Clinical Trials Register

Summary
EudraCT Number:	2018-002591-40
Sponsor's Protocol Code Number:	P180501J
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:	2018-09-27
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

2018-002591-40

A.3

Full title of the trial

Evaluation of bronchial remodeling during mepolizumab treatment in severe eosinophilic asthma

Evaluation du remodelage bronchique lors d’un traitement par mépolizumab dans l’asthme sévère éosinophile

A.3.1

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

Evaluation of bronchial remodeling during mepolizumab treatment in severe eosinophilic asthma

Evaluation du remodelage bronchique lors d’un traitement par mépolizumab dans l’asthme sévère éosinophile

A.3.2

Name or abbreviated title of the trial where available

REMOMEPO

A.4.1

Sponsor's protocol code number

P180501J

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 - HOPITAUX 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	LABORATOIRE GLAXOSMITHKLINE
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 - HOPITAUX DE PARIS
B.5.2	Functional name of contact point	Sophie Courtial-Destembert
B.5.3	Address:
B.5.3.1	Street Address	DRCI Hôpital St Louis, 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	33140275591
B.5.5	Fax number	33144841701
B.5.6	E-mail	sophie.courtial-destembert@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	Nucala
D.2.1.1.2	Name of the Marketing Authorisation holder	GlaxoSmithKline Trading Services 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.3.4	Pharmaceutical form	Powder for 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	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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

severe oesinophilic asthma

asthme sévère éosinophile

E.1.1.1

Medical condition in easily understood language

severe oesinophilic asthma

asthme sévère éosinophile

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

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	10068462
E.1.2	Term	Eosinophilic asthma
E.1.2	System Organ Class	100000004855

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

caractériser les modifications du remodelage et de l'inflammation bronchiques chez des patients avec asthme sévère à éosinophiles au cours des 12 premiers mois de traitement par mépolizumab

characterize changes in bronchial remodeling and inflammation in patients with severe eosinophilic asthma in the first 12 months of treatment with mepolizumab

E.2.2

Secondary objectives of the trial

- Describe the clinical and functional response after 6 and 12 months of treatment.
- Study the association of histopathological changes with the clinical and functional response to treatment.
- Study the association of changes in markers of inflammation with the clinical and functional response to treatment.
- To compare the evolution of bronchial remodeling and inflammation in patients treated for 12 months with mepolizumab in untreated patients (historical control group).
- Subsequently test new pathophysiological hypotheses, by the constitution of a biological collection of serum, BAL and bronchial tissue slides, for the identification of biomarkers of interest.

- Décrire la réponse clinique et fonctionnelle après 6 et 12 mois de traitement.
- Etudier l'association des modifications histopathologiques avec la réponse clinique et fonctionnelle au traitement.
- Etudier l'association des modifications des marqueurs de l'inflammation avec la réponse clinique et fonctionnelle au traitement.
- Comparer l'évolution du remodelage et de l'inflammation bronchiques des patients traités 12 mois par mépolizumab à l'évolution de patients non traités (groupe contrôle historique).
- Tester ultérieurement de nouvelles hypothèses physiopathologiques, par la constitution d'une collection biologique de sérum, de LBA et de lames de tissu bronchique, pour l'identification de biomarqueurs d'intérêt.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Age ≥ 18 years
- Severe asthmatics for which the indication of a treatment by mepolizumab is posed by the clinician, according to the criteria of prescription defined in France:
• a blood eosinophil level ≥ 300 / μL in the last 12 months;
• and at least one of the following two criteria:
- at least two episodes of asthmatic exacerbations requiring treatment with oral corticosteroid (≥3 days each) in the last 12 months despite a combination of high dose inhaled corticosteroids and a long-acting bronchodilator (LABA) ( stage 4/5 GINA);
- or treatment with oral corticosteroids for at least six months in the last twelve months.

- Age ≥ 18 ans
- Asthmatiques sévères pour lesquels l’indication d’un traitement par mépolizumab est posée par le clinicien, conformément aux critères de prescription définis en France :
• un taux d'éosinophiles sanguins ≥ 300/µL dans les douze derniers mois ;
• et au moins un des deux critères suivants :
- au moins deux épisodes d'exacerbations asthmatiques ayant nécessité un traitement par corticoïde oral (≥ 3 jours chacun) dans les douze derniers mois malgré un traitement de fond associant des corticoïdes inhalés à dose élevée et un bronchodilatateur d'action longue (LABA) (stade 4/5 GINA) ;
- ou un traitement par corticothérapie orale pendant au moins six mois au cours des douze derniers mois.

E.4

Principal exclusion criteria

- Refusal to sign a written consent to participation.
- Contraindication to bronchial endoscopy (asthma exacerbation, contraindication to the use of Xylocaine 5% for oral solution) or contraindication to performing bronchial biopsies (taking anticoagulant or the combination of two antiplatelet treatments
- Contraindication to mepolizumab according to the Summary of Product Characteristics
- Pregnant or lactating woman
- Not affiliated to a social security scheme

- Refus de signer un consentement écrit de participation.
- Contre-indication à la réalisation d’une endoscopie bronchique (asthme en exacerbation, contre-indication à l’utilisation de Xylocaïne 5% pour solution buccale) ou contre-indication à la réalisation de biopsies bronchiques (prise d’un traitement anticoagulant ou de l’association de deux traitements antiplaquettaires
- Contre-indication au mépolizumab selon le Résumé des Caractéristiques du Produit
- Femme enceinte ou allaitante
- Non affilié à un régime de sécurité sociale

E.5 End points

E.5.1

Primary end point(s)

Histological evaluation
The histological elements that will be evaluated before initiation of treatment and after 6 and 12 months of treatment are as follows:
• Thickness of the basement membrane measured on morphometric bronchial biopsies, expressed in microns (19).
• Smooth muscle area, measured in morphometry in μm2 and expressed as a percentage of smooth muscle area reported on the surface of the biopsy (7).
• Number of proliferating muscle cells evaluated by anti-proliferating cell nuclear antigen (PCNA) labeling in immunohistochemistry, expressed as a number of positive cells per muscle area.
• Number of nerve endings evaluated by PGP9 labeling in immunohistochemistry and expressed in number of positive cells per biopsy area in mm2 (7).
• Number of vascular sections, as measured by anti-CD31 antibody labeling, expressed as the number of sections per mm2.
• Number of different inflammatory cells (eosinophils / neutrophils / mast cells / lymphocytes), in immunohistochemistry, expressed in number of positive cells per area of biopsies in mm2 (7,19).
• Proportion of eosinophils expressing MBP / IL3R in immunohistochemistry (13) on biopsies, expressed as number of cells per biopsy area in mm2.

Evaluation of bronchial and serum markers of inflammation
Regarding the markers of inflammation in BAL and serum, the elements that will be evaluated before initiation of treatment and after 6 and 12 months of treatment, are as follows:
• Concentrations of the different markers (interferon gamma, IL-13, periostin, IL17a and IL22, IL33, TSLP, fibulin-1, tenascin, fibronectin, MCP1, EGF, bFGF and PDGF-BB) measured by Luminex or ELISA in BAL and the serum.
• Proportion of eosinophils expressing IL-3R on BAL in immunohistochemistry, expressed as a percentage of the number of eosinophils.
• Number of eosinophils at NFS
Clinical and functional evaluation
The criteria evaluated are the following:
• Asthma control: ACT score, annual rate of exacerbations, annual rate of oral corticosteroid therapy, average daily prednisone dose in all patients and in patients with corticosteroids, respiratory function parameters (FEV 1 and VESM) / CV, VR, CPT, before and after salbutamol), annual rate of asthma hospitalizations, annual rate of unscheduled asthma visits, annual rate of emergency room visits for asthma, measured before initiation of treatment, and after 6 and 12 months of treatment.
• Overall evaluation of mepolizumab (Global Evaluation of Treatment Effectiveness, TETE), evaluated after 6 and 12 months. This composite measure is based on the investigator's assessment of the treatment response that is rated by the physician from 1 to 5 (1 = excellent response, 2 = good response, 3 = moderate response, 4 = poor response, 5 = worsening of the disease).
• Clinical response to treatment: proportion of patients classified responders (corresponding to patients rated 1 = excellent response or 2 = good response to TEAP), evaluated by the investigator after 6 and 12 months of treatment.
• Functional response to treatment: proportion of patients with pre-bronchodilator FEV1 greater than 80% after 6 and 12 months of treatment, proportion of patients with pre-bronchodilator FEV1 increase greater than 20% between baseline value and those at 6 and 12 months of treatment.

Evaluation histologique
Les éléments histologiques qui seront évalués avant l’initiation du traitement et après 6 et 12 mois de traitement, sont les suivants :
• Epaisseur de la membrane basale mesurée sur les biopsies bronchiques en morphométrie, exprimée en µm (19).
• Surface de muscle lisse, mesurée en morphométrie en µm2 et exprimée en pourcentage de surface de muscle lisse rapportée à la surface de la biopsie (7).
• Nombre de cellules musculaires proliférantes évaluées par marquage par anticorps anti proliferating cell nuclear antigen (PCNA) en immunohistochimie, exprimé en nombre de cellules positives par surface de muscle.
• Nombre de terminaisons nerveuses évaluées par marquage par PGP9 en immunohistochimie et exprimé en nombre de cellules positives par surface de biopsie en mm2 (7).
• Nombre de sections vasculaires, mesurée par le marquage avec un anticorps anti CD31, exprimé en nombre de sections par mm2.
• Nombre des différentes cellules inflammatoires (éosinophiles/neutrophiles/ mastocytes/lymphocytes), en immunohistochimie, exprimé en nombre de cellules positives par surface de biopsies en mm2 (7,19).
• Proportion d’éosinophiles exprimant MBP/IL3R en immunohistochimie (13) sur les biopsies, exprimée en nombre de cellules par surface de biopsie en mm2.

Evaluation des marqueurs bronchiques et sériques d’inflammation
Concernant les marqueurs de l’inflammation dans le LBA et le sérum, les éléments qui seront évalués avant l’initiation du traitement et après 6 et 12 mois de traitement, sont les suivants :
• Concentrations des différents marqueurs (interferon gamma, IL-13, periostine, IL17a et IL22, IL33, TSLP, fibulin-1, tenascine, fibronectine, MCP1, EGF, bFGF et PDGF-BB) mesurées par Luminex ou ELISA dans le LBA et le sérum.
• Proportion d’éosinophiles exprimant IL-3R sur le LBA en immunohistochimie, exprimé en pourcentage du nombre d’éosinophiles.
• Nombre d’éosinophiles à la NFS.

Evaluation clinique et fonctionnelle
Les critères évalués sont les suivants :
• Contrôle de l’asthme : Score ACT, taux annuel d’exacerbations, taux annuel de cures de corticoïdes oraux, dose moyenne quotidienne de prednisone chez l’ensemble des patients et chez les patients corticodépendants, paramètres de la fonction respiratoire (VEMS et VESM/CV, VR, CPT, avant et après salbutamol), taux annuel d’hospitalisations pour asthme, taux annuel de consultations non programmées pour asthme, taux annuel de visites aux urgences pour asthme, mesurés avant l’initiation du traitement et après 6 et 12 mois de traitement.
• Evaluation globale de l’efficacité du mépolizumab (Global Evaluation of Treatment Effectiveness, GETE), évaluée après 6 et 12 mois. Cette mesure composite repose sur l’évaluation par l’investigateur de la réponse au traitement qui est classée par le médecin de 1 à 5 (1 = réponse excellente ; 2 = bonne réponse ; 3 = réponse modérée ; 4 = réponse faible ; 5 = aggravation de la maladie).
• Réponse clinique au traitement : proportion de patients classés répondeurs (correspondant au patients classés 1 = réponse excellente ou 2 = bonne réponse au GETE), évaluée par l’investigateur après 6 et 12 mois de traitement.
• Réponse fonctionnelle au traitement : proportion de patients ayant un VEMS pré-bronchodilatateurs supérieur à 80% après 6 et 12 mois de traitement, proportion de patients ayant une augmentation du VEMS pré- bronchodilatateurs supérieure à 20% entre la valeur à l’inclusion et celles à 6 et 12 mois de traitement.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months

12 mois

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

12 months

12 mois

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

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)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

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.8.3

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

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

dernière visite du dernier sujet

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

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

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

2018-11-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-11-14

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-06-21

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