Trauma Acute Pain Treatment With Methoxyflurane Vaporized (PENTHROX®): Efficacy and Safety Study (MEDITA)

Study Overview
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Brief Summary
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The prompt treatment of pain due to minor trauma is often an unmet need in both Emergency Room Department and Ambulance Rescue. Most of the available drugs are intravenously administered and such route of administration may account for delay in the pain relief onset. Methoxyflurane is an halogenated anesthetic, self-administered by the patient at sub-anesthetic dose through an easy to handle inhaler (Penthrox®). The efficacy and safety of Penthrox® in the treatment of acute traumatic pain will be investigated in an out-of-hospital and in hospital emergency medical care setting.

Official Title
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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

Conditions
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Acute Traumatic Pain

Intervention / Treatment
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* Combination Product: Methoxyflurane and Penthrox inhaler
* Drug: Morphine
* Drug: Paracetamol
* Drug: Ketoprofen


Participation Criteria
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Eligibility Criteria
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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) Exclusion Criteria: Personal or family history (parents or siblings) for malignant hyperthermia. History of severe adverse reactions to inhaled anesthetics. History of renal failure History of liver failure. Trauma risky dynamics (ejection from the vehicle, cabin deformation, death of an occupant of the same vehicle, motor vehicle / pedestrian or cyclist impact with a motor vehicle in motion, projection / overturn, fall from a height of> 3 meters, extraction on event place > 20 min). Altered level of vigilance and / or conscience (GCS <15) Symptomatic hypotension or Systolic Pressure <100 mm / Hg Discomfort with Respiratory Rate > 20 and Oxygen Saturation <95% Known pregnancy status.Note: a 1 day delay with respect to the planned menstruation date (28days since the beginning of the previous one) has to be considered a suspected pregnancy. Hypersensitivity to methoxyflurane, to any fluorinated anesthetic or to the E321 butylhydroxytoluene excipient. Current treatment with any analgesic for chronic pain or in the previous 5 hours (8 hours in the case of diclofenac). Known allergy to both paracetamol and non-steroidal anti-inflammatory drugs or known hypersensitivity to morphine All types of acute abdomen and paralytic ileus Hearth failure Recent (within2 months) biliary tract surgery Current bronchial asthma attack Uncontrolled epilepsy Depressive state treated with Monoamine Oxidase Inhibitors (ongoing or interrupted less 3 wks ago) Treatment with naltrexone History of active or recurrent peptic ulcer/hemorrhage (2 or more episodes of documented ulceration or bleeding in the last 6 months) Bleeding diathesis Current Intensive diuretic therapy Chronic dyspepsia, gastritis with significant episodes in the last 2 months Leucopenia and thrombocytopenia, current hemorrhages Current anticoagulant therapy

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
Interventional Model Description: Eligible patients will be randomly assigned to Penthrox (test group) or standard analgesic treatment (comparison group). As per local clinical practice, the standard analgesic will vary according to pain intensity score measured by Numerical Rating Scale (NRS): morphine, in case of score ≥ 7 or paracetamol/ketoprofen in case of score 4-6. Penthrox treatment will be performed by inhalatory route and will last maximum 25 minutes. the standard of care will be administered by an intravenous drip lasting at maximum 10 minutes.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A_test drug_Methoxyflurane (Penthrox®)<br>Pain from moderate to severe (NRS score 4-10). 3 ml of methoxyflurane vaporized through the Penthrox® inhaler. The drug is self administered under the supervision of investigators/study nurse. The treatment duration is about 25 minutes. The patient is instructed to breath normally and to close the diluter aperture via his/her forefinger to increase the analgesic effect, if needed. In case of pain increase or insufficient pain relief the investigator is allowed to administer a rescue medication as per local routine practice. | Combination Product: Methoxyflurane and Penthrox inhaler<br>* 3ml of methoxyflurane vaporized through an inhaler (Penthrox). Inhalation, by regular breathing, last about 25 minutes.<br>* Other names: Penthrox;|
| Active Comparator: B_comparator_Morphine/Paracetamol/Ketoprofen<br>The comparator to be administered will vary according to pain intensity and local clinical practice. In case of severe pain (NRS score ≥ 7), morphine will be administered at a dose of 0.10 mg/kg body weight. In case of moderate pain (NRS score 4-6) paracetamol or ketoprofen will be administered respectively at a 1 g and 100 mg dose. All comparator will be administered by intravenous drip in a maximum 10 minutes time of infusion. . Maximum time of infusion 10 minutes. | Drug: Morphine<br>* Each site will use the commercial available product already in use as per local clinical practice. The drug will be intravenously administered at a dose of 0.10 mg/Kg body weight. The time of infusion should be not longer than 10 minutes.<br>* Other names: Morphine for intravenous use;Drug: Paracetamol<br>* Each site will use the commercial available product already in use as per local clinical practice. The drug will be intravenously administered at a 1 g dose The time of infusion should be not longer than 10 minutes.<br>* Other names: Paracetamol for intravenous use;Drug: Ketoprofen<br>* Each site will use the commercial available product already in use as per local clinical practice. The drug will be intravenously administered at a 100 mg dose. The time of infusion should be not longer than 10 minutes.<br>* Other names: Ketoprofen for intravenous use;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the intensity of pain within 10 minutes. | The change in the pain intensity occurring from baseline (patient randomization) up to 10 minutes later. The pain intensity is measured by a 100 mm Visual-Analogic Scale (VAS). The pain intensity is measured at the baseline and after 3, 5, 10 minutes and the difference with the baseline measure is calculated. The changes (differences) from baseline will be compared between the two arms regardless the class of intensity pain (moderate + severe) and for the class of moderate pain. | From baseline up to 10 minutes later. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Need for rescue medication. | Percentage of patients who are using rescue medication for insufficient or unsatisfactory therapeutic effect of the trial drugs. | From baseline up to 30 minutes later. | 
| Change in the intensity of pain within 30 minutes. | The change in the pain intensity occurring from baseline up to 30 minutes later. The pain intensity is measured by a 100 mm Visual-Analogic Scale (VAS). The pain intensity is measured after 15, 20, 25, 30 minutes from baseline and the difference with the baseline measure is calculated. The changes (differences) from baseline will be compared between the two arms regardless the class of intensity pain (moderate + severe). | From baseline up to 30 minutes later. | 
| Time to pain relief. | Time to get relief from pain starting from randomization. The patient will be asked to refer when he/she feel better. | From baseline up to 30 minutes. | 
| Global assessment of treatment efficacy perceived by the patient. | 30 minutes after randomization the patient will be asked to rate according to a 5 levels Likert scale (poor, moderate, good, very good, excellent) the global efficacy of the treatment. | From baseline to 30 minutes later or to the end of the treatment (whichever occurs first). | 
| Global assessment of treatment practicality in the investigator's opinion. | 30 minutes after randomization the treating investigator will be asked to rate according to a 5 levels Likert scale (poor, moderate, good, very good, excellent) the practicality of the administered treatment. | From baseline to 30 minutes later or to the end of the treatment (whichever occurs first). | 
| Need for dilution hole closure (only Experimental Arm). | The closure of the dilution hole of the Penthrox device increases the inhalated amount of methoxyflurane and its antalgic effect. The patient will be instructed about the chance to close that hole and will be asked to refer the occurrence. | From baseline up to 30 minutes later. | 
| Change in the intensity of pain within 30 minutes by trauma type. | The change in the pain intensity occurring from baseline (patient randomization) up to 30 minutes later. The pain intensity is measured by a 100 mm Visual-Analogic Scale (VAS). The pain intensity is measured at the baseline and after 3, 5, 10, 15, 20, 25, 30 minutes and the difference with the baseline measure is calculated. The changes (differences) from baseline to each of the following timepoints for each trauma type will be compared between the two arms regardless the class of intensity pain (moderate + severe). | From baseline up to 30 minutes later. | 
| Incidence of Treatment-Emergent Adverse Events (AE) | Each untoward clinical event not related, in the Investigator judgement, to the underlying patient inclusion condition (trauma) will be recorded. Seriousness, relationship with the investigational drug, action taken for AE treatment will recorded for each AE. | From baseline up to 16 days later. | 
| Change in pulse rate | The pulse rate (beats/min) will be measured (either manually or automatically) at baseline and 10, 30 minutes later. The difference between the baseline values and the following ones will be calculated. | From baseline up to 30 minutes later. | 
| Change in blood pressure | The Blood Systolic and Diastolic pressure (mmHg) will be measured at baseline and 10, 30 minutes later. The difference between the baseline values and the following ones will be calculated. | From baseline up to 30 minutes later. | 
| Change in respiration rate | The respiration rate (breaths/min) will be measured (either manually or automatically) at baseline and 10, 30 minutes later. The difference between the baseline values and the following ones will be calculated. | From baseline up to 30 minutes later. | 
| Incidence of treatment-emergent pregnancy | Pregnant patients or suspected to be pregnant are excluded from the trial. In case of occurrence the pregnancy will be recorded and followed up until delivery for pharmacovigilance purposes. | From baseline up to 16 days later. The follow-up until delivery is out from the scope of the trial. | 
| Incidence of investigational medicinal drug misuse/abuse | The occurrence of Investigational medicinal drug abuse (persistent or sporadic, intentional excessive use of medicinal products which is accompanied by harmful physical or psychological effects) or misuse (intentionally and inappropriately use not in accordance with the prescribed dose) during the treatment phase will be recorded. | From baseline up to 30 minutes later or to the end of the treatment (whichever occurs first). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pain, methoxyflurane, Penthrox