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

Acute Traumatic Pain Clinical Trial

— MEDITA  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03585374
• Other study ID #: MR311-3504
• Status: Completed
• Phase: Phase 3
• Start date: February 8, 2018
• Est. completion date: February 22, 2019

Study information

• Verified date: December 2018
• Source: Mundipharma Pharmaceuticals srl
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 272
• Est. completion date: February 22, 2019
• Est. primary completion date: February 8, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Traumatic Pain

Intervention

Combination Product:
• Methoxyflurane and Penthrox inhaler
3ml of methoxyflurane vaporized through an inhaler (Penthrox). Inhalation, by regular breathing, last about 25 minutes.

Drug:
• Morphine
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.
• Paracetamol
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.
• Ketoprofen
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.

Locations

Country	Name	City	State
Italy	Azienda Sanitaria di Firenze Ospedale Santa Maria Annunziata DEA -Medicina D'Urgenza	Bagno A Ripoli	FI
Italy	AO per l'Emergenza- Cannizzaro UO Servizio di Urgenza Emergenza Sanitaria 118	Catania	CT
Italy	AO Universitaria- Policlinico V.Emanuele Medicina e Chirurgia d'Accettazione e d'Urgenza	Catania	CT
Italy	Medicina D'Urgenza ed Accettazione Azienda Ospedaliera di Catanzaro "Pugliese-Ciaccio"	Catanzaro	CZ
Italy	AUSL della ROMAGNA Ospedale M. Bufalini Pronto Soccorso - Medicina d'Urgenza	Cesena	Forlì-Cesena
Italy	OSPEDALE DI FAENZA Pronto Soccorso - Medicina d'Urgenza	Faenza	Ravenna
Italy	Azienda USL della Romagna - Forlì Unità Operativa Pronto Soccorso, Medicina d'Urgenza, 118	Forlì	FC
Italy	IRCCS San Martino Servizio 118	Genova	GE
Italy	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Dipartimento di Anestesia e Terapia Intensiva Donna-Bambino	Milano	MI
Italy	ULSS 6 EUGANEA ex Ulss 16 Pronto Soccorso e Medicina d'Urgenza Ospedale S. Antonio	Padova	PD
Italy	Azienda USL Toscana Centro U.O. Centrale Operativa 118	Pistoia
Italy	AUSL della ROMAGNA Ospedale degli Infermi U.O. Pronto Soccorso - Medicina d'Urgenza	Rimini
Italy	Istituto Clinico Humanitas - Pneumologia e Medicina d'urgenza	Rozzano	Milan
Italy	AOU (Azienda Ospedaliera Universitaria) Sassari Unità Operativa Complessa Medicina d'Accettazione e d'Urgenza - P.S. - O.B.I.	Sassari	SS
Italy	ATS (Azienda tutela Salute)_Struttura Complessa Centrale Operativa 118	Sassari	SS
Italy	Medicina e Chirurgia di accettazione e di urgenza Humanitas Gradenigo - Presidio Sanitario	Torino	TO

Sponsors (2)

Lead Sponsor	Collaborator
Mundipharma Pharmaceuticals srl	Bioikos Ambiente Srl

Country where clinical trial is conducted

Italy, 

References & Publications (13)

Berben SA, Schoonhoven L, Meijs TH, van Vugt AB, van Grunsven PM. Prevalence and relief of pain in trauma patients in emergency medical services. Clin J Pain. 2011 Sep;27(7):587-92. doi: 10.1097/AJP.0b013e3182169036. — View Citation

Brown JC, Klein EJ, Lewis CW, Johnston BD, Cummings P. Emergency department analgesia for fracture pain. Ann Emerg Med. 2003 Aug;42(2):197-205. — View Citation

Coffey F, Wright J, Hartshorn S, Hunt P, Locker T, Mirza K, Dissmann P. STOP!: a randomised, double-blind, placebo-controlled study of the efficacy and safety of methoxyflurane for the treatment of acute pain. Emerg Med J. 2014 Aug;31(8):613-8. doi: 10.1136/emermed-2013-202909. Epub 2014 Apr 17. — View Citation

Dale J, Bjørnsen LP. Assessment of pain in a Norwegian Emergency Department. Scand J Trauma Resusc Emerg Med. 2015 Oct 29;23:86. doi: 10.1186/s13049-015-0166-3. — View Citation

Dayan AD. Analgesic use of inhaled methoxyflurane: Evaluation of its potential nephrotoxicity. Hum Exp Toxicol. 2016 Jan;35(1):91-100. doi: 10.1177/0960327115578743. Epub 2015 Apr 28. Review. — View Citation

Grindlay J, Babl FE. Review article: Efficacy and safety of methoxyflurane analgesia in the emergency department and prehospital setting. Emerg Med Australas. 2009 Feb;21(1):4-11. doi: 10.1111/j.1742-6723.2009.01153.x. Review. — View Citation

Guru V, Dubinsky I. The patient vs. caregiver perception of acute pain in the emergency department. J Emerg Med. 2000 Jan;18(1):7-12. — View Citation

Jacobs IG. Health effects of patients given methoxyflurane in the prehospital setting: a data linkage study. The Open Emergency Medicine Journal 3: 7-13, 2010.

Mills AM, Shofer FS, Chen EH, Hollander JE, Pines JM. The association between emergency department crowding and analgesia administration in acute abdominal pain patients. Acad Emerg Med. 2009 Jul;16(7):603-8. doi: 10.1111/j.1553-2712.2009.00441.x. Epub 2009 Jun 22. — View Citation

Pines JM, Hollander JE. Emergency department crowding is associated with poor care for patients with severe pain. Ann Emerg Med. 2008 Jan;51(1):1-5. Epub 2007 Oct 25. — View Citation

Rupp T, Delaney KA. Inadequate analgesia in emergency medicine. Ann Emerg Med. 2004 Apr;43(4):494-503. Review. — View Citation

Todd KH, Ducharme J, Choiniere M, Crandall CS, Fosnocht DE, Homel P, Tanabe P; PEMI Study Group. Pain in the emergency department: results of the pain and emergency medicine initiative (PEMI) multicenter study. J Pain. 2007 Jun;8(6):460-6. Epub 2007 Feb 15. — View Citation

Tomi K, Mashimo T, Tashiro C, Yagi M, Pak M, Nishimura S, Nishimura M, Yoshiya I. Alterations in pain threshold and psychomotor response associated with subanaesthetic concentrations of inhalation anaesthetics in humans. Br J Anaesth. 1993 Jun;70(6):684-6. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.
Secondary	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.
Secondary	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.
Secondary	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).
Secondary	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).
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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).

External Links

•   Italian Scientific Societies Guidelines on pain management in emergency conditions.
•   Penthrox Summary of Product Characteristics