Methoxyflurane Analgesia for Paediatric Injuries

Study Overview
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Brief Summary
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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.

Detailed Description
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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. Following enrolment and initial assessments, the research nurse will assist the patient to self administer ten successive inhalations of PENTHROX® (methoxyflurane) or placebo. The research nurse, the treating clinician and the patient will be blind to the treatment administered. Patients/parents/legal guardians will be advised that rescue medication will be available immediately on request at any time during or after the completion of the treatment. The rescue medication to be used will be at the discretion of the blinded clinician. Rescue analgesia should be near the potency equivalence of active PENTHROX. Depending on the standard practice of the participating site, this may include intranasal fentanyl, intranasal diamorphine, intranasal ketamine, Entonox (50% nitrous oxide and 50% oxygen mixture), intravenous morphine, or oral morphine.

Official Title
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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)

Conditions
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Pain, Acute

Intervention / Treatment
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* Drug: Methoxyflurane
* Drug: Normal saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PENTHROX® (methoxyflurane)<br>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. | Drug: Methoxyflurane<br>* PENTHROX 3mL inhalation vapour, liquid<br>* Other names: Penthrox®;|
| Placebo Comparator: Normal saline<br>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) | Drug: Normal saline<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in pain intensity between active drug and placebo as measured by VAS from baseline to 15 minutes after the commencement of treatment. | The primary analysis shall be an intention to treat (ITT) analysis of the difference between treatment and placebo on the VAS pain score. The IIT population includes patients who were randomised, received at least one dose of IMP and had at least one post-baseline efficacy assessment. The primary model shall be an analysis of covariance (ANCOVA) of the VAS pain score at 15 minutes following the start of inhalation of IMP, with baseline pain as covariate, treatment and age group as fixed effect and site as random effect using the ITT population. The treatment effect shall be estimated as the average difference between the methoxyflurane treated group and the placebo group at 15 minutes. | Baseline to 15 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Responder analysis - number of responders, who achieve 30% reduction in VAS score compared to baseline, at 15 minutes. | The difference between treatment and placebo on the responder. Logistic regression analyses will be performed for the responder (30% reduction in VAS score compared to baseline, at 15 minutes) variables adjusted for baseline VAS score and age group. Odds ratio and 95% CI for the odds ratio of treatment group comparisons will be given. | Baseline to 15 minutes | 
| Responder analysis - exploratory: Total number (and representative percentage total) of responders who achieve 30% reduction in VAS score compared to baseline at 5, 10 and 20 minutes. | The difference between treatment and placebo on the responder. Logistic regression analyses will be performed for the responder (30% reduction in VAS score compared to baseline, at 5, 10 and 20 minutes) variables adjusted for baseline VAS score and age group. Odds ratio and 95% CI for the odds ratio of treatment group comparisons will be given. | Baseline to 5, 10, and 20 minutes | 
| Change in pain intensity as measured using VAS from baseline to 5, 10, 15, 20 and 30 minutes, followed by a 30-minute interval thereafter until the point of ED discharge/in-patient admission decision. | Repeated measure analysis of variance (ANOVA) mixed model repeated measures (MMRM) of the VAS pain score at 5, 10, 15 and 20 minutes following the start of inhalation of IMP, will include age group as fixed term and baseline VAS pain score as the covariate using the ITT population. The treatment effect will be estimated as the average difference between the methoxyflurane treated group and the placebo group across these time points. An unstructured covariance matrix shall be assumed for the repeated measures and a single variance component for the random centre effect. The repeated measures analysis shall include fixed-effect terms for treatment and time and random centre effect. Analysis of Covariance (ANCOVA) of the VAS pain scores at 30, 60, 90 and 120 minutes and so forth following the start of inhalation of IMP until discharge/in-patient admission decision, with baseline pain as covariate, treatment and age group as fixed effect and site as random effect. | Baseline to 5, 10, 15, 20 and 30 minutes, followed by a 30-minute interval thereafter until the point of either Emergency Department discharge/in-patient admission or up to 4 hours after study start. | 
| Rescue medication requested within 20 minutes of start of treatment and any time during treatment. | Rescue medication requested within 20 minutes of start of treatment will be assessed by logistic regression adjusted for baseline VAS score and age group, and summaries of the name, dose and route will be presented. | Baseline until point of either Emergency Department discharge/in-patient admission or up to 4 hours after study start. | 
| The time to request for rescue medication. | Rescue medication requested anytime during treatment beyond 20 minutes of start of treatment assessed by logistic regression adjusted for baseline VAS score and age group, and summaries of the name, dose and route will be presented. | Baseline until time at which rescue medication is first requested during the Emergency Department admission, or up to 4 hours after study start. | 
| The time to first pain relief. | The time to first pain relief will be assessed by Proportional Hazards modelling adjusted for the baseline VAS score and age group. | Baseline until time at which first pain relief is reported during the Emergency Department admission, or up to 4 hours after study start. | 
| The number of inhalations taken before first pain relief and whether the patient covered the hole in the Inhaler during inhalation. | The number of inhalations taken before first pain relief will be assessed by normal regression adjusted for baseline VAS score and age group. | Baseline until time at which first pain relief is reported during the Emergency Department admission, or up to 4 hours after study start. | 
| Global medication performance assessment by patient, clinician and research nurse: 0 = poor to 4 = excellent, measured after completion of treatment. | Global assessment of medication performance using a 5-point Likert scale will be completed by the patient, the treating clinician and the research nurse, prior to ED discharge/in-patient admission decision, to rate the global medication performance on a scale of 0 to 4 (poor to excellent) where score of 0 is Poor, 1 is Fair, 2 is Good, 3 is Very Good and 4 is Excellent. The assessment by the patient, treating clinical and research nurse of the global medication performance following completion of treatment will all be assessed by ordinal logistic regression. | Baseline until point of Emergency Department discharge, or up to 4 hours after study start. | 
| Number of adverse events (AEs) experienced during treatment, not associated with the underlying minor trauma | The safety outcome variables will be analysed by means of descriptive statistics. Summaries will be presented overall, for AEs of Grade ≥ 3, for related treatment emergent adverse events (TEAEs) and SAEs. The number and percentage of patients with at least 1 AE, SAE, discontinuation of IMP due to AEs, and AEs of severe intensity will be summarised separately for TEAEs and all AEs. Any AEs determined to be of interest or occurring frequently may be summarised separately using the same methodology. Key information tables and narratives will be presented for SAEs, discontinuation of IMP due to AE and deaths. | Baseline until point of Emergency Department discharge, or up to 4 hours after study start. | 
| Change in blood pressure (mmHg) (systolic/diastolic) | Blood pressure data will be summarised by treatment at each time point using standard summary statistics. The mean change in blood pressure will be calculated for methoxyflurane and placebo. | Baseline to 5, 10, 15, 20 and 30 minutes, followed by a 30-minute interval thereafter until the point of either Emergency Department discharge/in-patient admission or up to 4 hours after study start. | 
| Change in heart rate (beats/minute) | Heart rate data will be summarised by treatment at each time point using standard summary statistics. The mean change in heart rate will be calculated for methoxyflurane and placebo. | Baseline to 5, 10, 15, 20 and 30 minutes, followed by a 30-minute interval thereafter until the point of either Emergency Department discharge/in-patient admission or up to 4 hours after study start. | 
| Change in respiratory rate (breaths/minute) | Respiratory rate data will be summarised by treatment at each time point using standard summary statistics. The mean change in respiratory rate will be calculated for methoxyflurane and placebo. | Baseline to 5, 10, 15, 20 and 30 minutes, followed by a 30-minute interval thereafter until the point of either Emergency Department discharge/in-patient admission or up to 4 hours after study start. | 
| Change in oxygen saturation (%) | Oxygen saturation data will be summarised by treatment at each time point using standard summary statistics. The mean change in respiratory rate will be calculated for methoxyflurane and placebo. | Baseline to 5, 10, 15, 20 and 30 minutes, followed by a 30-minute interval thereafter until the point of either Emergency Department discharge/in-patient admission or up to 4 hours after study start. | 
| Change in sedation score | Patient sedation will be assessed using University of Michigan sedation scale (UMSS). The UMSS is a simple, valid and reliable tool to assess and document depth of sedation in children. The UMSS assesses the level of alertness on a 5-point scale ranging from 0 (awake and alert) to 4 (unarousable). The mean change in sedation score will be calculated for methoxyflurane and placebo. | Baseline to 5, 10, 15, 20 and 30 minutes, followed by a 30-minute interval thereafter until the point of either Emergency Department discharge/in-patient admission or up to 4 hours after study start. | 
| Total number (and representative percentage total) of AE(s) at 14 ± 2 days following ED discharge | The patient/parent will be given a diary card and asked to record any symptoms experienced from the time of discharge until Day 14 ± 2 days telephonic follow-up. During the follow-up consultation, the research nurse will complete a questionnaire to record AEs and assess potential hepatotoxicity and nephrotoxicity. The follow-up questionnaire contains a set of four questions. If the response to any question is marked as Yes, detailed response will be needed. Each AE is to be evaluated for duration, severity, seriousness and causal relationship to the IMP or study procedures. Patients who are randomised but did not receive IMP, are not required to complete the diary card or perform the Day 14 ± 2 day follow-up call. AEs until at least 14 ± 2 days following ED discharge, using follow-up questionnaire that includes high output nephrotoxicity, will be summarised for each treatment by means of descriptive statistics. | Baseline to 14 ± 2 days post-treatment | 
| Total number (and representative percentage total) of Patients at 14 ± 2 days following ED/in-patient discharge with at least one or more AE(s) | The number and percentage of Patients with at least 1 AE, SAE or AE of severe intensity will be summarised separately for all AEs. Any AE determined to be of interest or occurring frequently may be summarised separately. Key information tables and narratives will be presented for SAEs. Adverse events until at least 14 ± 2 days following ED discharge, using follow-up questionnaire that includes high output nephrotoxicity, will be summarised for each treatment. | Baseline to 14 ± 2 days post-treatment |