Clinical Trials Register

Summary
EudraCT Number:	2017-001565-25
Sponsor's Protocol Code Number:	MR311-3504
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:	2018-03-02
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

2017-001565-25

A.3

Full title of the trial

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

Efficacia e sicurezza del metossiflurano vaporizzato(PENTHROX®) nel trattamento del dolore acuto da trauma nell’ambiente pre-ospedaliero e nel pronto soccorso in Italia: studio multicentrico, randomizzato, controllato, in aperto.

A.3.1

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

Trauma acute pain treatment with methoxyflurane vaporized (PENTHROX®): efficacy and safety study.

Trattamento del dolore acuto da trauma con metossiflurano vaporizzato (PENTHROX®): studio di efficacia e sicurezza.

A.3.2

Name or abbreviated title of the trial where available

MEDITA

A.4.1

Sponsor's protocol code number

MR311-3504

A.5.4

Other Identifiers

Name:

MEDITA

Number:

MR311-3504

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 PHARMACEUTICALS SRL
B.1.3.4	Country	Italy
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 Pharmaceuticals 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 Pharmaceuticals S.r.l.
B.5.2	Functional name of contact point	Responsabile medico e della conduzi
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	United Kingdom
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.3.4	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	metossiflurano
D.3.9.2	Current sponsor code	Penthrox®
D.3.9.3	Other descriptive name	Penthrox®
D.3.10	Strength
D.3.10.1	Concentration unit	ml millilitre(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3
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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	MORFINA CLORIDRATO MOLTENI - 10 MG/ML SOLUZIONE INIETTABILE 5 FIALE1 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	L. MOLTENI e C. DEI F.LLI ALITTI SOCIETA' DI ESERCIZIO S.P.A.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	MORFINA CLORIDRATO
D.3.9.1	CAS number	57-27-2
D.3.9.2	Current sponsor code	MORFINA CLORIDRATO
D.3.9.3	Other descriptive name	MORFINA CLORIDRATO
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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	No
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.IMP: 3
D.1.2 and D.1.3	IMP Role	Comparator
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	IBIFEN - 100 MG/5 ML SOLUZIONE INIETTABILE PER USO ENDOVENOSO 6 FIALE
D.2.1.1.2	Name of the Marketing Authorisation holder	ISTITUTO BIOCHIMICO ITALIANO GIOVANNI LORENZINI S.P.A.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	KETOPROFENE
D.3.9.1	CAS number	22071-15-4
D.3.9.2	Current sponsor code	KETOPROFENE
D.3.9.3	Other descriptive name	KETOPROFENE
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
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	No
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.IMP: 4
D.1.2 and D.1.3	IMP Role	Comparator
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	PARACETAMOLO KABI - 10 MG/ML SOLUZIONE PER INFUSIONE 10 FLACONCINI IN VETRO DA 100 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	FRESENIUS KABI ITALIA S.R.L.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PARACETAMOLO
D.3.9.1	CAS number	103-90-2
D.3.9.2	Current sponsor code	PARACETAMOLO
D.3.9.3	Other descriptive name	PARACETAMOLO
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
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

Acute trauma pain

Dolore traumatico acuto

E.1.1.1

Medical condition in easily understood language

Acute trauma pain

Dolore traumatico acuto

E.1.1.2

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutic techniques [E02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
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 treating acute traumatic pain associated with moderate-to-severe pain defined on the NRS scale, comparing it to those of the drugs that currently represent the standard of care in Italy:
1) intravenous morphine for the treatment of severe pain (NRS ≥ 7);
2) intravenous paracetamol or ketoprofen for the treatment of moderate pain (NRS 4-6).

L’obiettivo primario dello studio è valutare l’efficacia di Penthrox® nel trattamento del dolore acuto da trauma associato a dolore moderato-severo definito in base alla scala NRS, confrontandola con quella dei farmaci che ad oggi rappresentano lo standard of care in Italia:
1)morfina per via endovenosa per il trattamento del dolore severo (NRS ≥ 7);
2) paracetamolo o ketoprofene per via endovenosa per il trattamento del dolore moderato (NRS 4-6).

E.2.2

Secondary objectives of the trial

• demonstrate that the efficacy of Penthrox® is superior to that of standard care in treating acute pain (within 10 minutes) of moderate to severe degree
• compare the efficacy of Penthrox® vs the standard of care in terms of use of additional analgesia (rescue medication) in acute
• compare the efficacy of Pentrox® vs. the standard of care in treating acute pain (after 15, 20, 25, 30 minutes) of moderate to severe degree
• compare the efficacy of Penthrox® vs the standard of care in terms of rate of onset of the analgesic effect
• compare Penthrox® vs the standard of care in terms of efficacy according to patient judgment and ease of use according to the healthcare provider's judgment
• to assess the safety and tolerability of Penthrox® and comparator treatments (standard of care)

•dimostrare che l’efficacia di Penthrox® è superiore a quella dello standard of care nel trattamento del dolore acuto (entro 10 minuti) di grado moderato - severo
•confrontare l’efficacia di Penthrox® vs quella dello standard of care in termini di ricorso ad analgesia addizionale (rescue medication) in acuto
•confrontare l’efficacia di Pentrox® vs quella dello standard of care nel trattamento del dolore acuto (dopo 15, 20, 25, 30 minuti) di grado moderato - severo
•confrontare l’efficacia di Penthrox® vs quella dello standard of care in termini di velocità di insorgenza dell’effetto analgesico
•confrontare Penthrox® vs lo standard of care in termini di efficacia secondo giudizio del paziente e praticità di utilizzo secondo giudizio dell’operatore sanitario
•valutare la sicurezza e tollerabilità di Penthrox® e dei trattamenti di confronto

E.2.3

Trial contains a sub-study

E.3

Principal 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)

•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 testimoniato che non appena in grado il paziente sarà tenuto a confermare autonomamente.
•Paziente stabile, vigile e collaborante ovvero in grado di comprendere e comunicare con lo sperimentatore per eseguire le attività di studio
•Età ≥ 18 anni
•Trauma agli arti (frattura, dislocazione, 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.
•Dolore moderato-severo, rilevato tramite Numerical Rating Scale (punteggi NRS ≥4)

E.4

Principal 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 FR> 20 and SatO2 in air <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 IMAO (ongoing or interrupted less 3 wks ago)
•Theatment with naltrexone
•History of active or recurrent peptic ulcer/hemorrhage (2 or more episodes of documented ulceration or bleeing 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

•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.
•Dinamica di trauma a rischio (eiezione dal veicolo, deformazione abitacolo, decesso di un occupante del medesimo veicolo, impatto veicolo a motore/pedone o ciclista con veicolo a motore in movimenti, proiezione / sbalzamento, caduta da altezza > 3 metri, estricazione sul luogo dell’evento > 20 min).
•Alterato livello di vigilanza e/o coscienza (GCS < 15)
•Ipotensione sintomatica oppure Pressione Arteriosa Sistolica < 100 mm/Hg
• Dispnea con FR >20 e SatO2 in aria < 95%
•Condizione di gravidanza nota. NB: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).
•Ipersensibilità al metossiflurano, a qualsiasi anestetico fluorurato o all’eccipiente Butilidrossitoluene E321.
•Trattamento in corso con qualsiasi analgesico per dolore cronico, oppure nelle 5 ore precedenti (8 ore nel caso di diclofenac).
•Allergia nota ad entrambi paracetamolo e farmaci antiinfiammatori non steroidei o ipersensibilità nota a morfina
•Tutte le forme di addome acuto e ileo paralitico.
•Insufficienza cardiaca.
•Recenti (entro 2 mesi) interventi chirurgici delle vie biliari.
•Attacco di asma bronchiale in corso.
•Epilessia non controllata.
•Stato depressivo in terapia con farmaci inibitori delle monoamino-ossidasi (IMAO) in corso o sospesa da meno di tre settimane.
•Trattamento con naltrexone.
•Storia di ulcera peptica attiva o ricorrente/emorragia (due o più episodi distinti di dimostrata ulcerazione o sanguinamento negli ultimi 6 mesi)
•Diatesi emorragica.
•Terapia diuretica intensiva in corso.
•Dispepsia cronica, gastrite con episodi rilevanti negli ultimi 2 mesi.
•Leucopenia e piastrinopenia, soggetti con emorragie in atto
•Trattamento con anticoagulanti in corso.

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 baseline to 10 minutes later (3, 5, 10 minutes), evaluated overall without distinction of pain class (moderate + severe) and only in patients with moderate pain in the two treatment arms

L’endpoint primario dello studio è la variazione dell’intensità del dolore dal momento della randomizzazione (basale) fino a 10 minuti dopo (3, 5, 10 minuti) valutata complessivamente senza distinzione di classe del dolore (moderato + severo) e sui soli pazienti con dolore moderato nei due bracci di trattamento

E.5.1.1

Timepoint(s) of evaluation of this end point

BASELINE AND 3, 5, 10 MINUTES LATER

BASALE E 3, 5, 10 MINUTI DOPO

E.5.2

Secondary end point(s)

1 • Pain intensity variation from randomization (baseline) up to 10 minutes (3, 5, 10 minutes) evaluated overall without distinction of pain class (moderate + severe) in each of the two treatment arms
2 • Percentage of patients who are using rescue medication within 30 minutes in each of the two treatment arms
3 • Change in pain intensity from randomization (baseline) to 15, 20, 25, 30 minutes after evaluated overall without distinction of pain class (moderate + severe) in each of the two treatment arms
4 • Time to get relief from pain starting from randomization, evaluated overall without distinction of pain class (moderate + severe), in each of the two treatment arms
5 • Assessment of the therapy efficacy as perceived by patient and measured by Likert scale 30 minutes after randomization , evaluated overall without distinction of pain class (moderate +severe) in each of the two treatment arms
6 • Evaluation of the practicality of use of therapy evaluated by Likert scale by healthcare staff who administered the treatment, evaluated overall without distinction of pain class (moderate + severe) in each of the two treatment arms
7 • incidence of adverse events (organized for Preferred Term and System Organ Class) and trend of vital signs detected at 10 and 30 minutes after baseline
8 • Pain intensity variation from randomization (baseline) to 3, 5, 10, 15, 20, 25, 30 minutes later, overall without distinction of pain class (moderate + severe) for each type of inclusion trauma in each arm of treatment
9 • percentage of patients who use the dilution hole closure (ONLY TREATED WITH PENTHROX)

1 • variazione dell’intensità del dolore dal momento della randomizzazione (basale) fino a 10 minuti (3, 5, 10 minuti) valutata complessivamente senza distinzione di classe del dolore (moderato + severo) in ciascuno dei due bracci di trattamento
2 • Percentuale di pazienti che ricorrono ad analgesia addizionale (rescue medication) entro 30 minuti in ciascuno dei due bracci di trattamento
3 • variazione dell’intensità del dolore dal momento della randomizzazione (basale) a 15, 20, 25, 30 minuti dopo valutata complessivamente senza distinzione di classe del dolore (moderato + severo), in ciascuno dei due bracci di trattamento
4 • tempo necessario per ottenere il sollievo dal dolore a partire dalla randomizzazione valutato complessivamente senza distinzione di classe del dolore (moderato + severo), in ciascuno dei due bracci di trattamento
5 • giudizio di efficacia della terapia percepita del paziente e valutata mediante scala Likert dopo 30 minuti dalla randomizzazione valutato complessivamente senza distinzione di classe del dolore (moderato + severo) in ciascuno dei due bracci di trattamento
6 • giudizio di praticità di utilizzo della terapia valutata mediante scala Likert dal personale sanitario che ha somministrato il trattamento, valutato complessivamente senza distinzione di classe del dolore (moderato + severo) in ciascuno dei due bracci di trattamento
7 • incidenza di eventi avversi (organizzati per Preferred Term e System Organ Class) e andamento dei segni vitali rilevati a 10 e 30 minuti dopo il basale
8 • variazione dell’intensità del dolore dal momento della randomizzazione (basale) a 3, 5, 10, 15, 20, 25, 30 minuti dopo, complessivamente senza distinzione di classe del dolore (moderato + severo) per ciascun tipo di trauma di inclusione in ciascun braccio di trattamento
9 • percentuale di pazienti che ricorrono alla chiusura del foro diluitore (SOLO PER TRATTATI CON PENTHROX)

E.5.2.1

Timepoint(s) of evaluation of this end point

1 • BASELINE AND 3, 5, 10 MINUTES LATER
2 • WITHIN 30 MINUTES FROM BASELINE
3 • BASELINE AND 15,20,25,30 MINUTES LATER
4 • WITHIN 30 MINUTES FROM BASELINE
5 • 30 MINUTES FROM BASELINE
6 • 30 MINUTES FROM BASELINE (AS CLOSEST AS POSSIBILE TO TREATMENT CONCLUSION)
7 • WITHIN 14 +/- 2 DAYS FROM BASELINE
8 • BASELINE AND 3, 5, 10, 15, 20, 25, 30 MINUTES LATER
9 • AT OCCURENCE WITHIN THE END OF TREATMENT

1 • BASALE E 3, 5, 10 MINUTI DOPO
2 • ENTRO 30 MINUTI DAL BASALE
3 • BASALE E 15, 20,25,30 MINUTI DOPO
4 • ENTRO 30 MINUTI DAL BASALE
5 • 30 MINUTI DAL BASALE
6 • 30 MINUTI DAL BASALE (NEL PIU BREVE TEMPO POSSIBILE DOPO LA CONCLUSIONE DEL TRATTAMENTO)
7 • ENTRO 14 +/- 2 GIORNI DAL BASALE
8 • BASALE E 3, 5, 10, 15, 20, 25, 30 DOPO
9 • ALL'OCCORRENZA, ENTRO LA FINE DEL TRATTAMENTO

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

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)

Yes

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.8.5.1

Number of sites anticipated in the EEA

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

Data base lock

Chiusura del Data Base

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

Number of subjects for this age range:

F.1.1.1

In Utero

Information not present in EudraCT

F.1.1.2

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

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

200

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

Yes

F.3.3.1

Women of childbearing potential not using contraception

Yes

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

Yes

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

272

F.4.2

For a multinational trial

F.4.2.1

In the EEA

272

F.4.2.2

In the whole clinical trial

272

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)

After 14 days of randomization and therapy, the patient will undergo a telephone visit to assess the safety.

Dopo 14 giorni dalla randomizzazione e dalla somministrazione della terapia, il paziente sarà sottoposto ad una visita telefonica per la valutazione della sicurezza.

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

2017-10-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-11-21

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

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IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
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