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    Summary
    EudraCT Number:2018-001686-17
    Sponsor's Protocol Code Number:P170925J
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:
    Date on which this record was first entered in the EudraCT database:2018-06-06
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2018-001686-17
    A.3Full title of the trial
    Essai Bayésien de phase I/II évaluant l’efficacité et la tolérance du danazol chez les patients ayant une atteinte hématologique ou pulmonaire sévère liée à une téloméropathie
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    ANDROTELO: Phase I / II Bayesian Trial Evaluating the Efficacy and Safety of Danazol in Patients with Hematologic or Pulmonary Damage Related to Telomeropathy
    A.3.2Name or abbreviated title of the trial where available
    ANDROTELO
    A.4.1Sponsor's protocol code numberP170925J
    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 SponsorASSISTANCE PUBLIQUE - HOPITAUX DE PARIS (AP-HP)
    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 supportDGOS
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationASSISTANCE PUBLIQUE - HOPITAUX DE PARIS (AP-HP)
    B.5.2Functional name of contact pointDRCI Hôpital St Louis
    B.5.3 Address:
    B.5.3.1Street Address 1 av. Claude Vellefaux
    B.5.3.2Town/ cityPARIS
    B.5.3.3Post code75010
    B.5.3.4CountryFrance
    B.5.6E-mailelodie.lemadre@aphp.fr
    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 DANAZOL 200mg
    D.2.1.1.2Name of the Marketing Authorisation holderSANOFI-AVENTIS FRANCE
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 nameDANAZOL 200mg
    D.3.2Product code G03XA01
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPBuccal 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 Yes
    D.3.11.13.1Other medicinal product typeDANATROL, dérivé synthétique isoxazole de l'éthistérone, est
    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
    Patients older than 15 years with hematologic or pulmonary lesions of telomeropathies.
    Patients âgés de plus de 15 ans présentant des atteintes hématologiques ou pulmonaires de téloméropathies.
    E.1.1.1Medical condition in easily understood language
    telomeropathy
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10062759
    E.1.2Term Congenital dyskeratosis
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Main Objective: To evaluate the benefit of danazol at 12 months on the clinical response.
    Objectif Principal : Evaluer le bénéfice à 12 mois du danazol sur la réponse clinique.
    E.2.2Secondary objectives of the trial
    Objectifs secondaires :
    Evaluer :
    - la tolérance hépatique et extra hépatique du danazol dans cette indication,
    - la corrélation entre la réponse clinique et l'évolution de la longueur des télomères,
    - l'apparition d'anomalies cytologiques et cytogénétiques médullaires sous traitement,
    - l'apparition d'anomalies parenchymateuses pulmonaires sous traitement,
    - la qualité de vie des patients,
    - la survie des patients.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patient (s):
    - having a telomeropathy defined by the existence of a constitutional deleterious mutation of a gene involved in the maintenance of telomeres (TERT, TERC, DKC1, TINF2, RTEL1, PARN, ACD, NHP2, NOP10, NAF1, WRAP53, CTC1, ERCC6L2, USB1, POT1, DNAJC21 or a newly identified gene responsible for telomeropathy),
    - 15 years of age or older,
    - with severe hematologic involvement (platelets <20 G / L or PNN <0.5 G / L and / or hemoglobin <8 g / dL and / or need for transfusions) and / or pulmonary fibrosis with superior parenchymal involvement at 10% on the scanner.
    - being able to give informed consent for patients 18 years and older,
    - being able to give his consent and have the consent of the holder (s) of parental authority for children over 15,
    - being a beneficiary of a social security scheme.
    Patient(e)s :
    - ayant une téloméropathie définie par l'existence d'une mutation délétère constitutionnelle d'un gène impliqué dans la maintenance des télomères (TERT, TERC, DKC1, TINF2, RTEL1, PARN, ACD, NHP2, NOP10, NAF1, WRAP53, CTC1, ERCC6L2, USB1, POT1, DNAJC21 ou d'un gène nouvellement identifié comme responsable d'une téloméropathie),
    - âgés de 15 ans ou plus,
    - ayant une atteinte hématologique sévère (plaquettes < 20 G/L ou PNN < 0,5 G/L et/ou hémoglobine < 8 g/dL et/ou avoir besoin de transfusions) et/ou une fibrose pulmonaire avec une atteinte parenchymateuse supérieure à 10% au scanner.
    - étant en mesure de donner son consentement éclairé pour les patients de 18 ans et plus,
    - étant en mesure de donner son consentement et avoir le consentement du ou des titulaire(s) de l'autorité parentale pour les enfants de plus de 15 ans,
    - étant bénéficiaire d'un régime de sécurité sociale.
    E.4Principal exclusion criteria
    Patient (s):
    - with HIV infection or active infection with hepatitis B or hepatitis C,
    - with severe hepatic impairment: transaminases ASAT and / or ALAT> 5N, or conjugated bilirubinemia> 30? mol / L, TP <50% (except vitamin K deficiency), or splanchnic thrombosis
    - having a tumoral pathology that has been active or treated for less than 5 years, with the exception of basal cell carcinoma or carcinoma in situ of the cervix,
    - having a history of organ transplantation or hematopoietic stem cells or having an indication for hematopoietic stem cell transplantation or organ transplantation within 6 months of inclusion,
    - having an absolute contraindication to treatment with danazol: active thrombosis or history of thromboembolic disease, porphyria, severe renal or cardiac insufficiency (NYHA stage III or IV), androgen-dependent tumor, pathological genital haemorrhage of etiology indeterminate,
    - having already received danazol for the treatment of telomeropathy,
    - having received another androgen within a period of less than 6 months,
    - receiving another experimental treatment,
    - receiving another hormonal treatment,
    - receiving treatment with simvastatin
    - unexplored pathological genital bleeding
    Concomitant treatment with Simvastatin
    - having a pregnancy plan and not committing to effective contraception while taking the treatment,
    - breastfeeding,
    - under tutorship or curatorship.
    Patient(e)s :
    - ayant une infection par le VIH ou infection active par l'hépatite B ou l'hépatite C,
    - ayant une atteinte hépatique sévèresévère : transaminases ASAT et/ou ALAT > 5N, ou une bilirubinémie conjuguée > 30 ? mol/L, un TP <50% (sauf carence en vitamine K), ou thrombose splanchnique
    - ayant une pathologie tumorale active ou traitée depuis moins de 5 ans à l'exception d'un carcinome basocellulaire ou d'un carcinome in situ du col utérin,
    - ayant un antécédent de greffe d'organe ou de cellules souches hématopoïétiques ou ayant une indication de greffe de cellules souches hématopoïétiques ou de greffe d'organe dans les 6 mois suivant l'inclusion,
    - ayant une contre-indication absolue au traitement par danazol : thrombose évolutive ou antécédent de maladie thrombo-embolique, porphyrie, insuffisance rénale ou cardiaque sévère (stade III ou IV de la NYHA), tumeur androgéno-dépendante, hémorragie génitale pathologique d'étiologie indéterminée,
    - ayant déjà reçu du danazol pour le traitement de la téloméropathie,
    - ayant reçu un autre androgène dans un délai de moins de 6 mois,
    - recevant un autre traitement expérimental,
    - recevant un autre traitement hormonal,
    - recevant un traitement par simvastatine
    - saignement génital pathologique non exploré
    - traitement concomitant par Simvastatine
    - ayant un projet de grossesse et ne pas s'engager à avoir une contraception efficace pendant la prise du traitement,
    - allaitante,
    - sous tutelle ou curatelle.
    E.5 End points
    E.5.1Primary end point(s)
    Main Evaluation Criterion:
    For patients with bone marrow failure, the hematologic response at 12 months depending on the line (s) affected:
    - 1.5 point increase in hemoglobin (g / dL)
    - and / or increase of 20 G / L of the platelet count
    and / or an increase of 0.5 G / L in the neutrophil counts.
    For patients with pulmonary fibrosis, a decrease of less than 5% in forced vital capacity at 12 months

    Secondary evaluation criteria:
    For all patients:
    - Hepatic tolerance (biological at 1, 2, 3, 6, 9 and 12 months, ultrasound imaging at 6 months and MRI at 12 months),
    - Systemic tolerance: endocrinology (virilization, weight, blood glucose, LDL, HDL cholesterol and triglycerides) at 3, 6, 9, 12 months, bone (bone events and change in osteodensitometry) at 12 months, muscle (cramps and muscle enzymes) at 3, 6, 9 and 12 months, increase in PSA at 3, 6 and 12 months for men,
    - Evolution of pulmonary parenchymal abnormalities at CT scan at 6 and 12 months,
    - Evolution of the telomere length by Flow Fish at 12 months,
    - appearance of cytological and cytogenetic abnormalities at 12 months (myelogram with karyotype at M12),
    - Quality of life (EORTC QLQ-C30, v3.0) at 3, 6 and 12 months,
    - Survival at 3, 6, 9 and 12 months.
    For patients with bone marrow failure
    - Haematological response at 3, 6 and 9 months,
    - Complete haematological response at 3, 6, 9 and 12 months (Hb> 10 g / dL, PNN> 1 G / L and platelets> 100 G / L),
    - Transfusion independence at 3, 6, 9 and 12 months,
    - Evolution of forced vital capacity and DLCO at 6 and 12 months,
    - Evolution of pulmonary parenchymal abnormalities at 12 months.
    For patients with pulmonary fibrosis:
    - Variation of the hemogram under treatment at 3, 6 and 12 months,
    - Evolution of forced vital capacity at 3, 6, 9 months,
    - Evolution of the DLCO at 3, 6, 9 and 12 months,
    - Evolution of pulmonary parenchymal abnormalities at CT scan at 6 and 12 months.
    Critère d'évaluation Principal :
    Pour les patients présentant une insuffisance médullaire, la réponse hématologique à 12 mois en fonction de la ou des lignées atteintes :
    - augmentation de 1,5 point de l'hémoglobine (g/dL)
    - et/ou augmentation de 20 G/L du compte plaquettaire
    - et/ou augmentation de 0,5 G/L du compte de polynucléaires neutrophiles.
    Pour les patients présentant une fibrose pulmonaire, une diminution de moins de 5% de la capacité vitale forcée à 12 mois

    Critères d'évaluation secondaires :
    Pour tous les patients :
    - Tolérance hépatique (biologique à 1, 2, 3, 6, 9 et 12 mois, imagerie par échographie à 6 mois et IRM à 12 mois),
    - Tolérance systémique : endocrinologique (virilisation, poids, glycémie, LDL, HDL cholestérol et triglycérides) à 3, 6, 9, 12 mois, osseuse (évènements osseux et modification de l'ostéo-densitométrie) à 12 mois, musculaire (crampes et enzymes musculaires) à 3, 6, 9 et 12 mois, augmentation des PSA à 3, 6 et 12 mois pour les hommes,
    - Evolution des anomalies parenchymateuses pulmonaires au scanner à 6 et 12 mois,
    - Evolution de la longueur des télomères par Flow Fish à 12 mois,
    - Apparition d'anomalies cytologiques et cytogénétiques à 12 mois (myélogramme avec caryotype à M12),
    - Qualité de vie (EORTC QLQ-C30, v3.0) à 3, 6 et 12 mois,
    - Survie à 3, 6, 9 et 12 mois.
    Pour les patients ayant une insuffisance médullaire
    - Réponse hématologique à 3, 6 et 9 mois,
    - Réponse hématologique complète à 3, 6, 9 et 12 mois (Hb > 10 g/dL, PNN > 1 G/L et plaquettes > 100 G/L),
    - Indépendance transfusionnelle à 3, 6, 9 et 12 mois,
    - Evolution de la capacité vitale forcée et de la DLCO à 6 et 12 mois,
    - Evolution des anomalies parenchymateuses pulmonaires au scanner à 12 mois.
    Pour les patients ayant une fibrose pulmonaire :
    - Variation de l'hémogramme sous traitement à 3, 6 et 12 mois,
    - Evolution de la capacité vitale forcée à 3, 6, 9 mois,
    - Evolution de la DLCO à 3, 6, 9 et 12 mois,
    - Evolution des anomalies parenchymateuses pulmonaires au scanner à 6 et 12 mois.
    E.5.1.1Timepoint(s) of evaluation of this end point
    12mois
    E.5.2Secondary end point(s)
    For all patients:
    • Hepatic tolerance (biological at 1, 2, 3, 6, 9 and 12 months, ultrasound imaging at 6 months and MRI at 12 months),
    • Systemic tolerance: endocrinology (virilization, weight, blood glucose, LDL, HDL cholesterol and triglycerides) at 3, 6, 9, 12 months, bone (bone events and change in osteodensitometry) at 12 months, muscle (cramps and muscle enzymes) at 3, 6, 9 and 12 months, increase in PSA at 3, 6 and 12 months for men,
    • Evolution of pulmonary parenchymal abnormalities at CT scan at 6 and 12 months,
    • Evolution of the telomere length by Flow Fish at 12 months,
    • appearance of cytological and cytogenetic abnormalities at 12 months (myelogram with karyotype at M12),
    • Quality of life (EORTC QLQ-C30, v3.0) at 3, 6 and 12 months,
    • Survival at 3, 6, 9 and 12 months.
    For patients with bone marrow failure
    • Haematological response at 3, 6 and 9 months,
    • Complete haematological response at 3, 6, 9 and 12 months (Hb> 10 g / dL, PNN> 1 G / L and platelets> 100 G / L),
    • Transfusion independence at 3, 6, 9 and 12 months,
    • Evolution of forced vital capacity and DLCO at 6 and 12 months,
    • Evolution of lung parenchymal abnormalities at 12 months.
    For patients with pulmonary fibrosis:
    • Variation of the hemogram under treatment at 3, 6 and 12 months,
    • Evolution of forced vital capacity at 3, 6, 9 months,
    • Evolution of the DLCO at 3, 6, 9 and 12 months,
    • Evolution of pulmonary parenchymal abnormalities at 6 and 12 months.
    E.5.2.1Timepoint(s) of evaluation of this end point
    12mois
    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 No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Study for a different indication than MA: Endometriosis and Hereditary angioneurotic edema.
    Etude pour une autre indication que AMM : Endométriose et Oedème angioneurotique héréditaire.
    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 Yes
    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 concerned19
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 40
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 40
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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 state40
    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 Decision2018-07-11
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial Status
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