Clinical Trials Register

Summary
EudraCT Number:	2017-005162-22
Sponsor's Protocol Code Number:	PSS2017/PCE-aGVHD-RUBIO/VS
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-02-28
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

2017-005162-22

A.3

Full title of the trial

A multi-center randomized phase II study comparing corticosteroids alone versus corticosteroids and extracorporal photopheresis (ECP) as first-line treatment of standard risk Grade II acute graft-versus-host disease after allogeneic stem cell transplantation

Etude randomisée multicentrique de phase II comparant l’association corticoïdes et photophérèse extracorporelle au traitement conventionnel par corticoïdes dans le traitement de première ligne de la réaction aiguë du greffon contre l’hôte de grade II avec atteinte cutanée survenant après allogreffe de cellules souches hématopoïétiques

A.3.1

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

Etude comparant l’association corticoïdes et photophérèse extracorporelle au traitement conventionnel par corticoïdes dans le traitement de première ligne de la réaction aiguë du greffon contre l’hôte de grade II

A study comparing corticosteroids alone versus corticosteroids and extracorporal photopheresis (ECP) as first-line treatment of standard II acute graft-versus-host disease

A.3.2

Name or abbreviated title of the trial where available

ECP-aGVHD

PEC-aGVHD

A.4.1

Sponsor's protocol code number

PSS2017/PCE-aGVHD-RUBIO/VS

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	CHRU de Nancy
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	Therakos, Inc., a Mallinckrodt company
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CHRU de Nancy
B.5.2	Functional name of contact point	Véronique SAUNIER
B.5.3	Address:
B.5.3.1	Street Address	DRI - Bâtiment Recherche - rue du Morvan
B.5.3.2	Town/ city	VANDOEUVRE LES NANCY
B.5.3.3	Post code	54511
B.5.3.4	Country	France
B.5.4	Telephone number	+330383155458
B.5.5	Fax number	+330383157451
B.5.6	E-mail	dripromoteur@chru-nancy.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	UVADEX
D.2.1.1.2	Name of the Marketing Authorisation holder	THERAKOS (UK) LTD 3 LOTUS PARK, THE CAUSEWAY STAINES-UPON-THAMES SURREY TW18 3AG ROYAUME-UNI
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	Yes
D.2.5.1	Orphan drug designation number	132163/2006
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Solution for blood fraction modification
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Extracorporeal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Methoxsalen
D.3.9.3	Other descriptive name	METHOXSALEN
D.3.9.4	EV Substance Code	SUB14541MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(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	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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Standard II acute graft-versus-host disease following allogeneic stem cell transplantation

Maladie du greffon versus hôte aiguë après allogreffe de cellules souches hématopoïétiques

E.1.1.1

Medical condition in easily understood language

standard II acute graft-versus-host disease

Maladie du greffon versus hôte aiguë

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

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

Compare the probability of being free of treatment failure (probability of survival without relapse, additional line of treatment for aGVHD and systemic therapy for chronic GVHD) after 6 months of the acute GVHS treatement between the experimental group (steroids + ECP) and the control group (steroids alone).

Comparaison de la probabilité de ne pas être en échec de traitement (FFTF) à 6 mois du début du traitement de la GHV aiguë entre le bras de traitement conventionnel (corticoïdes seuls) et le bras expérimental (corticoïdes + PCE)

E.2.2

Secondary objectives of the trial

- cumulative dose of steroids over time,
- infections (bacteremia, septicemia, fungal infection and virus reactivation) at 6 months,
- the incidence and severity of chronic GVHD (diagnosed and graded according to NIH criteria ),
- non-relapse mortality (death due to any cause except relapse),
- disease relapse (relapse is defined on the basis of morphological evidence of leukemic or lymphoma cells in the bone marrow or other sites),
- the disease-free survival
- the overall survival
- health-related quality of life using the French validated FACT-BMT (version 4.0)
- Immune reconstitution (T, B, NK, gammaglobulins)

- Dose cumulée de corticoïdes
- Incidence d’infections (bactériémies, septicémies, infections fongiques, reactivations virales ou parasitaires)
- Incidence et la sévérité de la GVH chronique
- Mortalité non liée à la rechute
- Incidence de rechute de la maladie sous-jacente
- Survie sans rechute
- Survie globale
- Evaluation de la qualité de vie
- Reconstitution immunitaire (T, B, NK, gammaglobulines)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Age ≥ 18 years ;
- Having received an allogeneic stem cell transplantation for any malignant or non-malignant hemopathy and whatever the type of donor and graft.
- with grade II acute GVHD with skin involvement (stage 1-3 skin +/- stage 1 gastro intestinal) in the 3 months following the allogeneic stem cell transplantation;
- acute GVHD in the first line treatment
- validation of the presence of peripheral or central venous access allowing to perform 2 ECP per week during 3 months;
- Leucocytes > 1.5 G/L
- Platelets > 30 G/L, Haematocrite > 27% (allowed transfusions)
- Patient affiliated to a French Sécurité Social regimen
- information consent form signed.

• Adultes ≥ 18 ans
• Ayant reçu une allogreffe de cellules souches hématopoïétiques pour toute hémopathie maligne ou non maligne et quel que soit le type de donneur et greffon
• Développant une GVH aigue de grade II avec atteinte cutanée (stade 1 à 3 cutané +/- stade 1 digestif) dans le 3 mois qui suivent la greffe de CSH
• GVH aigue en première ligne de traitement
• Patient pouvant débuter une PCE dans les 3 jours suivants la randomisation dans l’étude,
• Validation de la présence d’un accès veineux périphérique ou central permettant la réalisation de 2 séances de PCE par semaine pendant 3 mois
• Leucocytes > 1.5 G/L sur le dernier bilan biologique réalisé
• Plaquettes > 30 G/L, Hématocrite > 27% (transfusions autorisées) sur le dernier bilan biologique réalisé
• Affilié à un régime de sécurité sociale ou bénéficiaire d’un tel régime
• Information complète sur l’organisation de la recherche et ayant signé son consentement éclairé

E.4

Principal exclusion criteria

- acute GVHD of grade I
- acute GVHD of grade > II (Gastro intestinal stage > 1 or hepatic involvement) ;
- progressive hematologic disease at inclusion
- uncontrolled ongoing infection at time of inclusion: bacterial or fungal infections, increasing CMV viral load.
- HIV positivity or replicative HBV or HCV infection ;
- Contraindications for UVADEX / photopheresis / stéroids
- Pregnancy ;
- Women of child bearing potentiel not using contaception

• GVH aigue de grade I
• Toute GVH aigue de grade >II ou avec atteinte digestive > 1 ou hépatique
• Maladie hématologique progressive au moment de la GVH aigue
• Infection non contrôlée au moment de l’inclusion: sepsis bactérien, infection fongique, réactivation CMV avec charge virale en augmentation
• HIV positif ou HBV ou HCV réplicatif
• contre-indication à l’UVADEX /photophérèse / corticoïdes
• Femme enceinte
• Femme en âge de procréer et ne disposant pas de moyen de contraception

E.5 End points

E.5.1

Primary end point(s)

Probability of being free of treatment failure (probability of survival without relapse, additional line of treatment for aGVHD and systemic therapy for chronic GVHD) at 6 months after randomization.

Probabilité d’absence d’échec de traitement la GVH (survie sans rechute, sans avoir recours à une deuxième ligne de traitement pour la GVH aigue et sans nécessiter de traitement systémique pour GVH chronique)

E.5.1.1

Timepoint(s) of evaluation of this end point

at 6 months after the start of treatement (randomization)

6 mois après le début de traitement (randomisation).

E.5.2

Secondary end point(s)

1 - the mean of the cumulative dose of steroids,
2 - the cumulative incidence rate of infections (bacteremia, septicemia, fungal infection and virus reactivation),
3 - the incidence and severity of chronic GVHD (diagnosed and graded according to NIH criteria)
4 - the incidence rate of non-relapse mortality (death due to any cause except relapse),
5 - the incidence of disease relapse (relapse is defined on the basis of morphological evidence of leukemic or lymphoma cells in the bone marrow or other sites),
6 - the disease-free survival
7 - the overall survival
8 - the mean scores of health-related quality of life using the French validated FACT-BMT (version 4.0)
9- Immune reconstitution (T lymphocytes, T CD4, TCD8, B, NK, and gammaglobulins)

1- Dose cumulée moyenne de corticoïdes reçus
2- Incidence cumulée d’infections à 6 et 12 mois (bactériémies, septicémies, infections fongiques, réactivations virales ou parasitaires),
3- Incidence et sévérité de la GVH chronique (selon les critères du NIH 19),
4- Incidence de mortalité non liée à la rechute (mortalité liée à toute cause en dehors de la rechute de la maladie sous-jacente),
5- Incidence de rechute de la maladie sous-jacente (définie sur la mise en évidence d’une réapparition de blastes ou cellules tumorales dans la moelle ou autres sites tumoraux),
6- Survie sans rechute (DFS-disease-free survival)
7- Survie globale
8- Evaluation de la qualité de vie (version française du FACT-BMT version 4.0
9- Reconstitution immunitaire sur sang périphérique (lymphocytes T totaux, T CD4, TCD8, B, NK, et taux de gammaglobulines)

E.5.2.1

Timepoint(s) of evaluation of this end point

1- randomization-1 month, 1-2 month, 2-3 month, 3-6 month and 6-12 month periods
2- at 6 et 12 months
3- at 6 and 12 months,
4- at 6 and 12 months
5- at 6 and 12 months
6- at 6 and 12 months (time from transplantation to either first relapse or death in complete remission),
7- at 6 and 12 months (time from transplantation to death from any cause),
8- at 3, 6 and 12 months,
9- at 3, 6 and 12 months,

1 - randomisation à 1 mois, 1 à 2 mois, 2 à 3 mois, 3 à 6 mois et 6 à 12 mois,
2- à 6 et 12 mois
3- à 6 et 12 mois
4- à 6 et 12 mois
5- à 6 et 12 mois
6- à 6 et 12 mois (temps entre la date de randomisation et la date de la première rechute ou la date du décès qu’elle qu’en soit la cause),
7- à 6 et 12 mois (temps entre la date de randomisation et la date de décès qu'elle qu’en soit la cause),
8- à 3, 6 et 12 mois post-greffe,
9- à 3, 6 et 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

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)

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

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

corticoïdes seuls (traitement standard)

steroïds alone (standard treatment)

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.8.6 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

the last visit of the last subject

dernière visite 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

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:

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. The choice of treatment is left to the investigator's discretion

Aucun. Le choix du traitement est laissé à la convenance de l'investigateur.

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

2018-04-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-05-22

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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