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

NCT03585374 | Completed Phase 3

• 1 other identifier: MR311-3504
• Study Type: interventional
• Target: 272
• Locations: 1 country
• Sites: 16

Brief 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.

Conditions

Acute Traumatic Pain

Keywords

pain; methoxyflurane; Penthrox

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (13)

• Need for rescue medication.

  From baseline up to 30 minutes later.

• Change in the intensity of pain within 30 minutes.

  From baseline up to 30 minutes later.

• Time to pain relief.

  From baseline up to 30 minutes.

• Global assessment of treatment efficacy perceived by the patient.

  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.

  From baseline to 30 minutes later or to the end of the treatment (whichever occurs first).

Study Arms (2)

A_test drug_Methoxyflurane (Penthrox®)

EXPERIMENTAL

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

B_comparator_Morphine/Paracetamol/Ketoprofen

ACTIVE COMPARATOR

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; Drug: Paracetamol; Drug: Ketoprofen

Interventions

Methoxyflurane and Penthrox inhaler COMBINATION_PRODUCT

3ml of methoxyflurane vaporized through an inhaler (Penthrox). Inhalation, by regular breathing, last about 25 minutes.

Also known as: Penthrox

A_test drug_Methoxyflurane (Penthrox®)

Morphine DRUG

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.

Also known as: Morphine for intravenous use

B_comparator_Morphine/Paracetamol/Ketoprofen

Paracetamol DRUG

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.

Also known as: Paracetamol for intravenous use

B_comparator_Morphine/Paracetamol/Ketoprofen

Ketoprofen DRUG

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.

Also known as: Ketoprofen for intravenous use

B_comparator_Morphine/Paracetamol/Ketoprofen

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Mundipharma Pharmaceuticals srl: lead
• Bioikos Ambiente Srl: collaborator

Study Sites (16)

AO Universitaria- Policlinico V.Emanuele Medicina e Chirurgia d'Accettazione e d'Urgenza

Catania, CT, 95123, Italy

Location

AO per l'Emergenza- Cannizzaro UO Servizio di Urgenza Emergenza Sanitaria 118

Catania, CT, 95126, Italy

Location

Medicina D'Urgenza ed Accettazione Azienda Ospedaliera di Catanzaro "Pugliese-Ciaccio"

Catanzaro, CZ, 88100, Italy

Location

Azienda USL della Romagna - Forlì Unità Operativa Pronto Soccorso, Medicina d'Urgenza, 118

Forlì, FC, 47121, Italy

Location

Azienda Sanitaria di Firenze Ospedale Santa Maria Annunziata DEA -Medicina D'Urgenza

Bagno a Ripoli, FI, 50126, Italy

Location

AUSL della ROMAGNA Ospedale M. Bufalini Pronto Soccorso - Medicina d'Urgenza

Cesena, Forlì-Cesena, 47522, Italy

Location

IRCCS San Martino Servizio 118

Genova, GE, 16132, Italy

Location

Istituto Clinico Humanitas - Pneumologia e Medicina d'urgenza

Rozzano, Milan, 20089, Italy

Location

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Dipartimento di Anestesia e Terapia Intensiva Donna-Bambino

Milan, MI, 20122, Italy

Location

ULSS 6 EUGANEA ex Ulss 16 Pronto Soccorso e Medicina d'Urgenza Ospedale S. Antonio

Padua, PD, 35127, Italy

Location

OSPEDALE DI FAENZA Pronto Soccorso - Medicina d'Urgenza

Faenza, Ravenna, 48018, Italy

Location

AOU (Azienda Ospedaliera Universitaria) Sassari Unità Operativa Complessa Medicina d'Accettazione e d'Urgenza - P.S. - O.B.I.

Sassari, SS, 07100, Italy

Location

ATS (Azienda tutela Salute)_Struttura Complessa Centrale Operativa 118

Sassari, SS, 07100, Italy

Location

Medicina e Chirurgia di accettazione e di urgenza Humanitas Gradenigo - Presidio Sanitario

Torino, TO, 10153, Italy

Location

Azienda USL Toscana Centro U.O. Centrale Operativa 118

Pistoia, 51100, Italy

Location

AUSL della ROMAGNA Ospedale degli Infermi U.O. Pronto Soccorso - Medicina d'Urgenza

Rimini, 47923, Italy

Location

Related Publications (16)

• 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. doi: 10.1016/j.jpain.2006.12.005. Epub 2007 Feb 15.

  PMID: 17306626 BACKGROUND

• 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. doi: 10.1016/s0736-4679(99)00153-5.

  PMID: 10645828 BACKGROUND

• 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. doi: 10.1067/mem.2003.275.

  PMID: 12883507 BACKGROUND

• Rupp T, Delaney KA. Inadequate analgesia in emergency medicine. Ann Emerg Med. 2004 Apr;43(4):494-503. doi: 10.1016/j.annemergmed.2003.11.019.

  PMID: 15039693 BACKGROUND

• 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.

  PMID: 21505324 BACKGROUND

• Dale J, Bjornsen 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.

  PMID: 26514633 BACKGROUND

• 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.

  PMID: 19549018 BACKGROUND

• 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. doi: 10.1016/j.annemergmed.2007.07.008. Epub 2007 Oct 25.

  PMID: 17913299 BACKGROUND

• 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.

  PMID: 25926525 BACKGROUND

• 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. doi: 10.1093/bja/70.6.684.

  PMID: 8329263 BACKGROUND

• 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.

  PMID: 24743584 BACKGROUND

• 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.

  PMID: 19254307 BACKGROUND

• 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.

  BACKGROUND

• Serra S, Voza A, Ruggiano G, Fabbri A, Bonafede E, Sblendido A, Soldi A, Farina A; MEDITA Study Group. Efficacy, Practicality, and Safety of Inhaled Methoxyflurane in Elderly Patients with Acute Trauma Pain: Subgroup Analysis of a Randomized, Controlled, Multicenter, Open-Label Trial (MEDITA). J Pain Res. 2020 Jul 16;13:1777-1784. doi: 10.2147/JPR.S255532. eCollection 2020.

  PMID: 32765053 DERIVED

• Mercadante S, Voza A, Serra S, Ruggiano G, Carpinteri G, Gangitano G, Intelligente F, Bonafede E, Sblendido A, Farina A, Soldi A, Fabbri A; MEDITA Study Group. Analgesic Efficacy, Practicality and Safety of Inhaled Methoxyflurane Versus Standard Analgesic Treatment for Acute Trauma Pain in the Emergency Setting: A Randomised, Open-Label, Active-Controlled, Multicentre Trial in Italy (MEDITA). Adv Ther. 2019 Nov;36(11):3030-3046. doi: 10.1007/s12325-019-01055-9. Epub 2019 Oct 12.

  PMID: 31612359 DERIVED

• Fabbri A, Carpinteri G, Ruggiano G, Bonafede E, Sblendido A, Farina A, Soldi A; MEDITA Study Group. Methoxyflurane Versus Standard of Care for Acute Trauma-Related Pain in the Emergency Setting: Protocol for a Randomised, Controlled Study in Italy (MEDITA). Adv Ther. 2019 Jan;36(1):244-256. doi: 10.1007/s12325-018-0830-x. Epub 2018 Nov 22.

  PMID: 30467809 DERIVED

Related Links

• Penthrox Summary of Product Characteristics

MeSH Terms

Conditions

Pain

Interventions

Methoxyflurane; Morphine; Acetaminophen; Ketoprofen

Condition Hierarchy (Ancestors)

Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Ethyl Ethers; Ethers; Organic Chemicals; Methyl Ethers; Morphine Derivatives; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Acetanilides; Anilides; Amides; Aniline Compounds; Amines; Phenylpropionates; Acids, Carbocyclic; Carboxylic Acids

Study Officials

• Germana Ruggiano, Dr

  Azienda Sanitaria di Firenze Ospedale Santa Maria Annunziata DEA -Medicina D'Urgenza

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: May 31, 2018
• First Posted: July 13, 2018
• Study Start: February 8, 2018
• Primary Completion: February 8, 2019
• Study Completion: February 22, 2019
• Last Updated: May 9, 2019

Record last verified: 2018-12

Locations

IT (16)