Methoxyflurane Analgesia for Paediatric Injuries

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.

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.

At least 220 eligible children and adolescents aged 9 to \< 18 years (110 children aged 9 to \< 12 years and 110 adolescents aged 12 to \< 18 years) were to be randomised in a 1:1 ratio to receive either methoxyflurane or placebo from the PENTHROX inhaler. Additionally, at least 36 eligible children aged 6 to \< 9 years were to be randomized in a 1:1 ratio. Randomisation was stratified by age group (6 to \< 9 years; 9 to \< 12 years; 12 to \< 18 years).

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. In order to improve patient recruitment, a protocol amendment in July 2019 widened the range of the eligible VAS pain score from 60 to 80 mm to 55 to 85 mm. However, this amendment was quite late in study conduct and shortly prior to the COVID pandemic, hence the majority of patients were recruited under the original criterion (60 to 80mm).

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.

Eligibility Criteria:
Inclusion Criteria:

1. Patients aged 6 to less than 18 years.
2. Attending ED following minor trauma.
3. 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\*.
4. Pain scores 55 to 85 mm as measured using VAS or 6 to 8 using Wong-Baker FACES Pain Rating scale.

Note: the range for VAS pain scores was widened from 60 to 80 mm to 55 to 85 mm to improve patient recruitment but very few patients were recruited after that amendment.

Exclusion Criteria:

1. Critical, life-or limb-threatening condition requiring immediate management.
2. Open fractures.
3. 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.
4. Patients deemed not cognitively capable of effectively self-administering the study drug using the PENTHROX® inhaler.
5. 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.
6. Patients with chronic pain.
7. Patients having received an Investigational Medicinal Product (IMP) in the preceding 3 months.
8. Known pregnancy or breastfeeding females.
9. Personal or familial hypersensitivity to PENTHROX® or any fluorinated anaesthetics.
10. Patients requiring oxygen therapy.
11. Patients with known or genetic susceptibility to malignant hyperthermia or a history of severe adverse reactions in either patient or relatives.
12. Clinically evident respiratory depression.
13. Previous use of methoxyflurane (including as an IMP).
14. History of signs of liver damage including after previous PENTHROX® (methoxyflurane) use or halogenated hydrocarbon anaesthesia.
15. Known significant renal impairment.
16. Altered level of consciousness due to any cause including head injury, drugs, or alcohol.
17. Known significant cardiovascular instability (e.g., pathological arrhythmia).
18. Inability to participate in telephonic follow-up on (Day 14 ± 2 days) as per study requirement