Clinical Trials Register

Summary
EudraCT Number:	2019-003091-39
Sponsor's Protocol Code Number:	APHP180158
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2019-11-04
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

France - ANSM

A.2

EudraCT number

2019-003091-39

A.3

Full title of the trial

To relieve dyspnea with low dose titration of morphine in patients admitted to intensive care for acute respiratory failure:
A pilot study - OPIDYS

Soulager la dyspnée au moyen d’une titration par de faibles doses de morphine chez les patients admis en réanimation pour insuffisance respiratoire aiguë :
Une étude pilote - OPIDYS

A.3.1

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

To relieve dyspnea with low dose titration of morphine in patients admitted to intensive care for acute respiratory failure

Soulager la dyspnée au moyen d’une titration par de faibles doses de morphine chez les patients admis en réanimation pour insuffisance respiratoire aiguë

A.3.2

Name or abbreviated title of the trial where available

OPIDYS

A.4.1

Sponsor's protocol code number

APHP180158

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	Assistance Publique des Hôpitaux de Paris
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	DGOS
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Assistance Publique des Hôpitaux de Paris
B.5.2	Functional name of contact point	DRCI Hôpital Saint Louis
B.5.3	Address:
B.5.3.1	Street Address	1 av Claude Vellefaux
B.5.3.2	Town/ city	PARIS
B.5.3.3	Post code	75010
B.5.3.4	Country	France
B.5.4	Telephone number	330140 27 55 73
B.5.5	Fax number	330144 84 17 01
B.5.6	E-mail	riad.baameur@aphp.fr

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	MORPHINE (CHLORHYDRATE) LAVOISIER 10 mg/ml, solution injectable
D.2.1.1.2	Name of the Marketing Authorisation holder	LABORATOIRES CHAIX ET DU MARAIS
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	MORPHINE (CHLORHYDRATE) LAVOISIER 10 mg/ml, solution injectable
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	Subcutaneous use
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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
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.IMP: 2
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	MORPHINE (CHLORHYDRATE) RENAUDIN 1 mg/ml, solution injectable
D.2.1.1.2	Name of the Marketing Authorisation holder	LABORATOIRE RENAUDIN
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	MORPHINE (CHLORHYDRATE) RENAUDIN 1 mg/ml, solution injectable
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.3.11 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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Subcutaneous use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Adult patients admitted to intensive care for ARI: severe dyspnea (defined by a visual analogue dyspnea scale (EVA-dyspnea) ≥ 40)

Patients adultes admis en réanimation pour une IRA : dyspnée sévère (définie par une échelle visuelle analogique de dyspnée (EVA-dyspnée) ≥ 40)

E.1.1.1

Medical condition in easily understood language

To determine whether the administration of low-dose, low-dose opioids compared to placebo in patients admitted to intensive care with severe dyspnea reduces the 24-hour dyspnea score.

Déterminer si l'administration d'opioïdes titrés à faible dose, comparé à un placebo, chez les patients admis en réanimation présentant une dyspnée sévère diminue le score de dyspnée sur 24 heures.

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine whether the administration of low-dose titrated opioids compared to placebo in patients admitted to ARI intensive care with severe dyspnea (defined as a visual dyspnoea scale (EVA-dyspnea) ≥ 40) decreases the average 24-hour dyspnoea score (EVA-dyspnea).

Déterminer si l'administration d'opioïdes titrés à faible dose, comparativement à un placebo, chez les patients admis en réanimation pour IRA et présentant une dyspnée sévère (définie par une échelle visuelle analogique de dyspnée (EVA-dyspnée) ≥ 40), diminue le score de dyspnée (EVA-dyspnée) moyen sur 24 heures.

E.2.2

Secondary objectives of the trial

To evaluate the impact of low dose opioid administration compared to placebo on the following criteria:
- Incidence of severe dyspnea (EVA-dyspnea ≥ 40) and its intensity within 24 hours
- Incidence and severity of anxiety every 4 hours
- Level of alertness every 4 hours
- Incidence of delirium, incidence of coma during the first 24 hours
- Respiratory rate every 4 hours
- Rate of change from one oxygenation technique to another
- Intensity of pain every 4 hours
- Duration of sleep and quality on the first night
- Signs of intolerance to the oxygenation technique, such as dry eye, nasal dryness, sensation of gastric distension
- Signs of digestive intolerance to opioids: constipation, nausea
- Adherence of nurses to protocol, satisfaction of nurses
- Intubation rate within 24 hours
- Number and duration of NIV or HFNCO sessions

Évaluer l'impact de l'administration d'opioïdes à faible dose, comparativement à un placebo, sur les critères suivants:
- Incidence de la dyspnée sévère (EVA-dyspnée ≥ 40) et son intensité dans les 24 heures
- Incidence et sévérité de l'anxiété toutes les 4 heures
- Niveau de vigilance toutes les 4 heures
- Incidence du delirium, incidence du coma au cours des 24 premières heures
- Fréquence respiratoire toute les 4 heures
- Taux de passage d'une technique d'oxygénation à une autre
- Intensité de la douleur toute les 4 heures
- Durée du sommeil et qualité sur la première nuit
- Signes d'intolérance à la technique d'oxygénation, tels que sécheresse oculaire, sécheresse nasale, sensation de distension gastrique
- Signes d'intolérance digestive aux opioïdes: constipation, nausées
- Adhésion des infirmières au protocole, satisfaction des infirmières
- Taux d’intubation dans les 24 heures
- Nombre et durée de séances de VNI ou HFNCO

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Adult patients ≤ 75 years
- Admitted to resuscitation for an IRA defined as a respiratory rate> 24 / min or signs of respiratory distress such as a draw or paradoxical inspiration, or SpO2 <90% in ambient air
- Spontaneous ventilation, whether under standard oxygen, OHD or VNI
- Dyspnoea ≥ 40 on an EVA-dyspnoea from zero (no dyspnea) to 100 (worst possible dyspnoea)
- Richmond agitation and sedation scale (RASS) between 0 and 2.
- No confusion, as defined by the CAM-ICU method
- Signed informed consent

- Patients adultes ≤ 75 ans
- Admis en réanimation pour une IRA définie comme une fréquence respiratoire > 24 / min ou des signes de détresse respiratoire tels qu’un tirage ou une inspiration paradoxale, ou une SpO2 < 90% en air ambiant
- Ventilation spontanée, que ce soit sous oxygène standard, sous OHD ou sous VNI
- Dyspnée ≥ 40 sur une EVA- dyspnée allant de zéro (pas de dyspnée) à 100 (pire dyspnée possible)
- Echelle d’agitation et sédation de Richmond (RASS) entre 0 et 2.
- Absence de confusion, tel que définie par la méthode CAM-ICU
- Signature d’un consentement éclairé

E.4

Principal exclusion criteria

- Intensity of dyspnea every 4 hours (PRO)
- Incidence of severe dyspnea (EVA-dyspnea ≥40) within 24 hours (PRO)
- Anxiety (anxiety EVA) every 4 hours as well as on the first 24 hours (PRO)
- Incidence of moderate to severe anxiety every 4 hours (PRO)
- Intubation in the first 48 hours
- Level of vigilance (Glasgow Coma Scale every 4 hours as well as the first 48 hours: impairment of vigilance defined by a Glasgow Coma Scale ≤ 12
- Incidence of coma over the first 48 hours
- Incidence of delirium (CAM-ICU) every 4 hours and the first 48 hours
- Respiratory rate every 4 hours and on the first 24 hours
- Proportion of patients requiring the switch from one oxygenation technique to another
- Intensity of pain every 4 hours (PRO)
- Duration of night sleep the first night
- Quality of sleep the first night (PRO)
- Severity of dry eye over the first 24 hours (PRO)
- Severity of nasal dryness over the first 24 hours (PRO)
- Severity of feeling of gastric distension over the first 24 hours (PRO)
- Constipation on the first 48 hours
- Nausea over the first 48 hours (PRO)
- Accession of nurses to the protocol
- Nurses' satisfaction with the protocol
- Number of NIV sessions over the first 24 hours
- Total duration of the NIV on the first 24 hours
- Tolerance of NIV over the first 24 hours
- Duration of HFNCO on the first 24 hours
- Tolerance of HFNCO over the first 24 hours
- Duration of standard oxygen over the first 24 hours
- Standard oxygen tolerance over the first 24 hours
- Any undesirable or serious event occurring during the first 48 hours.
Treatments received by the patient will be collected and described.

- Patient intubé
- Intubation planifiée dès l’admission
- Déficience auditive ou visuelle
- Maîtrise insuffisante du français
- Troubles psychiatriques ou cognitifs antérieurs connus
- Patient moribond
- Hypersensibilité connue aux opioïdes
- Insuffisance rénale sévère (clairance de la créatinine <30 ml/min)
- Insuffisance hépatocellulaire sévère (facteur V < 50 %)
- Toute indication formelle aux opiacés
- Patient ayant reçu de la morphine 24h avant l’inclusion
- Grossesse ou allaitement
- Mineurs et majeurs protégés
- Période d'exclusion due à une inclusion dans un autre essai clinique
- Inclusion antérieure dans la présente étude
- Non affiliation à la sécurité sociale

E.5 End points

E.5.1

Primary end point(s)

Average dyspnea over 24 hours. Dyspnea will be assessed by EVA-dyspnea (ranging from zero: no dyspnea to 100: worst dyspnea possible) systematically every 4 hours and whenever necessary.

Dyspnée moyenne sur 24 heures. La dyspnée sera évaluée par une EVA-dyspnée (allant de zéro : pas de dyspnée à 100 : pire dyspnée possible) systématiquement toutes les 4 heures et chaque fois que nécessaire.

E.5.1.1

Timepoint(s) of evaluation of this end point

48 hours after first administration of Morphine, systematic evaluation every 4 hours and whenever necessary

48 heures après première administration de la Morphine, évaluation systématique toute les 4 heures et chaque fois que nécessaire

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

first 48 hours after administration of morphine

premières 48 heures après administration de la morphine

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

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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)

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

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

E.8.7

Trial has a data monitoring committee

Yes

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

Last Visit of Last Subject (LVLS)

Dernier suivi du dernier patient

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

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:

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

F.3.3.2

Women of child-bearing potential using contraception

Yes

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

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)

None

Aucun

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

2020-01-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-02-10

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-10-10

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