Clinical Trials Register

Summary
EudraCT Number:	2017-004601-40
Sponsor's Protocol Code Number:	MR311-3505
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-05-24
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2017-004601-40

A.3

Full title of the trial

Efficacy and safety of methoxyflurane in helicopter emergency medical system and hostile environment: a prospective, multicentre clinical trial

Studio clinico prospettico, multicentrico di valutazione della efficacia e sicurezza del metossiflurano vaporizzato (Penthrox®) nel trattamento del dolore acuto da trauma in elisoccorso ed in ambiente impervio

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Methoxyflurane efficacy and safety in hostile environment

Efficacia e sicurezza del metossiflurano vaporizzato somministrato a pazienti soccorsi mediante elisoccorso in ambienti non raggiungibili da altri mezzi di soccorso

A.3.2

Name or abbreviated title of the trial where available

METEORA

A.4.1

Sponsor's protocol code number

MR311-3505

A.5.4

Other Identifiers

Name:

METEORA

Number:

MR 311-3505

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	MUNDIPHARMA RESEARCH LIMITED
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Mundipharma Pharmaceutical s.r.l.
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Mundipharma Pharmaceutical S.r.l.
B.5.2	Functional name of contact point	Responsabile Medico della conduzion
B.5.3	Address:
B.5.3.1	Street Address	Via Filippo Turati 40
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20121
B.5.3.4	Country	Italy
B.5.4	Telephone number	023182881
B.5.5	Fax number	02318288216
B.5.6	E-mail	amedeo.soldi@mundipharma.it

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Penthrox®
D.2.1.1.2	Name of the Marketing Authorisation holder	Napp Pharmaceuticals Limited
D.2.1.2	Country which granted the Marketing Authorisation	France
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	metossiflurano vaporizzato
D.3.2	Product code	[metossiflurano vaporizzato]
D.3.4	Pharmaceutical form	Nebuliser solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Methoxyflurane
D.3.9.1	CAS number	76-38-0
D.3.9.2	Current sponsor code	MR 311-3505
D.3.9.4	EV Substance Code	PRD6424521
D.3.10	Strength
D.3.10.1	Concentration unit	% percent
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	99
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Yes
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

moderate to severe pain secondary to minor trauma

dolore da moderato a severo secondario a trauma minore

E.1.1.1

Medical condition in easily understood language

traumatic pain

dolore in seguito a trauma

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10072132
E.1.2	Term	Fracture pain
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of the study is to evaluate the efficacy of Penthrox® in the treatment of acute trauma pain, of moderate-severe pain defined according to the NRS scale, in patients rescued in a hostile environment.
Specifically, the study primarily intends to demonstrate that Penthrox® is effective in acute (within 10 minutes)

L’obiettivo primario dello studio è valutare l’efficacia di Penthrox® nel trattamento del dolore acuto da trauma, di grado moderato-severo definito in base alla scala NRS, in pazienti soccorsi in ambiente impervio.
Nello specifico lo studio intende primariamente dimostrare che Penthrox® è efficace in acuto, entro cioè 10 minuti.

E.2.2

Secondary objectives of the trial

1. To evaluate the efficacy of Penthrox® in the treatment of acute (after 5,10,15, 20,30,45 and 60 minutes) of moderate to severe pain.
2. To evaluate the efficacy of Penthrox® in terms of the use of additional analgesia (rescue medication).
3. Evaluate the efficacy of Penthrox® according to the patient's judgment and the practicality of use according to the investigator’s judgment.
4. Evaluate the safety and tolerability of Penthrox®.
5. To evaluate the efficacy of Penthrox® compared to the type of trauma characteristic of the inclusion condition.

1. Valutare l’efficacia di Penthrox® nel trattamento del dolore acuto (dopo 5,10,15, 20,30,45 e 60 minuti) di grado moderato – severo.
2. Valutare l’efficacia di Penthrox® in termini di ricorso ad analgesia addizionale (rescue medication) in acuto.
3. Valutare l’efficacia di Penthrox® secondo giudizio del paziente e la praticità di utilizzo secondo giudizio dell’operatore sanitario.
4. Valutare la sicurezza e tollerabilità di Penthrox®.
5. Valutare l’efficacia di Penthrox® rispetto al tipo di trauma caratteristico della condizione di inclusione.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age = 18 years.
• •Stable, vigilant and collaborating patient able to understand and communicate with the investigator to perform the study activities.
• Minor trauma to the limbs (fracture, dislocation, dislocation, crushing, contusion) in a single district. N.B. for the recruitment, given the particular setting, instrumental confirmation is not required but the suspicion of involvement of a single district is sufficient.
• Patient with moderate to severe pain secondary to minor trauma, measured by Numerical Rating Scale (NRS scores =4).
• Written informed consent must be given by each patient before any study-specific activity. In cases where the patient is not able to write autonomously, verbal consent must be obtained in the presence of an impartial witness who, as soon as he is able, will be required to confirm independently

• Età = 18 anni.
• Paziente stabile, vigile e collaborante ovvero in grado di comprendere e comunicare con lo sperimentatore per eseguire le attività di studio.
• Trauma minore agli arti (frattura, dislocazione,lussazione,schiacciamento, contusione) in singolo distretto. N.B. per il reclutamento, dato il particolare setting non è richiesta la conferma strumentale ma è sufficiente il sospetto di coinvolgimento di singolo distretto.
• Paziente con dolore da moderato a severo secondario a trauma minore, misurato tramite Numerical Rating Scale (punteggi NRS =4).
• Consenso informato scritto dovrà essere prestato da ciascun paziente prima di qualunque attività studio-specifica. Nei casi in cui il paziente non sia in grado di scrivere autonomamente dovrà essere ottenuto un consenso verbale in presenza di un testimone imparziale che, non appena in grado, il paziente sarà tenuto a confermare autonomamente.

E.4

Principal exclusion criteria

• Hypersensitivity to methoxyflurane, to any fluorinated anesthetic or to the excipient Butylhydroxytoluene E321.
• Personal or family history (parents or siblings) for malignant hyperthermia.
• A history of serious adverse reactions to inhaled anesthetics.
• A history of renal failure.
• Positive history of liver failure.
• Clinically evident cardiovascular instability.
• Clinically evident respiratory depression.
• Lactation and known or suspected pregnancy condition as reported by the patient. N.B. a delay of only one day is also considered suspect of pregnancy with respect to the scheduled date of menstruation (28 days from the beginning of the last one).
• Treatment in progress with any analgesic for chronic pain or in the previous 8 hours.
• Acute intoxication by drugs, drugs or alcohol.
• Imminent risk of life requiring hospitalization or resuscitation.
• Altered vigilance and / or conscience level [Glasgow Coma Scale (GCS) <15]

• Ipersensibilità al metossiflurano, a qualsiasi anestetico fluorurato o all’eccipiente Butilidrossitoluene E321.
• Anamnesi positiva personale o familiare (genitori o fratelli) per ipertermia maligna.
• Anamnesi positiva per gravi reazioni avverse agli anestetici inalatori.
• Anamnesi positiva per insufficienza renale.
• Anamnesi positiva per insufficienza epatica.
• Instabilità cardiovascolare clinicamente evidente.
• Depressione respiratoria clinicamente evidente.
• Allattamento e condizione di gravidanza nota o sospetta secondo quanto riferito dalla paziente. N.B. si considera sospetto di gravidanza anche il ritardo di 1 solo giorno rispetto alla data prevista di mestruazione (28 giorni dall’inizio della precedente ultima).
• Trattamento in corso con qualsiasi analgesico per dolore cronico oppure nelle 8 ore precedenti.
• Intossicazione acuta da farmaci, droghe o alcool.
• Imminente rischio di vita che richieda ricovero in sala operatorio o rianimazione.
• Alterato livello di vigilanza e/o coscienza [Glasgow Coma Scale (GCS) < 15]

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of the study is the change in the intensity of pain from the time the drug is taken up to 10 minutes after evaluated overall without distinction of class of pain (moderate + severe).
Specifically, we intend to evaluate the percentage of patients who have achieved a = 30% reduction in pain intensity, measured using the VAS scale, compared to baseline within the first 10 min. from the administration of Penthrox®.

L’endpoint primario dello studio è la variazione dell’intensità del dolore dal momento dell’ assunzione del farmaco fino a 10 minuti dopo valutata complessivamente senza distinzione di classe del dolore (moderato + severo).
Nello specifico si intende Valutare la percentuale di pazienti che abbiano ottenuto un riduzione = 30% dell’intensità di dolore, misurata tramite scala VAS, rispetto al valore basale entro i primi 10 min. dalla somministrazione di Penthrox®.

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline and 5, 10 minutes later

Basale e 5,10 minuti dopo

E.5.2

Secondary end point(s)

Evaluate the percentage of patients who achieved a = 30% reduction in pain intensity, measured using the VAS Scale, compared to baseline within the first 10 min. from the administration of Penthrox® and also simultaneously show an NRS score between 0 and 3 after the first ten minutes.; Assess changes in pain intensity after 5, 10, 15, 20, and 30 minutes after the first administration of Penthrox® and after 45 and 60 when using the second Penthrox® inhaler.; Evaluate the percentage of patients who achieved a = 50% reduction in pain intensity compared to baseline within the first 10 min. from taking Penthrox®.; Evaluate the intensity of pain when positioning the patient on the spinal axis or on the stretcher; Evaluate the percentage of patients using a second Penthrox® inhaler; Evaluate the percentage of patients who resort to additional analgesia (rescue medication) within 30 minutes of Penthrox® administration; Evaluate the patient's level of satisfaction in terms of effectiveness before being discharged (via Likert scale).; Evaluate the degree of satisfaction of the investigator in terms of practicality detected before the release of the rescue patient (using the Likert scale).; Incidence of adverse events and the progress of the vital signs measured at 10 and 30 minutes and 60 minutes only when using the second Penthrox® inhaler after the baseline.; Evaluate the effectiveness of Penthrox® compared to the type of trauma characteristic of the inclusion condition

Valutare la percentuale di pazienti che abbiano ottenuto un riduzione = 30% dell’intensità di dolore, misurata tramite Scala VAS, rispetto al valore basale entro i primi 10 min. dalla somministrazione di Penthrox® ed inoltre evidenzino contemporaneamente un punteggio NRS tra 0 e 3 dopo i primi dieci minuti; Valutare le variazioni dell’intensità di dolore dopo 5, 10, 15, 20, e 30 minuti dopo la prima somministrazione di Penthrox® e dopo 45 e 60 in caso di utilizzo del secondo inalatore di Penthrox®.; Valutare la percentuale di pazienti che abbiano ottenuto un riduzione = 50% dell’intensità di dolore rispetto al valore basale entro i primi 10 min. dalla assunzione di Penthrox®.; Valutare l’intensità di dolore durante il posizionamento del paziente sull’asse spinale o sulla barella.; Valutare la percentuale di pazienti che utilizzano un secondo inalatore di Penthrox®.; Valutare la percentuale di pazienti che ricorrono ad analgesia addizionale (rescue medication) entro 30 minuti dalla somministrazione di Penthrox®.; Valutare il grado di soddisfazione del paziente in termini di efficacia prima di essere dimesso (mediante scala Likert). ; Valutare il grado di soddisfazione dell’ operatore sanitario in termini di praticità rilevato prima del rilascio del paziente soccorso (mediante scala Likert).; 1. Incidenza di eventi avversi e l’andamento dei segni vitali rilevati a 10 e 30 minuti e 60 minuti solo in caso di utilizzo del secondo inalatore di Penthrox® dopo il basale.; Valutare l’efficacia di Penthrox® rispetto al tipo di trauma caratteristico della condizione di inclusione

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline and 5, 10 minutes later; Baseline and 5,10,15,20,30,45,60 minutes later; Baseline and 5, 10 minutes later; Within 30 minutes from the baseline; Within 60 minutes from the baseline; Within 30 minutes from the baseline; Within 30 minutes from baseline, or 60 minutes in case of use of the second inhaler; 30 minutes from baseline, or 60 minutes in case of use of the second inhaler; At 10 and 30 minutes from baseline, or 60 minutes in case of use of the second inhaler for vital signs; within 3 ± 1 days from baseline in case of AE; within 3 ± 1 days from baseline

Basale e 5,10 minuti dopo; Basale e 5,10,15,20,30,45,60 minuti dopo; Basale e 5,10 minuti dopo; Entro 30 minuti dal basale; Entro 60 minuti dal basale; Entro 30 minuti dal basale; Entro 30 minuti dal basale, oppure 60 minuti nel caso di uso del secondo inalatore; 30 minuti dal basale, oppure 60 minuti nel caso di uso del secondo inalatore; A 10 e 30 minuti dal basale, oppure 60 minuti nel caso di uso del secondo inalatore per i segni vitali; entro 3± 1 giorni dal basale in caso di AE; entro 3± 1 giorni dal basale

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS (last telephone Follow up performed 3 days after taking the treatment for the last patient enrolled)

LVLS (ultimo Follow up telefonico effettuato dopo 3 giorni dall'assunzione del trattamento per l'ultimo paziente arruolato)

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

150

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

200

F.4.2

For a multinational trial

F.4.2.1

In the EEA

200

F.4.2.2

In the whole clinical trial

200

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

a telephone follow-up will be performed 3 days after taking the treatment to check for any adverse events.

verrà effettuato un follow up telefonico dopo 3 giorni dall'assunzione del trattamento per verificare eventuali eventi avversi

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-11-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-11-22

P. End of Trial
P.	End of Trial Status	Completed

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