Clinical Trials Register

Summary
EudraCT Number:	2015-004779-64
Sponsor's Protocol Code Number:	ALMED-15-C2-054
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-07-22
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

Germany - BfArM

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

A.3.1

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

Treatment of Peripheral Neuropathic Pain

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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Nitrous oxide
D.3.9.1	CAS number	10024-97-2
D.3.9.3	Other descriptive name	NITROUS OXIDE
D.3.9.4	EV Substance Code	SUB03447MIG
D.3.10	Strength
D.3.10.1	Concentration unit	% percent
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Oxygen
D.3.9.1	CAS number	7782-44-7
D.3.9.3	Other descriptive name	OXYGEN
D.3.9.4	EV Substance Code	SUB14733MIG
D.3.10	Strength
D.3.10.1	Concentration unit	% percent
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
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

E.1.1.1

Medical condition in easily understood language

Treatment Peripheral Neuropathic Pain

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	20.0
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.

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 study 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 "on demand" and/or rescue therapies
-To assess safety during the study

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

E.4

Principal exclusion criteria

-Legal incapacity or limited legal capacity
-Chronic pain with mixed mechanisms, including inflammatory process such as radiculopathy
-Patient with another co-located or not distinct concomitant chronic pain
-Ongoing major depression
-Patient with psychiatric disorders (schizophrenia, bipolar disorder...
-Patient with drug addiction
-Chemotherapy-induced peripheral neuropathic pain
-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 4 weeks before selection
-Any complementary medicine treatment (including hypnosis sessions) not stable within 4 weeks before selection
-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 (serum level) or folic acid (serum and red blood cell levels) deficiency

E.5 End points

E.5.1

Primary end point(s)

Change in mean pain intensity (assessed by NRS)

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

E.5.2

Secondary end point(s)

Evolution of pain intensity by NRS
- Proportion of patients with 1-point decrease in NRS scale at different time points
- Time to reach a 1-point decrease in NRS scale
- Duration of the 1-point decrease in NRS scale

E.5.2.1

Timepoint(s) of evaluation of this end point

up to 28 days after the last study treatment administration

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

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)

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:

250

F.1.3

Elderly (>=65 years)

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