Efficacy and safety of methoxyflurane vaporized (PENTHROX®) in the treatment of acute trauma pain in pre-hospital setting and in the emergency department in Italy: a multicentre, randomized, controlled, open-label study

INTERVENTION: Trade Name: Penthrox® Pharmaceutical Form: Nebuliser solution INN or Proposed INN: metossiflurano Current Sponsor code: Penthrox® Other descriptive name: Penthrox® Concentration unit: ml millilitre(s) Concentration type: equal Concentration number: 3‐ Trade Name: MORFINA CLORIDRATO MOLTENI ‐ 10 MG/ML SOLUZIONE INIETTABILE 5 FIALE1 ML Pharmaceutical Form: Solution for injection INN or Proposed INN: MORFINA CLORIDRATO CAS Number: 57‐27‐2 Current Sponsor code: MORFINA CLORIDRATO Other descriptive name: MORFINA CLORIDRATO Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 10‐ Trade Name: IBIFEN ‐ 100 MG/5 ML SOLUZIONE INIETTABILE PER USO ENDOVENOSO 6 FIALE Pharmaceutical Form: Solution for injection INN or Proposed INN: KETOPROFENE CAS Number: 22071‐15‐4 Current Sponsor code: KETOPROFENE Other descriptive name: KETOPROFENE Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 20‐ Trade Name: PARACETAMOLO KABI ‐ 10 MG/ML SOLUZIONE PER INFUSIONE 10 FLACONCINI IN VETRO DA 100 ML Pharmaceutical Form: Solution for injection INN or Proposed INN: PARACETAMOLO CAS Number: 103‐90‐2 Current Sponsor code: PARACETAMOLO Other descriptive name: PARACETAMOLO Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 10‐ CONDITION: Acute trauma pain ; MedDRA version: 20.0 Level: PT Classification code 10072132 Term: Fracture pain System Organ Class: 10028395 ‐ Musculoskeletal and connective tissue disorders Therapeutic area: Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] ‐ Therapeutic techniques [E02] PRIMARY OUTCOME: Main Objective: The primary objective of the study is to evaluate the efficacy of Penthrox® in treating acute traumatic pain associated with moderate‐to‐severe pain defined on the NRS scale, comparing it to those of the drugs that currently represent the standard of care in Italy:; 1) intravenous morphine for the treatment of severe pain (NRS = 7);; 2) intravenous paracetamol or ketoprofen for the treatment of moderate pain (NRS 4‐6).; Primary end point(s): The primary endpoint of the study is the change in the intensity of pain from baseline to 10 minutes later (3, 5, 10 minutes), evaluated overall without distinction of pain class (moderate + severe) and only in patients with moderate pain in the two treatment arms Secondary Objective: • demonstrate that the efficacy of Penthrox® is superior to that of standard care in treating acute pain (within 10 minutes) of moderate to severe degree; • compare the efficacy of Penthrox® vs the standard of care in terms of use of additional analgesia (rescue medication) in acute; • compare the efficacy of Pentrox® vs. the standard of care in treating acute pain (after 15, 20, 25, 30 minutes) of moderate to severe degree; • compare the efficacy of Penthrox® vs the standard of care in terms of rate of onset of the analgesic effect; • compare Penthrox® vs the standard of care in terms of efficacy according to patient judgment and ease of use according to the healthcare provider's judgment; • to assess the safety and tolerability of Penthrox® and comparator treatments (standard of care) Timepoint(s) of evaluation of this end point: BASELINE AND 3, 5, 10 MINUTES LATER ; 2 • Percentage of patients who are using rescue medication within 30 minutes in each of the two treatment arms ; 4 • Time to get relief from pain starting from randomization, evaluated overall without distinction of pain class (moderate + severe), in each of the two treatment arms ; 7 • incidence of adverse events (organized for Preferred Term and System Organ Class) and trend of vital signs detected at 10 and 30 minutes after baseline ; 9 • percentage of patients who use the dilution hole closure (ONLY TREATED WITH PENTHROX) Timepoint(s) of evaluation of this end point: 1 • BASELINE AND 3, 5, 10 MINUTES LATER SECONDARY OUTCOME: Secondary end point(s): 1 • Pain intensity variation from randomization (baseline) up to 10 minutes (3, 5, 10 minutes) evaluated overall without distinction of pain class (moderate + severe) in each of the two treatment arms ; 3 • Change in pain intensity from randomization (baseline) to 15, 20, 25, 30 minutes after evaluated overall without distinction of pain class (moderate + severe) in each of the two treatment arms ; 5 • Assessment of the therapy efficacy as perceived by patient and measured by Likert scale 30 minutes after randomization , evaluated overall without distinction of pain class (moderate +severe) in each of the two treatment arms ; 6 • Evaluation of the practicality of use of therapy evaluated by Likert scale by healthcare staff who administered the treatment, evaluated overall without distinction of pain class (moderate + severe) in each of the two treatment arms ; 8 • Pain intensity variation from randomization (baseline) to 3, 5, 10, 15, 20, 25, 30 minutes later, overall without distinction of pain class (moderate + severe) for each type of inclusion trauma in each arm of treatment ; 2 • WITHIN 30 MINUTES FROM BASELINE ; 3 • BASELINE AND 15,20,25,30 MINUTES LATER ; 4 • WITHIN 30 MINUTES FROM BASELINE ; 5 • 30 MINUTES FROM BASELINE ; 6 • 30 MINUTES FROM BASELINE (AS CLOSEST AS POSSIBILE TO TREATMENT CONCLUSION) ; 7 • WITHIN 14 +/‐ 2 DAYS FROM BASELINE ; 8 • BASELINE AND 3, 5, 10, 15, 20, 25, 30 MINUTES LATER ; 9 • AT OCCURENCE WITHIN THE END OF TREATMENT INCLUSION CRITERIA: • Written informed consent must be provided by each patient prior to any study‐specific activity. In cases where the patient is unable to write autonomously, it must be obtained a verbal consent in presence of a witness that the patient will have to confirm autonomously as soon as (s)he is able • Stable, vigilant and collaborative patient i.e. able to understand and communicate with the examiner in order to carry out the study activities • Age = 18 years • Trauma to the limbs (fracture, dislocation, crushing, bruising) in a single district. N.B. For recruiting, given the particular setting, no instrumental confirmation is required but suspicion of involvement of a single district is sufficient. • Moderate to severe pain, detected by the Numerical Rating Scale (NRS score =4) Are the trial subjects under 18? no Number of subjects for this age range: 1 F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 200<