Efficacy and Safety of Penthrox® Combined With a Standard Analgesia (SoC) in Adult Patients Admitted to the Emergency Department With Moderate to Severe Pain Associated With Trauma

Study Overview
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Brief Summary
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A phase 4 randomised, double-blind study to assess the efficacy and safety of Penthrox® used from the outset in multimodal analgesia, in combination with the standard analgesic protocol used in the department, for conscious adult patients presenting in an emergency department with moderate to severe pain associated with a trauma

Detailed Description
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On admission, the patient pain score will be measured using a numerical scale (NRS-11) to verify the eligibility of the patient in the study (NRS ≥ 4). At the time of randomisation, the patient's pain score will be measured using a VAS in order to verify the patient's eligibility for randomisation (VAS ≥ 40). Admissible patients will be randomised by IWRS (Interactive Web Response System) to receive: Either Penthrox® + SoC Or placebo + SoC (Figure 1). Randomisation will be stratified by sex, site and according to the baseline pain score (NRS 4-5 for a moderate-intensity pain versus NS 6-10 for a severe-intensity pain). The IWRS system will be based on the fact of including 50% patients with moderate pain and 50% patients with severe pain. Close weekly monitoring of this ratio will be set up. The decision to no longer include patients in one of the study subgroups according to pain, if necessary, or to change this ratio, will be made by the Study Sponsor and in agreement with the study investigator-coordinator and the study scientific committee. A minimum of 150 patients will be included in the severe pain subgroup (EN 6-10). The treatment (preparation of two inhalers, the second only being given to the patient on request) will only be administered once intermittently or continuously to patients on admission to the study (D0, T0). The pain score will be assessed using the VAS every 5 minutes up to 20 minutes, then at 30, 60, 90, and 120 minutes after the start of study treatment (T0). Patients will be assessed until their discharge from the emergency departments (hospitalization, transfer home, transfer to the operating room) or up to 120 minutes after the initial administration. A telephone interview will take place 14 (± 2) days after the first treatment administration to assess the medium-term safety of the product.

Official Title
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Multicentre, Randomised, Double-blind Study Assessing the Efficacy and Safety of Penthrox® Combined With a Standard Analgesia (SoC) in Comparison to a Placebo Combined With a Standard Analgesia (SoC) in Adult Patients Admitted to the Emergency Department With Moderate to Severe Pain Associated With 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: Men and women aged 18 or older Patients (in an emergency, parent or relative) who dated and signed their informed consent to participate in the study Patients admitted to the emergency department due to a trauma Patients having a pain score ≥ 4 measured using a numerical scale (NRS) at the time of admission to emergency departments. Patients having a pain score ≥ 40 measured using the VAS at the time of randomisation. Exclusion Criteria: Life-threatening conditions requiring immediate admission to the operating theatre or the intensive care unit; Impaired consciousness according to the investigator regardless of the cause, including head trauma or drug or alcohol consumption; Acute medicinal or alcohol intoxication, according to the investigator; Pregnant woman or woman at risk of pregnancy and not using highly effective contraception methods or known lactation; Analgesic treatment within 5 hours (8 h for sodium diclofenac) prior to admission, except for paracetamol, which is allowed; Treatment with nitrous oxide within 5 hours before presentation at the emergency department; Use of analgesics for chronic pain; Prior use of Penthrox®; Use of an investigational product one month before presentation at the emergency department; Hypersensitivity to Penthrox® or any other fluoridated anesthetic; History of signs of hepatic lesions after use of methoxyflurane or after anaesthesia by a halogenated hydrocarbon; Malignant hyperthermia: Known malignant hyperthermia or patient genetic predisposition or patient or family history of serious adverse reactions; Clinical evidence of respiratory depression according to the investigator; Clinical evidence of cardiovascular instability according to the investigator; Clinical renal or hepatic damage, according to the investigator, pre-existing or known; Presence of any other clinical condition that can, according to the investigator's opinion, have an impact on the patient's ability to participate in the study or the results of the study. Individuals protected by law

Ages Eligible for Study
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Minimum Age: 18 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>Patients will be asked to inhale Penthrox® intermittently or continuously to obtain adequate analgesia. Penthrox® or placebo will be administered in combination with standard analgesic treatments usually used according to the emergency department protocol (SoC). Duration of treatment: 1 administration (with a maximum of 2 inhalers) during passage to emergency. | Drug: Methoxyflurane<br>* PENTHROX 3mL inhalation vapour, liquid<br>* Other names: Penthrox®;|
| Placebo Comparator: Normal Saline<br>Patients will be asked to inhale Penthrox® intermittently or continuously to obtain adequate analgesia. Penthrox® or placebo will be administered in combination with standard analgesic treatments usually used according to the emergency department protocol (SoC). Duration of treatment: 1 administration (with a maximum of 2 inhalers) during passage to emergency. | Drug: Normal Saline<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| time until pain relief defined by the duration between the start of the study treatment (T0) and pain relief | Measured on Pain intensity visual analogue scale (PI-VAS) 0-100 where 100 is the highest pain | through study completion, maximum of 2 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration between the start of study treatment (T0) and pain relief reported by the patient | Pain measured on PI-VAS, 0-100 where 100 is the highest pain | through study completion, maximum of 2 hours | 
| Absolute Pain Intensity Difference (PID) measured using the PI-VAS at 5, 10, 15, 20 and 30 minutes after T0 | PID for a given assessment time is equal to the VAS score at T0 minus the VAS score at each assessment time provided in the study. Pain measured on PI-VAS, 0-100 where 100 is the highest pain | baseline to 5, 10, 15, 20 and 30 minutes | 
| Relative Pain Intensity Difference measured using the PI-VAS at 5, 10, 15, 20 and 30 minutes after T0 | Relative pain intensity difference for a given assessment time is equal to the VAS score at T0 minus the VAS score at each assessment time provided in the study divided by the VAS score at T0. Pain measured on PI-VAS, 0-100 where 100 is the highest pain | baseline to 5, 10, 15, 20 and 30 minutes | 
| Pain relief defined by pain intensity < 40 mm on the PI-VAS scale at 5, 10, 15, 20 and 30 minutes after T0 | Pain measured on PI-VAS, 0-100 where 100 is the highest pain | baseline to 5, 10, 15, 20 and 30 minutes | 
| Response defined by pain reduction of 20 mm on the PI-VAS at 5, 10, 15, 20 and 30 minutes after T0 | Pain measured on PI-VAS, 0-100 where 100 is the highest pain | baseline to 5, 10, 15, 20 and 30 minutes | 
| Response defined by pain reduction of 30% mm on the PI-VAS at 5, 10, 15, 20 and 30 minutes after T0 | Pain measured on PI-VAS, 0-100 where 100 is the highest pain | baseline to 5, 10, 15, 20 and 30 minutes | 
| Summed Pain Intensity Difference (SPID) measured on the PI-VAS at 5, 10, 15, 20 and 30 minutes | SPID will be calculated by using the pain intensity difference (PID) at each of these assessment times provided in the study. SPID is the sum of the PID at each study assessment time, weighted by using the time elapsed since the previous assessment, and approaches the area under the curve for the PID over time. Relative to the VAS score, the SPID measurement has the advantage of considering individual differences at the level of initial pain intensity (baseline) as well as time. | baseline to 30 minutes | 
| Proportion of patients attaining an SPID of at least 33% | The proportion of patients attaining an SPID of at least 33% of the maximum possible SPID will be calculated (maximum possible SPID is the the value that would be obtained if the patient was pain free (VAS=0) for the entire study period); this will be considered as corresponding to the responder rate. A % SPID of 33% was previously established as being a clinically significant measurement in pain results. | through study completion, maximum of 2 hours | 
| Quantity of opioids received (in milligrams of morphine) |  | through study completion, maximum of 2 hours | 
| Description of the Standard of Care and concomitant analgesic treatments | Descriptions from the World Health Organization (http://www.who.int/cancer/palliative/painladder/en/): Type of drug, doses, administration periods, and treatment duration | through study completion, maximum of 2 hours | 
| Sedation score (Ramsay scale) | Measured using the Ramsay sedation scale | through study completion, maximum of 2 hours | 
| Patient satisfaction score (Likert 0-5 scale) | Satisfaction is rated by patient as Poor, Fair, Good, Very Good or Excellent | through study completion, maximum of 2 hours | 
| Physician satisfaction scale (Likert 0-5 scale) | Satisfaction is rated by Physician as Poor, Fair, Good, Very Good or Excellent | through study completion, maximum of 2 hours | 
| Nurse satisfaction scale (Likert 0-5 scale) | Satisfaction is rated by Nurse as Poor, Fair, Good, Very Good or Excellent | through study completion, maximum of 2 hours | 
| Length of stay (LOS) in emergency |  | through study completion, maximum of 2 hours | 
| Assess the time until medical decision to discharge |  | through study completion, maximum of 2 hours | 
| Incidence of adverse events (AE) not associated with the underlying trauma and occurring during treatment |  | through study completion, maximum of 2 hours | 
| Change in blood pressure | The Blood Systolic and Diastolic pressure (mmHg) will be measured at baseline and 30 minutes. The difference between the values will be calculated. | baseline to 30 minutes | 
| Change in oxygen saturation | Oxygen saturation (%) will be measured at baseline and 30 minutes. The difference between the values will be calculated. | baseline to 30 minutes | 
| Change in respiration rate | Respiration rate (breaths/min) will be measured at baseline and 30 minutes. The difference between the values will be calculated. | baseline to 30 minutes | 
| Change in heart rate | Heart rate (beats/min) will be measured at baseline and 30 minutes. The difference between the values will be calculated. | baseline to 30 minutes | 
| Incidence of tachycardia, hypotension, hypertension and respiratory depression |  | through study completion, maximum of 2 hours | 
| Incidence of premature withdrawal of patients for safety or tolerability reasons |  | through study completion, maximum of 2 hours |