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

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ClinicalTrials.gov Identifier: NCT03585374
Recruitment Status : Completed
First Posted : July 13, 2018
Last Update Posted : May 9, 2019
Sponsor:
Collaborator:
Bioikos Ambiente Srl
Information provided by (Responsible Party):
Mundipharma Pharmaceuticals srl

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.


Condition or disease Intervention/treatment Phase
Acute Traumatic Pain Combination Product: Methoxyflurane and Penthrox inhaler Drug: Morphine Drug: Paracetamol Drug: Ketoprofen Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 272 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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)
Primary Purpose: Treatment
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
Actual Study Start Date : February 8, 2018
Actual Primary Completion Date : February 8, 2019
Actual Study Completion Date : February 22, 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Ketoprofen

Arm Intervention/treatment
Experimental: A_test drug_Methoxyflurane (Penthrox®)
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
3ml of methoxyflurane vaporized through an inhaler (Penthrox). Inhalation, by regular breathing, last about 25 minutes.
Other Name: Penthrox

Active Comparator: B_comparator_Morphine/Paracetamol/Ketoprofen

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
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.
Other Name: Morphine for intravenous use

Drug: 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.
Other Name: Paracetamol for intravenous use

Drug: 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.
Other Name: Ketoprofen for intravenous use




Primary Outcome Measures :
  1. Change in the intensity of pain within 10 minutes. [ Time Frame: From baseline up to 10 minutes later. ]
    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.


Secondary Outcome Measures :
  1. Need for rescue medication. [ Time Frame: From baseline up to 30 minutes later. ]
    Percentage of patients who are using rescue medication for insufficient or unsatisfactory therapeutic effect of the trial drugs.

  2. Change in the intensity of pain within 30 minutes. [ Time Frame: From baseline up to 30 minutes later. ]
    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).

  3. Time to pain relief. [ Time Frame: From baseline up to 30 minutes. ]
    Time to get relief from pain starting from randomization. The patient will be asked to refer when he/she feel better.

  4. Global assessment of treatment efficacy perceived by the patient. [ Time Frame: From baseline to 30 minutes later or to the end of the treatment (whichever occurs first). ]
    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.

  5. Global assessment of treatment practicality in the investigator's opinion. [ Time Frame: From baseline to 30 minutes later or to the end of the treatment (whichever occurs first). ]
    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.

  6. Need for dilution hole closure (only Experimental Arm). [ Time Frame: From baseline up to 30 minutes later. ]
    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.

  7. Change in the intensity of pain within 30 minutes by trauma type. [ Time Frame: From baseline up to 30 minutes later. ]
    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).

  8. Incidence of Treatment-Emergent Adverse Events (AE) [ Time Frame: From baseline up to 16 days later. ]
    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.

  9. Change in pulse rate [ Time Frame: From baseline up to 30 minutes later. ]
    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.

  10. Change in blood pressure [ Time Frame: From baseline up to 30 minutes later. ]
    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.

  11. Change in respiration rate [ Time Frame: From baseline up to 30 minutes later. ]
    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.

  12. Incidence of treatment-emergent pregnancy [ Time Frame: From baseline up to 16 days later. The follow-up until delivery is out from the scope of the trial. ]
    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.

  13. Incidence of investigational medicinal drug misuse/abuse [ Time Frame: From baseline up to 30 minutes later or to the end of the treatment (whichever occurs first). ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03585374


Locations
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Italy
AO Universitaria- Policlinico V.Emanuele Medicina e Chirurgia d'Accettazione e d'Urgenza
Catania, CT, Italy, 95123
AO per l'Emergenza- Cannizzaro UO Servizio di Urgenza Emergenza Sanitaria 118
Catania, CT, Italy, 95126
Medicina D'Urgenza ed Accettazione Azienda Ospedaliera di Catanzaro "Pugliese-Ciaccio"
Catanzaro, CZ, Italy, 88100
Azienda USL della Romagna - Forlì Unità Operativa Pronto Soccorso, Medicina d'Urgenza, 118
Forlì, FC, Italy, 47121
Azienda Sanitaria di Firenze Ospedale Santa Maria Annunziata DEA -Medicina D'Urgenza
Bagno A Ripoli, FI, Italy, 50126
AUSL della ROMAGNA Ospedale M. Bufalini Pronto Soccorso - Medicina d'Urgenza
Cesena, Forlì-Cesena, Italy, 47522
IRCCS San Martino Servizio 118
Genova, GE, Italy, 16132
Istituto Clinico Humanitas - Pneumologia e Medicina d'urgenza
Rozzano, Milan, Italy, 20089
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Dipartimento di Anestesia e Terapia Intensiva Donna-Bambino
Milano, MI, Italy, 20122
ULSS 6 EUGANEA ex Ulss 16 Pronto Soccorso e Medicina d'Urgenza Ospedale S. Antonio
Padova, PD, Italy, 35127
OSPEDALE DI FAENZA Pronto Soccorso - Medicina d'Urgenza
Faenza, Ravenna, Italy, 48018
AOU (Azienda Ospedaliera Universitaria) Sassari Unità Operativa Complessa Medicina d'Accettazione e d'Urgenza - P.S. - O.B.I.
Sassari, SS, Italy, 07100
ATS (Azienda tutela Salute)_Struttura Complessa Centrale Operativa 118
Sassari, SS, Italy, 07100
Medicina e Chirurgia di accettazione e di urgenza Humanitas Gradenigo - Presidio Sanitario
Torino, TO, Italy, 10153
Azienda USL Toscana Centro U.O. Centrale Operativa 118
Pistoia, Italy, 51100
AUSL della ROMAGNA Ospedale degli Infermi U.O. Pronto Soccorso - Medicina d'Urgenza
Rimini, Italy, 47923
Sponsors and Collaborators
Mundipharma Pharmaceuticals srl
Bioikos Ambiente Srl
Investigators
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Principal Investigator: Germana Ruggiano, Dr Azienda Sanitaria di Firenze Ospedale Santa Maria Annunziata DEA -Medicina D'Urgenza

Additional Information:
Publications:
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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Mundipharma Pharmaceuticals srl
ClinicalTrials.gov Identifier: NCT03585374     History of Changes
Other Study ID Numbers: MR311-3504
First Posted: July 13, 2018    Key Record Dates
Last Update Posted: May 9, 2019
Last Verified: December 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Mundipharma Pharmaceuticals srl:
pain
methoxyflurane
Penthrox

Additional relevant MeSH terms:
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Acetaminophen
Ketoprofen
Morphine
Methoxyflurane
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Analgesics, Non-Narcotic
Antipyretics
Anti-Inflammatory Agents, Non-Steroidal
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anesthetics, Inhalation
Anesthetics, General
Anesthetics