Methoxyflurane Analgesia for Paediatric Injuries

NCT03215056 | Completed Phase 3 DMC

• 2 other identifiers: MEOF-0022016-004290-41
• Study Type: interventional
• Target: 192
• Locations: 2 countries
• Sites: 11

Brief Summary

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.

Conditions

Pain, Acute

Outcome Measures

Primary Outcomes (1)

• 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.

  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.

  Baseline to 15 minutes

Secondary Outcomes (12)

• 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, &gt;30 inhalations, or no relief recorded) 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.

• 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;amp;lt;18 years).

  From baseline until request of rescue medication, assessed until point of either Emergency Department discharge or inpatient admission.

Other Outcomes (3)

• Treatment-emergent adverse events (TEAEs); all, prior to discharge and post discharge up to (14 ± 2 days following ED discharge/inpatient decision).

  Baseline until 14 days post discharge

• Patient sedation score based on University of Michigan Sedation Scale (UMSS).

  Baseline to 5, 10, 15, 20 and 30 minutes, followed by a 30-minute interval thereafter, assessed up to ED discharge/inpatient admission.

• Blood pressure

  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.

Study Arms (2)

PENTHROX® (methoxyflurane)

EXPERIMENTAL

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

Normal saline

PLACEBO COMPARATOR

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

Interventions

Methoxyflurane DRUG

PENTHROX 3mL inhalation vapour, liquid

Also known as: Penthrox®

PENTHROX® (methoxyflurane)

Normal saline DRUG

Placebo

Normal saline

Eligibility Criteria

• Age: 6 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Medical Developments International Limited: lead
• Pediatric Emergency Research in the UK and Ireland (PERUKI): collaborator
• Quintiles, Inc.: collaborator

Study Sites (11)

Our Lady's Children's Hospital

Crumlin, Dublin, D12 N512, Ireland

Location

Royal Aberdeen Children's Hospital

Aberdeen, Aberdeenshire, AB25 2ZG, United Kingdom

Location

Bristol Royal Hospital for Children

Bristol, Avon, BS2 8BJ, United Kingdom

Location

Royal Devon and Exeter Hospital (Wonford)

Exeter, Devon, EX2 5DW, United Kingdom

Location

Royal Alexandra Children's Hospital

Brighton, East Sussex, BN2 5BE, United Kingdom

Location

Royal London Hospital

London, Greater London, E1 1BB, United Kingdom

Location

Alder Hey Children's Hospital

Liverpool, Merseyside, L12 2AP, United Kingdom

Location

Nottingham University Hospitals City Campus

Nottingham, Notttinghamshire, NG5 1PB, United Kingdom

Location

Birmingham Children's Hospital

Birmingham, West Midlands, B4 6NH, United Kingdom

Location

Leicester Royal Infirmary

Leicester, LE1 5WW, United Kingdom

Location

Ormskirk District Hospital

Ormskirk, L39 2AZ, United Kingdom

Location

Related Publications (2)

• Hartshorn S, Barrett MJ, Lyttle MD, Yee SA, Irvine AT; in collaboration with Paediatric Emergency Research in the UK and Ireland (PERUKI). Inhaled methoxyflurane (Penthrox(R)) versus placebo for injury-associated analgesia in children-the MAGPIE trial (MEOF-002): study protocol for a randomised controlled trial. Trials. 2019 Jul 4;20(1):393. doi: 10.1186/s13063-019-3511-4.

  PMID: 31272493 BACKGROUND

• Hartshorn S, Barrett MJ, Bloom B, Lyttle MD, Walton E, Steel K, Yee SA, Irvine A; Paediatric Emergency Research in the United Kingdom & Ireland (PERUKI). Treatment of acute trauma-related pain in children and adolescents with methoxyflurane (Penthrox(R)) compared to placebo (MAGPIE): A randomised clinical trial. Injury. 2025 Dec;56(12):112830. doi: 10.1016/j.injury.2025.112830. Epub 2025 Oct 20.

  PMID: 41242203 DERIVED

MeSH Terms

Conditions

Acute Pain

Interventions

Methoxyflurane; Saline Solution

Condition Hierarchy (Ancestors)

Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Ethyl Ethers; Ethers; Organic Chemicals; Methyl Ethers; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Stuart Hartshorn

  Birmingham Children's Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 2, 2017
• First Posted: July 12, 2017
• Study Start: August 14, 2017
• Primary Completion: June 15, 2022
• Study Completion: June 15, 2022
• Last Updated: September 19, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

GB (10); IE (1)