Table 2.

Trial objectives and endpoints

Objective	Endpoint
Primary objective
To demonstrate that the efficacy of inhaled methoxyflurane in acute cases (within 10 min) is non-inferior to the SoC for the treatment of moderate-to-severe pain (IV morphine/ketoprofen/paracetamol)	Change in VAS pain intensity from baseline (randomisation) to 3, 5, and 10 min (all patients)
Co-primary objective
To demonstrate that the efficacy of inhaled methoxyflurane is superior to that of the SoC for the treatment of moderate pain (IV ketoprofen/paracetamol)	Change in VAS pain intensity from baseline (randomisation) to 3, 5 and 10 min (patients with moderate pain only)
Secondary objectives
To demonstrate that the efficacy of inhaled methoxyflurane in acute cases (within 10 min) is superior to the SoC for the treatment of moderate-to-severe pain (IV morphine/ketoprofen/paracetamol)	Change in VAS pain intensity from baseline (randomisation) to 3, 5, and 10 min (all patients)
To compare the efficacy of inhaled methoxyflurane with SoC in terms of the use of additional analgesia (rescue medication) in acute cases	Percentage of patients resorting to additional analgesia (rescue medication) within 30 min (all patients)
To compare the efficacy of inhaled methoxyflurane with SoC in the treatment of moderate-to-severe acute pain (after 15, 20, 25, and 30 min)	Change in VAS pain intensity from baseline (randomisation) to 15, 20, 25 and 30 min (all patients)
To compare the efficacy of inhaled methoxyflurane with SoC in terms of the rate of onset of the analgesic effect	Time from randomisation to the onset of pain relief (all patients)
To compare inhaled methoxyflurane with SoC in terms of efficacy in the opinion of the patient and the practicality of use in the opinion of the healthcare professional	Rating of study treatment efficacy as perceived by the patient and rating of the practicality of study treatment assessed by the healthcare professional who administered the treatment, assessed using a 5-point Likert scale 30 min after randomisation (all patients)
To assess the safety and tolerability of inhaled methoxyflurane and the comparison treatments	Incidence of adverse events and vital signs measurements at 10 and 30 min after randomisation (all patients)
Exploratory objectives
To assess the efficacy of inhaled methoxyflurane and SoC with regard to trauma category (fracture, dislocation, crushing, contusion)	Change in VAS pain intensity from baseline (randomisation) to 3, 5, 10, 15, 20, 25, and 30 min (all patients, by trauma category)
To describe how many patients resort to closure of the diluter hole during self-administration of inhaled methoxyflurane	Percentage of patients who resort to closure of the diluter hole (patients randomised to methoxyflurane)