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    Summary
    EudraCT Number:2016-002358-18
    Sponsor's Protocol Code Number:GMED16-001
    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:2016-11-22
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2016-002358-18
    A.3Full title of the trial
    Phase II study of first line treatment of Chronic Graft versus Host Disease with Arsenic Trioxide
    Étude de phase II du traitement en première ligne de la réaction chronique du greffon contre l’hôte par le trioxyde d’arsenic
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase II study of first line treatment of Chronic Graft versus Host Disease with Arsenic Trioxide
    Étude de phase II du traitement en première ligne de la réaction chronique du greffon contre l’hôte par le trioxyde d’arsenic
    A.3.2Name or abbreviated title of the trial where available
    GvHD-ATO
    GvHD-ATO
    A.4.1Sponsor's protocol code numberGMED16-001
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMedsenic
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMedsenic
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFovea
    B.5.2Functional name of contact pointFranck Sévenier
    B.5.3 Address:
    B.5.3.1Street Address3 bis chemin de la Jonchère
    B.5.3.2Town/ cityRueil-Malmaison
    B.5.3.3Post code92500
    B.5.3.4CountryFrance
    B.5.4Telephone number33(0)147140495
    B.5.5Fax number33(0)147161110
    B.5.6E-mailf.sevenier@fovea-group.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Trisenox
    D.2.1.1.2Name of the Marketing Authorisation holderTeva
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTrioxyde d'arsenic
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another 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.1.1Medical condition(s) being investigated
    First line treatment of Chronic Graft versus Host Disease in patients having received a first allogeneic stem cell transplantation for a hematological disease
    Traitement en première ligne de la réaction chronique du greffon contre l'hôte chez des patients ayant reçu une première allogreffe de cellules souches pour une hémopathie
    E.1.1.1Medical condition in easily understood language
    First line treatment of Chronic Graft versus Host Disease in patients having received a first allogeneic stem cell transplantation for a hematological disease
    Traitement en première ligne de la réaction chronique du greffon contre l'hôte chez des patients ayant reçu une première allogreffe de cellules souches pour une hémopathie
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To improve the response rate (complete and partial remission) at 6 months after diagnosis of chronic graft versus host disease (GvHD) and treatment with arsenic trioxide (ATO) in combination with prednisone with or without ciclosporine as first line treatment
    Améliorer le taux de réponse (rémission complète et partielle) 6 mois après le diagnostic de la maladie chronique du greffon contre l’hôte (Graft versus Host Disease, GvHD) et un traitement par le trioxyde d’arsenic en association avec de la prednisone, avec ou sans ciclosporine, en traitement de première ligne
    E.2.2Secondary objectives of the trial
    1. To evaluate failure-free survival (FFS), defined as death, recurrent or progressive malignancy, or initiation of a new systemic treatment for chronic GvHD
    2. To decrease non-relapse mortality (NRM) of infectious and non-infectious origin
    3. To improve overall survival (OS) and progression-free survival (PFS)
    4. To spare patients from long-term use of corticosteroids (and their long-term side effects)
    5. To improve quality of life self-reported by patient using the Lee Symptom Scale (LSS) and Functional Assessment of Chronic Illness Therapy with Bone Marrow Transplantation subscale (FACT-BMT)
    6. To evaluate tolerability and safety of ATO in combination with prednisone, with or without ciclosporine, in patients with chronic GvHD after allo-SCT
    1. Évaluer la survie sans échec du traitement, défini par le décès, la récidive ou la progression maligne, ou l’instauration d’un nouveau traitement systémique pour la GvHD chronique
    2. Diminuer la mortalité non due à la récidive, d’origine infectieuse et non-infectieuse
    3. Améliorer la survie globale et la survie sans progression de la maladie
    4. Épargner aux patients l’utilisation à long terme de corticoïdes (ainsi que leurs effets secondaires à long terme)
    5. Améliorer la qualité de vie rapportée par le patient au moyen de l’échelle « Lee Symptom Scale » (LSS) et de l’échelle « Functional Assessment of Chronic Illness Therapy with Bone Marrow Transplantation » (FACT-BMT)
    6. Évaluer la tolérance et la sécurité d’emploi du trioxyde d’arsenic en association avec de la prednisone, avec ou sans ciclosporine, chez des patients atteints de GvHD chronique après une allogreffe de cellules souches
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Adult patients (≥18 years) who have received a first allogeneic stem cell transplantation for a hematological disease (any source of hematopoietic stem cells is authorized; any category of conditioning regimen prior to allo-SCT is authorized; any type of stem cell donors is authorized)
    2. Confirmed diagnosis of a first episode of chronic GvHD requiring systemic immunosuppressive therapy (any prior GvHD prophylaxis previously used is accepted). Chronic GvHD diagnosis is defined according to the NIH Working Group Consensus. Chronic GvHD diagnosis will be based on the evaluation of the severity of the different clinical manifestations including:
    a/ Performance status evaluation
    b/ Cutaneous evaluation measured by the percentage of extension or the presence of sclerotic features. If relevant, confirmation with a biopsy should be performed whenever possible
    c/ Oral symptoms
    d/ Ocular symptoms
    e/ Gastro-intestinal symptoms
    f/ Evaluation of liver involvement (total bilirubin, transaminases and alkaline phosphatases)
    g/ Pulmonary function evaluation
    h/ Evaluation of the musculoskeletal manifestations, especially the amplitude of the relevant articulations
    i/ Genital tract symptoms
    3. Signed informed consent
    4. Absence of contra-indications to the use of ATO
    5. Subjects affiliated with an appropriate social security system

    6. Women who are of childbearing potential must have a negative serum pregnancy test and agree to use a medically acceptable method of contraception throughout the study and for 3 months following the end of the study
    7. Patient not participating or not having participated in a clinical study in the 30 days prior to his/her inclusion in the study
    1. Patient adulte (âgé d’au moins 18 ans) ayant reçu une première allogreffe de cellules souches pour une hémopathie (toute source de cellules souches hématopoïétiques est autorisée ; toute catégorie de schéma de préparation avant une allogreffe de cellules souches est autorisée ; tout type de donneurs de cellules souches est autorisé)
    2. Diagnostic confirmé d’un premier épisode de GvHD chronique nécessitant un traitement immunosuppresseur systémique (toute prophylaxie de la GvHD précédemment utilisée est acceptée). Le diagnostic de GvHD chronique est défini conformément au consensus du groupe de travail des NIH (National Institutes of Health). Le diagnostic de GvHD chronique est basé sur l’évaluation de la gravité des différentes manifestations cliniques, dont :
    a/ Évaluation de l’indice de performance
    b/ Évaluation cutanée mesurée par le pourcentage de l’extension ou de la présence de caractéristiques sclérotiques. Si applicable, une confirmation par biopsie doit être effectuée dès que possible.
    c/ Symptômes buccaux
    d/ Symptômes oculaires
    e/ Symptômes gastro-intestinaux
    f/ Évaluation de l’atteinte hépatique (bilirubine totale, transaminases et phosphatases alcalines)
    g/ Évaluation de la fonction respiratoire
    h/ Évaluation des manifestations musculo-squelettiques, en particulier l’amplitude des articulations pertinentes
    i/ Symptômes de l’appareil génital
    3. Consentement éclairé signé
    4. Absence de contre-indication à l’utilisation du trioxyde d’arsenic
    5. Sujet affilié à un régime de sécurité sociale approprié
    6. Les femmes en âge de procréer doivent avoir un résultat négatif au test de grossesse sanguin et accepter d’utiliser une méthode de contraception médicalement efficace tout au long de l’étude et pendant les 3 mois suivant la fin de l’étude
    7. Patient ne participant pas à une étude clinique ou n’ayant pas participé à une étude clinique dans le mois précédant l’inclusion dans l’étude
    E.4Principal exclusion criteria
    1. Patient developing acute GvHD (whether early or “late onset” form)
    2. Patients developing overlap GvHD as defined by the 2014 NIH Working Group Consensus (presence of one or more acute GvHD manifestations in a patient with a diagnosis of chronic GvHD)
    3. A “mild” form of chronic GvHD not requiring systemic immunosuppressive therapy
    4. A “moderate” form of chronic GvHD limited to one organ site not requiring systemic immunosuppressive therapy
    5. Patient receiving mycophenolate mofetil
    6. GvHD occurring following donor lymphocytes infusion (DLI)
    7. Not the first episode of chronic GvHD needing systemic immunosuppressive therapy
    8. Second allogeneic stem cell transplant
    9. Significant arrhythmias, electrocardiogram (EKG) abnormalities:
    a/ Congenital QT syndromes
    b/ History or presence of significant ventricular or atrial tachyarrhythmia
    c/ Clinically significant resting bradycardia (< 50 beats per minutes)
    d/ QTc > 480 msec on screening EKG (using the QTcF formula)
    e/ Right bundle branch block plus left anterior hemiblock, bifascicular block
    10. Central or peripheral neuropathy
    11. Neutrophils < 0.5 × 109/L
    12. Platelets < 50 × 109/L
    13. Uncontrolled systemic infection which in the opinion of the investigator is associated with an increased risk of the patients’ death within 1 month after the start of therapy
    14. Severe neurological or psychiatric disorders
    15. Denied informed consent
    16. Pregnancy
    1. Patient développant une GvHD aiguë (que ce soit sous forme d’apparition précoce ou tardive)
    2. Patient développant une GvHD de type « overlap » comme définie par le consensus du groupe de travail des NIH 2014 (présence d’une ou plusieurs manifestations de GvHD aiguë chez un patient diagnostiqué comme atteint de GvHD chronique)
    3. Forme « légère » de la GvHD chronique ne nécessitant pas de traitement immunosuppresseur systémique
    4. Forme « modérée » de la GvHD chronique limitée à un site d’organe ne nécessitant pas un traitement immunosuppresseur systémique
    5. Patient recevant du mycophenolate mofetil
    6. GvHD survenant suite à une perfusion de lymphocytes de donneur
    7. Patient pour lequel il ne s’agit pas du premier épisode de GvHD chronique nécessitant un traitement immunosuppresseur systémique
    8. Deuxième allogreffe de cellules souches
    9. Arythmies significatives, anomalies à l’électrocardiogramme (ECG) :
    a/ Syndromes du QT congénital
    b/ Antécédents ou présence de tachyarythmies ventriculaires ou auriculaires significatives
    c/ Bradycardie au repos cliniquement significative (< 50 battements par minute)
    d/ QTc > 480 ms à l’ECG de la visite de sélection (déterminé à l’aide de la formule QTcF)
    e/ Bloc de branche droit plus hémibloc antérieur gauche, bloc bifasciculaire
    10. Neuropathie centrale ou périphérique
    11. Neutrophiles < 0,5 × 109/l
    12. Plaquettes < 50 × 109/l
    13. Infection systémique non contrôlée qui, selon l’opinion de l’investigateur, est associée à une augmentation du risque de décès du patient dans le mois suivant le début du traitement
    14. Troubles neurologiques ou psychiatriques sévères
    15. Consentement éclairé refusé
    16. Grossesse
    E.5 End points
    E.5.1Primary end point(s)
    Evaluation of response rate (complete and partial remission) of chronic GvHD at 6 months after diagnosis of chronic GvHD and treatment with arsenic trioxide (ATO) in combination with prednisone, with or without cyclosporine, as first line treatment
    Évaluation du taux de réponse (rémission complète et partielle) 6 mois après le diagnostic de la GvHD chronique et un traitement par le trioxyde d’arsenic en association avec de la prednisone, avec ou sans ciclosporine, en traitement de première ligne
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 months after the inclusion
    6 mois après l'inclusion
    E.5.2Secondary end point(s)
    1. Percentage of patients with documented failure free survival (FFS), defined as death, recurrent or progressive malignancy, or the initiation of a new systemic treatment for chronic GvHD
    2. Corticosteroids dosage and percentage of reduction in corticosteroids dosage at 6 and 12 months after diagnosis of chronic GvHD and treatment with ATO as first line treatment
    3. Cumulative incidence of transplant-related mortality (TRM) of infectious and non-infectious origin at 6 and 12 months after diagnosis of chronic GvHD and treatment with ATO as first line treatment
    4. OS and PFS at 6 and 12 months after diagnosis of chronic GvHD and treatment ATO as first line treatment
    5. Descriptive analysis of quality of life parameters at inclusion, at 6 and 14 weeks, and at 6, 9 and 12 months after diagnosis of chronic GvHD and treatment with ATO as first line treatment
    6. Tolerability and safety of ATO in combination with prednisone, with or without cyclosporine, in patients with chronic GvHD after allo-SCT
    1. Pourcentage de patients présentant une survie sans échec documentée du traitement, défini par le décès, la récidive ou la progression maligne, ou l’instauration d’un nouveau traitement systémique pour la GvHD chronique
    2. Dose de corticoïdes et pourcentage de la réduction de la dose de corticoïdes, 6 mois et 12 mois après le diagnostic de la GvHD chronique et un traitement par le trioxyde d’arsenic, en traitement de première ligne
    3. Incidence cumulée de la mortalité liée à la greffe d’origine infectieuse ou non-infectieuse, 6 mois et 12 mois après le diagnostic de la GvHD chronique et un traitement par le trioxyde d’arsenic, en traitement de première ligne
    4. Survie globale et survie sans progression 6 mois et 12 mois après le diagnostic de la GvHD chronique et un traitement par le trioxyde d’arsenic, en traitement de première ligne
    5. Analyse descriptive des paramètres de la qualité de vie à l’inclusion, à 6 et 14 semaines, 6, 9 et 12 mois après le diagnostic de la GvHD chronique et un traitement par le trioxyde d’arsenic, en traitement de première ligne
    6. Tolérance et sécurité d’emploi du trioxyde d’arsenic en association avec de la prednisone, avec ou sans ciclosporine, chez des patients atteints de GvHD chronique après une allogreffe de cellules souches
    E.5.2.1Timepoint(s) of evaluation of this end point
    At 6 and 14 weeks, and at 6, 9 and 12 months after the start of treatment with ATO
    A 6 et 14 semaines, 6, 9 et 12 mois après le début du traitement par le trioxyde d’arsenic
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 4
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state24
    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
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-08-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-09-14
    P. End of Trial
    P.End of Trial StatusCompleted
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