(Up to 96 hours)
- Time From First Dose of IMP Until Treatment Discontinuation Due to Lack of Efficacy(Up to 72 hours)
- Patient Global Impression of Change (PGIC)(Day 4)
- Palatability of IMP After Last Dose Assessed Using Facial 5-point Hedonic Scale(Up to 96 hours)