A Randomised, Double-blind, Multicentre, Placebo Controlled Study to Evaluate the Safety and Efficacy of Methoxyflurane (PENTHROX®) for the Treatment of Acute Pain in Children and Adolescents From 6 to Less Than 18 Years of Age (Presenting to an Emergency Department With Minor Trauma)
试验速览
- 阶段
- 3 期
- 入组人数
- 222
- 试验地点
- 11
- 主要终点
- Difference in pain intensity between methoxyflurane and placebo as measured by change from baseline in VAS pain scores at 15 minutes for patients aged 9 to < 18 years.
研究概览
简要总结
This is a randomised, double-blind, multicentre, placebo controlled study to evaluate the safety and efficacy of methoxyflurane (Penthrox®) for the treatment of acute pain in children and adolescents from 6 to less than 18 years of age (presenting to an Emergency Department with minor trauma). It is conducted as part of the Paediatric Investigation Plan (PIP) agreed with the Paediatric Committee (PDCO) of the European Medicines Agency (EMA).
The study aims to provide evidence under blinded controlled conditions that Penthrox is safe and effective in patients aged 6 to less than 18 years presenting to ED with pain associated with minor trauma.
详细描述
This is a randomised, double-blind, multicentre, placebo-controlled study in children and adolescents aged 6 to less than 18 years presenting to an ED requiring analgesia for acute pain, with visual analogue scale (VAS) score of 55 to 85 mm or Wong-Baker Faces score of 6 to 8 associated with minor trauma. In the context of the current study, minor trauma refers to "a non-critical and non-limb threatening physical wound or injury of the tissues", such as, soft tissue injuries, fractures of the extremities, burns, penetration by foreign bodies, lacerations, dislocation, contusions, etc.
This study will include screening and enrolment, followed by treatment and day 14 ± 2 day safety follow-up post treatment. The procedure for screening and enrolment including obtaining consent/assent is to occur on the same day. The expected duration for each patient in the study is up to 16 days.
The clinician/research nurse must ascertain that the patient has not been pre-medicated with an analgesic within 5 hours prior to randomisation, except Entonox (50% nitrous oxide and 50% oxygen mixture) which is prohibited within 30 minutes prior to randomisation, diclofenac which is prohibited within 8 hours prior to randomisation or oral morphine which is prohibited within 10 hours prior to randomisation.
Eligible children and adolescents will be randomised in a 1:1 ratio (222 eligible patients; 156 children and 66 adolescents) to have 111 patients per treatment arm (38 children aged 6 to 8 years, 40 children aged 9 to 11 years and 33 adolescents aged 12 to < 18 years). Eligible patients will receive either methoxyflurane or placebo from the PENTHROX® inhaler in a 1:1 ratio.
Pain scores will be assessed using the VAS or Wong-Baker FACES® Pain Rating scale in younger children who cannot utilise the VAS tool. A pain score will be measured at screening to establish study eligibility. After randomisation, a baseline pain score will be recorded between 5 to 60 minutes after the screening pain score and will act as a validation score. If the baseline pain score falls outside the range of 55 to 85 mm on the VAS or 6 to 8 on Wong-Baker FACES Pain Rating scale, the patient will be withdrawn from the study (randomised, but not treated). Patients who have a pain score between 55 and 85 mm on the VAS or 6 to 8 on Wong-Baker FACES Pain Rating scale at screening and baseline will be eligible to receive treatment.
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)
入排标准
- 年龄范围
- 6 Years 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients aged 6 to less than 18 years.
- •Attending ED following minor trauma.
- •Evidence of signed and dated informed consent/assent document indicating that the patient (and/or a parent/legal guardian) has been informed of all pertinent aspects of the study*.
- •Pain scores 55 to 85 mm as measured using VAS or 6 to 8 using Wong-Baker FACES Pain Rating scale.
排除标准
- •Critical, life-or limb-threatening condition requiring immediate management.
- •Open fractures.
- •Patients with any other clinical condition that may, in the opinion of the Investigator, impact the patient's ability to participate in the study, or the study results.
- •Patients deemed not cognitively capable of effectively self-administering the study drug using the PENTHROX® inhaler.
- •Treatment with any analgesic agent within 5 hours prior to randomisation, except Entonox (50% nitrous oxide and 50% oxygen mixture) which is prohibited within 30 minutes prior to randomisation, diclofenac which is prohibited within 8 hours prior to randomisation or oral morphine which is prohibited within 10 hours prior to randomisation.
- •Patients with chronic pain.
- •Patients having received an Investigational Medicinal Product (IMP) in the preceding 3 months.
- •Known pregnancy or breastfeeding females.
- •Personal or familial hypersensitivity to PENTHROX® or any fluorinated anaesthetics.
- •Patients requiring oxygen therapy.
- •Patients with known or genetic susceptibility to malignant hyperthermia or a history of severe adverse reactions in either patient or relatives.
- •Clinically evident respiratory depression.
- •Previous use of methoxyflurane (including as an IMP).
- •History of signs of liver damage including after previous PENTHROX® (methoxyflurane) use or halogenated hydrocarbon anaesthesia.
- •Known significant renal impairment.
- •Altered level of consciousness due to any cause including head injury, drugs, or alcohol.
- •Known significant cardiovascular instability (e.g., pathological arrhythmia).
- •Inability to participate in telephonic follow-up on (Day 14 ± 2 days) as per study requirement
研究组 & 干预措施
PENTHROX® (methoxyflurane)
PENTHROX® (methoxyflurane) administered as a liquid for inhalation and should be self-administered under supervision of research nurse trained in its administration, using the hand held PENTHROX® inhaler.
One vial of 3 mL PENTHROX® is to be vaporised in a PENTHROX® inhaler. On finishing the 3 mL dose, another 3 mL may be used.
Dose of PENTHROX® should not exceed 6 mL in a single administration.
The patient is instructed to inhale ten successive inhalations of PENTHROX® (methoxyflurane) followed by additional intermittent inhalations as required.
The maximum dose administered will not exceed 6 mL of methoxyflurane.
干预措施: Methoxyflurane (Drug)
Normal saline
Normal saline will be administered as a liquid for inhalation and should be self-administered under supervision of research nurse trained in its administration, using the hand held PENTHROX® inhaler.
One vial of 5 mL of normal saline is to be vaporised in a PENTHROX® inhaler. On finishing the 5 mL dose, another 5 mL may be used.
Dose of normal saline should not exceed 10 mL in a single administration.
In this study, the patient is instructed to inhale ten successive inhalations of placebo followed by additional intermittent inhalations as required.
The maximum dose administered will not exceed 10 mL of placebo (2 × 5 mL)
干预措施: Normal saline (Drug)
结局指标
主要结局
Difference in pain intensity between methoxyflurane and placebo as measured by change from baseline in VAS pain scores at 15 minutes for patients aged 9 to < 18 years.
时间窗: Baseline to 15 minutes
The primary analysis was conducted using an analysis of covariance (ANCOVA) model with change from baseline in pain score at 15 minutes as the dependent variable, continuous baseline pain, treatment and age group (9 to \< 12 years versus 12 to \< 18 years) as fixed effects and centre (site) as a random effect. Missing pain scores at 15 (± 2) minutes were imputed using worst observation carried forward (WOCF) and pain scores taken after the initiation of rescue medication were included. Note the population for the primary analysis was changed in the protocol following an amendment to the sample size across the age groups due to difficulties recruiting patients into the youngest (6 to \< 9 years) age group and agreement with agencies to focus the primary analysis on 9 to \< 18-year-olds.
次要结局
- Difference in pain intensity between methoxyflurane and placebo as measured by change from baseline in VAS pain scores at 15 minutes in the ITT Population (patients aged 6 to <18 years).(Baseline to 15 minutes)
- Responder analysis - number of responders, who achieve 30% reduction in VAS score compared to baseline, at 15 minutes in the ITT population (patients aged 6 to <18 years).(Baseline to 15 minutes)
- Longitudinal analysis of VAS pain scores at 5, 10, 15, and 20 minutes following commencement of treatment in the ITT population (patients aged 6 to <18 years).(Baseline to 5, 10, 15 and 20 minutes)
- Number of inhalations taken before first pain relief is summarised by category (1 to 10 inhalations, 11 to 20 inhalations, 21 to 30 inhalations, >30 inhalations, or no relief recorded) in the ITT population (patients aged 6 to <18 years).(From baseline until time at which first pain relief is reported, assessed up to Emergency Department discharge or inpatient admission.)
- Rescue medication requested within 20 (+2 minutes) minutes of start of treatment and any time during treatment in the ITT population (patients aged 6 to &amp;lt;18 years).(From baseline until request of rescue medication, assessed until point of either Emergency Department discharge or inpatient admission.)
- The time to request for rescue medication in the ITT population (patients aged 6 to &lt;18 years).(From baseline until time at which rescue medication is first requested, assessed up to time of Emergency Department discharge or inpatient admission.)
- The time to first pain relief derived as time in minutes since start of study treatment until first pain relief in the ITT population (patients aged 6 to &lt;18 years).(From baseline until time at which first pain relief is reported, assessed up to Emergency Department discharge or inpatient admission.)
- Number of inhalations taken before first pain relief split by whether the hole was covered at least once or not covered in the ITT population (patients aged 6 to &lt;18 years).(Baseline until time at which first pain relief is reported, assessed up to Emergency Department discharge or inpatient admission..)
- Global medication performance assessment by patient, clinician and research nurse: 0 = poor to 4 = excellent, measured after completion of treatment.(From baseline, assessed up to Emergency Department discharge or inpatient admission.)
- Heart rate(From baseline to 5, 10, 15, 20 and 30 minutes, followed by a 30-minute interval thereafter assessed until the point of either Emergency Department discharge or inpatient admission.)
- Respiratory rate(From baseline to 5, 10, 15, 20 and 30 minutes, followed by a 30-minute interval thereafter assessed until the point of either Emergency Department discharge or inpatient admission.)
- Oxygen saturation(From baseline to 5, 10, 15, 20 and 30 minutes, followed by a 30-minute interval thereafter assessed until the point of either Emergency Department discharge or inpatient admission.)