Clinical Trials Register

Summary
EudraCT Number:	2015-004779-64
Sponsor's Protocol Code Number:	ALMED-15-C2-054
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:	2016-10-27
Trial results	View 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

2015-004779-64

A.3

Full title of the trial

Equimolar Mixture of Oxygen and Nitrous Oxide (EMONO) for the Treatment of Peripheral Neuropathic Pain: a Randomised, International, Multicentre, Placebo-Controlled, Phenotype-stratified Phase IIa Study

Mélange équimolaire d'oxygène et de protoxyde d'azote pour le traitement de la douleur neuropathique périphérique : étude randomisée, internationale, multicentrique, contrôlée par placebo, stratifiée d'après le phénotype, de phase IIa

A.3.1

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

Treatment of Peripheral Neuropathic Pain

Traitement de la douleur neuropathique périphérique

A.4.1

Sponsor's protocol code number

ALMED-15-C2-054

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	Air Liquide Santé International
B.1.3.4	Country	France
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	Air Liquide Santé International
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	Air Liquide Santé International
B.5.2	Functional name of contact point	Medical R&D Vice President
B.5.3	Address:
B.5.3.1	Street Address	1, chemin de la porte des loges
B.5.3.2	Town/ city	Jouy en Josas
B.5.3.3	Post code	78354
B.5.3.4	Country	France
B.5.4	Telephone number	330139076342
B.5.5	Fax number	330139076199
B.5.6	E-mail	juan-fernando.ramirez@airliquide.com

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	Kalinox TM
D.2.1.1.2	Name of the Marketing Authorisation holder	Air Liquide Santé International
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.3.4	Pharmaceutical form	Medicinal gas, compressed
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation 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	Yes
D.3.11.13.1	Other medicinal product type	Medicinal gas

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	Medicinal gas, compressed
D.8.4	Route of administration of the placebo	Inhalation use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Treatment Peripheral Neuropathic Pain

Traitement douleurs neuropathiques périphériques

E.1.1.1

Medical condition in easily understood language

Treatment Peripheral Neuropathic Pain

Traitement douleurs neuropathiques périphériques

E.1.1.2

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10054095
E.1.2	Term	Neuropathic pain
E.1.2	System Organ Class	100000004852

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 assess the effect of 3 consecutive days of one-hour administration of Nitrous Oxide/Oxygen 50%/50% (EMONO) versus placebo as Oxygen/Nitrogen 22%/78% (synthetic medical air), in add-on therapy to chronic analgesic treatments, on average pain intensity in patients with chronic peripheral neuropathic pain.

Evaluer l’effet de trois jours consécutifs d’administration d’une heure d’un mélange Protoxyde d’azote/Oxygène 50 %/50 % (MEOPA) à celui d’un placebo se composant d’un mélange Oxygène/Azote 22 %/78 % (air médical synthétique) en ajout aux traitements analgésiques chroniques sur l’intensité moyenne des douleurs chez des patients souffrant de douleurs neuropathiques périphériques chroniques.

E.2.2

Secondary objectives of the trial

-To assess the magnitude and long-term effect on pain intensity over a 28 days period after treatment administration
-To characterise the treatment response according to the sensory phenotype profile, i.e. evoked/non evoked pain
-To assess the treatment effects on pain characteristics
-To assess the treatment effects on quality of life
-To assess the need for rescue therapy
-To assess safety during the study

-Évaluer l’effet sur l’intensité des douleurs et la durée à long terme sur une période de 28 jours après administration du traitement,
-Caractériser la réponse au traitement selon le profil du phénotype sensoriel (douleurs provoquées ou non provoquées)
-Évaluer les effets du traitement sur les caractéristiques des douleurs
-Évaluer les effets du traitement sur la qualité de vie
-Évaluer la nécessité d’un traitement de secours
-Évaluer la tolérance durant l’étude

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

-Male or female patient aged 18 years or older
-Definite or probable peripheral neuropathy confirmed by DN4 (score ≥ 4) and NeuPSIG criteria (“definite” or “probable” levels) (see Appendix 2 and 3)
-Neuropathic pain lasting for more than 3 months but less than 10 years
-Pain intensity ≥ 4 but ≤ 9 as assessed on the 11-point NRS (Numeric Rating Scale)
-Stable analgesic medications since at least 4 weeks prior the Selection visit V0
-Peripheral neuropathy with at least one of the following aetiologies :
Post-traumatic or post-surgical nerve injury
Polyneuropathy including diabetic neuropathy
Post-herpetic neuralgia
-Patient willing and able to complete the requirements of this study
-Written informed consent signed and dated by the patient after full explanation of the study prior to any study related procedures

-Homme ou femme âgé d’au moins 18 ans
-Neuropathie périphérique certaine ou probable confirmée selon les critères DN4 (score ≥ 4) et NeuPSIG (niveau « certain » ou « probable ») (voir annexes 2 et 3)
-Douleurs neuropathiques présentes depuis plus de 3 mois mais depuis moins de 10 ans
-Intensité des douleurs ≥ 4 mais ≤ 9 sur l’échelle d’évaluation numérique (Numeric Rating Scale [NRS]) à 11 points
-Médicaments analgésiques stables depuis au moins 4 semaines avant la visite de sélection V0
-Neuropathie périphérique dont l’étiologie est au moins l’une des suivantes :
Lésion nerveuse post-traumatique ou post-chirurgicale
Polyneuropathie, dont neuropathie diabétique
Névralgie post-zostérienne
-Patient acceptant de respecter les exigences de l’étude et apte à le faire
-Consentement éclairé par écrit signé par le patient après l’explication complète de l’étude et avant toute procédure liée à celle-ci.

E.4

Principal exclusion criteria

-Legal incapacity or limited legal capacity
-Patient with another concomitant chronic pain
-Ongoing major depression
-Patient with ongoing litigation
-Pregnancy or lactation
-Severe terminal illness
-Anticipated difficulties for administration of inhaled gas by mask (facial deformation that would make mask administration of inhaled gases inefficient)
-Risk of need for high inhaled oxygen concentrations
-Chronic respiratory failure requiring regular oxygen therapy
-Ketamine administered within one week before selection
-Hypnosis sessions (including self-hypnosis) or any other complementary medicine treatment planned during the study
-Participation in a drug or device trial within the previous 30 days
-Known contraindication to administration of Nitrous Oxide/Oxygen 50%/50% (EMONO) including documented and untreated vitamin B12 or folic acid deficiency

-Incapacité juridique ou capacité juridique limitée
-Patient souffrant d’autres douleurs chroniques concomitantes
-Épisode dépressif majeur en cours
-Patient engagé dans un litige en cours
-Grossesse ou allaitement
-Maladie au stade terminal
-Difficultés prévisibles pour l’administration de gaz inhalés au moyen d’un masque (déformation faciale qui rendrait inefficace cette administration)
-Risque de besoin d’inhalation d’oxygène à forte concentration
-Insuffisance respiratoire chronique nécessitant une oxygénothérapie régulière
-Administration de kétamine au cours des sept jours précédant la sélection
-Séances d’hypnose ou d’autohypnose ou tout autre traitement de médecine complémentaire ou alternative prévus durant l’étude
-Participation à un essai d’un médicament ou d’un dispositif au cours des 30 jours précédents
-Contre-indication connue à l’administration du mélange Protoxyde d’azote/Oxygène 50 %/50 % (MEOPA), incluant la présence d’une carence documentée et non traitée en vitamine B12 ou en acide folique

E.5 End points

E.5.1

Primary end point(s)

Change in mean pain intensity

Variation de l’intensité moyenne des douleurs

E.5.1.1

Timepoint(s) of evaluation of this end point

Between the 7-day baseline period (including pain intensity recorded in the morning before Inclusion visit ) and the first 7-day after the last administration of treatment

Entre la période de référence de 7 jours (incluant l’intensité des douleurs évaluée le matin avant la visite d’inclusion) et les 7 jours suivant la dernière administration du traitement.

E.5.2

Secondary end point(s)

Evolution of pain intensity by NRS

Évolution de l’intensité des douleurs par NRS

E.5.2.1

Timepoint(s) of evaluation of this end point

up to 28 days after treatment administration

jusqu’au 28ème jour suivant la dernière administration du traitement

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

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

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

en aveugle pour le patient et l'Investigateur 1 ; en ouvert pour l'investigateur 2

Blinded: Patient - Investigator 1 ; Not blinded: Investigator 2

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

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

Yes

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

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 Last Subject (LVLS)

Dernière Visite Dernier Patient (LVLS)

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:

350

F.1.3

Elderly (>=65 years)

F.1.3.1

Number of subjects for this age range:

350

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