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To Assess the Safety, Tolerability and Pharmacokinetics of AZD5634 Following Inhaled and Intravenous (IV)Dose Administration

16 mars 2018 mis à jour par: AstraZeneca

A Phase I, Randomized, Single-Blind, Placebo-Controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD5634 Following Single-Ascending Inhaled Doses (Part A) and After Single Inhaled and Intravenous Doses (Part B) in Healthy Subjects

This is a Phase 1, first-in-human (FIH) single ascending dose study being conducted to better understand the safety, tolerability and pharmacokinetics of AZD5634 in healthy subjects

Aperçu de l'étude

Description détaillée

This study is a Phase I, FIH, randomized, single-blinded (study center staff remain blinded during the dosing phase of the study), placebo-controlled, single ascending dose, sequential dose group study in healthy male subjects and/or female subjects of non-childbearing potential at a single study center to assess AZD5634 following inhaled and intravenous dose administration

Type d'étude

Interventionnel

Inscription (Réel)

63

Phase

  • La phase 1

Contacts et emplacements

Cette section fournit les coordonnées de ceux qui mènent l'étude et des informations sur le lieu où cette étude est menée.

Lieux d'étude

    • California
      • Glendale, California, États-Unis, 91206
        • Research Site
    • Maryland
      • Baltimore, Maryland, États-Unis, 21225
        • Research Site

Critères de participation

Les chercheurs recherchent des personnes qui correspondent à une certaine description, appelée critères d'éligibilité. Certains exemples de ces critères sont l'état de santé général d'une personne ou des traitements antérieurs.

Critère d'éligibilité

Âges éligibles pour étudier

18 ans à 50 ans (Adulte)

Accepte les volontaires sains

Oui

Sexes éligibles pour l'étude

Tout

La description

Inclusion Criteria:

  1. Provision of signed and dated, written informed consent prior to any study specific procedures.
  2. Healthy male and/or female subjects aged 18 - 50 years with suitable veins for cannulation or repeated venipuncture.
  3. Females must have a negative pregnancy test at screening and on admission to the unit, must not be lactating and must be of non-childbearing potential, confirmed at screening by fulfilling 1 of the following criteria:

    • Post-menopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle-stimulating hormone (FSH) levels in the post-menopausal range.
    • Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy, but not tubal ligation.
  4. Have a body mass index (BMI) between 18 and 30 kg/m2, inclusive, and weigh at least 50 kg and no more than 100 kg, inclusive.
  5. Have a FEV1 (Forced expiratory volume in 1 second in liters) ≥ 80% of the predicted value at screening.
  6. Provision of signed, written and dated informed consent for optional genetic/biomarker research.

Exclusion Criteria:

  1. History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study.
  2. History or presence of gastrointestinal (GI), hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
  3. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the administration of investigational medicinal product (IMP).
  4. Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, as judged by the investigator.
  5. Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV).
  6. Abnormal vital signs, after 10 minutes supine rest, at screening and check-in, defined as any of the following:

    • Systolic blood pressure (SBP) < 90mmHg (millimeter of mercury) or ≥ 140 mmHg
    • Diastolic blood pressure (DBP) < 50mmHg or ≥ 90 mmHg
    • Heart Rate < 45 or > 85 beats per minute (bpm)
  7. Any clinically significant abnormalities in rhythm, conduction or morphology of the resting electrocardiogram (ECG) and any clinically significant abnormalities in the 12-lead ECG, as considered by the investigator that may interfere with the interpretation of QTc (QT [ECG interval measured from the onset of the QRS complex to the end of the T wave] interval corrected for heart rate) interval changes, including abnormal ST-T-wave morphology, particularly in the protocol defined primary lead or left ventricular hypertrophy, at screening.
  8. PR (PQ [ECG interval measured from the onset of the P wave to the onset of the QRS complex]) interval prolongation (> 240 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third degree atrioventricular (AV) block, or AV dissociation, at screening.
  9. Persistent or intermittent complete bundle branch block (BBB), incomplete bundle branch block (IBBB), or intraventricular conduction delay (IVCD) with QRS > 110 ms. Subjects with QRS (ECG interval measured from the onset of the QRS complex to the J point) > 110 ms but < 115 ms are acceptable if there is no evidence of, for example, ventricular hypertrophy or pre-excitation, at screening.
  10. Serum/plasma potassium levels are outside the normal range and lower than 3.5 to 5.1 mEq/L (milliequivalents per liter) at screening and prior to dosing.
  11. Has active lung disease/asthma that requires treatment.
  12. Known or suspected history of drug abuse, as judged by the investigator.
  13. Current smokers or those who have smoked or used nicotine products within the previous 3 months.
  14. History of alcohol abuse or excessive intake of alcohol, as judged by the investigator.
  15. Positive screen for drugs of abuse, cotinine (nicotine), or alcohol at screening or admission to the unit.
  16. History of severe allergy/hypersensitivity or ongoing clinically significant allergy/hypersensitivity, as judged by the investigator or history of hypersensitivity to drugs with a similar chemical structure or class to AZD5634.
  17. Excessive intake of caffeine containing drinks or food (e.g., coffee, tea, chocolate), as judged by the investigator.
  18. Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks prior to the administration of IMP.
  19. Use of any prescribed or non-prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks prior to the administration of IMP or longer if the medication has a long half-life.
  20. Plasma donation within 1 month of screening or any blood donation/blood loss > 500 mL during the 3 months prior to screening.
  21. Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of the administration of IMP in this study. The period of exclusion is 3 months after the final dose from a previous study.

    Note: Subjects consented and screened, but not randomized in this study or a previous phase I study, are not excluded.

  22. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.
  23. Involvement of any Astra Zeneca, PAREXEL or study site employee or their close relatives.
  24. Judgment by the investigator that the subject should not participate in the study if they have any ongoing or recent (i.e., during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions and requirements.
  25. Subjects who are vegans or have medical dietary restrictions.
  26. Subjects who cannot communicate reliably with the investigator.

    In addition, any of the following is regarded as a criterion for exclusion from the genetic research:

  27. Previous bone marrow transplant.
  28. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection.

Plan d'étude

Cette section fournit des détails sur le plan d'étude, y compris la façon dont l'étude est conçue et ce que l'étude mesure.

Comment l'étude est-elle conçue ?

Détails de conception

  • Objectif principal: Science basique
  • Répartition: Randomisé
  • Modèle interventionnel: Affectation parallèle
  • Masquage: Seul

Armes et Interventions

Groupe de participants / Bras
Intervention / Traitement
Expérimental: Part A, Dose Level 1
Subjects will inhale single doses of AZD5634 or placebo under fasted conditions and will rinse his/her mouth with approximately 100 mL (up to 240 mL) of water which must be swallowed
Solution, citrate buffer, saline nebulizer solution; strength 0.1 - 5 mg/g; administered by jet nebulizer
inactive substance
Expérimental: Part A, Dose Level 2
Subjects will inhale single doses of AZD5634 or placebo under fasted conditions and will rinse his/her mouth with approximately 100 mL (up to 240 mL) of water which must be swallowed
Solution, citrate buffer, saline nebulizer solution; strength 0.1 - 5 mg/g; administered by jet nebulizer
inactive substance
Expérimental: Part A, Dose Level 3
Subjects will inhale single doses of AZD5634 or placebo under fasted conditions and will rinse his/her mouth with approximately 100 mL (up to 240 mL) of water which must be swallowed
Solution, citrate buffer, saline nebulizer solution; strength 0.1 - 5 mg/g; administered by jet nebulizer
inactive substance
Expérimental: Part A, Dose Level 4
Subjects will inhale single doses of AZD5634 or placebo under fasted conditions and will rinse his/her mouth with approximately 100 mL (up to 240 mL) of water which must be swallowed
Solution, citrate buffer, saline nebulizer solution; strength 0.1 - 5 mg/g; administered by jet nebulizer
inactive substance
Expérimental: Part A, Dose Level 5
Subjects will inhale single doses of AZD5634 or placebo under fasted conditions and will rinse his/her mouth with approximately 100 mL (up to 240 mL) of water which must be swallowed
Solution, citrate buffer, saline nebulizer solution; strength 0.1 - 5 mg/g; administered by jet nebulizer
inactive substance
Expérimental: Part A, Dose Level 6
Subjects will inhale single doses of AZD5634 or placebo under fasted conditions and will rinse his/her mouth with approximately 100 mL (up to 240 mL) of water which must be swallowed
Solution, citrate buffer, saline nebulizer solution; strength 0.1 - 5 mg/g; administered by jet nebulizer
inactive substance
Expérimental: Part A, Dose Level 7
Subjects will inhale single doses of AZD5634 or placebo under fasted conditions and will rinse his/her mouth with approximately 100 mL (up to 240 mL) of water which must be swallowed
Solution, citrate buffer, saline nebulizer solution; strength 0.1 - 5 mg/g; administered by jet nebulizer
inactive substance
Expérimental: Part B, Dose Level 1
Subjects will receive a single dose of IV AZD5634 and after a washout period of 14 days the same subjects will receive a single dose of inhaled AZD5634
Solution, citrate buffer, saline solution for infusion; strength 0.013 mg/mL

Que mesure l'étude ?

Principaux critères de jugement

Mesure des résultats
Description de la mesure
Délai
Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B).
Délai: Screening (serious adverse event, SAE), Day -1 (SAE), Spontaneous plus Predose, 3,12,24, and 48 h postdose (Days 1 to 3), Follow-up 7-10 days postdose, 2 months post final dose.
To assess the safety and tolerability of AZD5634 in terms of number of participants following inhaled administration of single-ascending doses (SAD) (Part A) and following administration of single inhaled and IV doses (Part B)
Screening (serious adverse event, SAE), Day -1 (SAE), Spontaneous plus Predose, 3,12,24, and 48 h postdose (Days 1 to 3), Follow-up 7-10 days postdose, 2 months post final dose.

Mesures de résultats secondaires

Mesure des résultats
Description de la mesure
Délai
Observed Maximum Plasma Concentration, Taken Directly From the Individual Concentration-time Curve (Cmax)- For Part A and Part B
Délai: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
To assess the pharmacokinetic (PK) parameter Cmax of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics.
At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Area Under Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC) for Part A and Part B
Délai: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
To assess the pharmacokinetic parameter AUC of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. AUC was estimated by AUC(0-last) + Clast/λz where Clast was the last observed quantifiable concentration. AUCs were calculated using the linear trapezoidal method when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing. AUC0-t is expanded as area under the plasma concentration-time curve from time zero to time of last quantifiable concentration. Note:Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics.
At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Area Under the Plasma Concentration-curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-t)] for Part A and Part B
Délai: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
To assess the pharmacokinetic parameter AUC(0-t) of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics.
At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Absolute Systemic Bioavailability After Inhalation (Part B Only) (Finhalation,Total)
Délai: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
To assess the Absolute systemic bioavailability after inhalation (%), calculated separately as 100*AUCinhalation*Doseiv/(AUCiv*Doseinhalation)
At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Renal Clearance (CLR), Estimated by Dividing Ae(0-last) by AUC0-t - For Part A and Part B
Délai: -12-0, 0-6, 6-12, 12-24, 24-48 h (Days 1 to 3)
To assess the pharmacokinetic parameter CLR of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics.
-12-0, 0-6, 6-12, 12-24, 24-48 h (Days 1 to 3)
Cmax, Divided by the Dose Aministered (Cmax/Dose) - For Part A and Part B
Délai: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
To assess the pharmacokinetic parameter Cmax/Dose of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics.
At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Terminal Half-life (t1/2λz), Estimated as (ln2)/λz - For Part A and Part B
Délai: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
To assess the pharmacokinetic parameter t1/2λz of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics.
At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
AUC0-t, Divided by the Dose Administered (AUC0-t/Dose) - For Part A and Part B
Délai: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
To assess the pharmacokinetic parameter AUC0-t/Dose of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics.
At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
AUC, Divided by the Dose Administered (AUC/Dose) - For Part A and Part B
Délai: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
To assess the pharmacokinetic parameter AUC/Dose of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics.
At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Systemic Clearance for AZD5634 Estimated as Dose Divided by AUC (Part B IV Dosing Only) (CL)
Délai: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
To assess the pharmacokinetic parameter CL of AZD5634 following single-dose IV administration of AZD5634 in Part B
At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Apparent Clearance for AZD5634 Estimated as Dose Divided by AUC (Part A and Part B Inhaled Dosing Only) (CL/F)
Délai: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
To assess the pharmacokinetic parameter CL/F of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics.
At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Mean Residence Time (MRT) - For Part A and Part B
Délai: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
To assess the pharmacokinetic parameter MRT of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics.
At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Mean Absorption Time, Calculated as MRTinhaled - MRTIV (Part B Only) (MAT)
Délai: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
To assess the pharmacokinetic parameter MAT of AZD5634 following single-dose IV or inhalation administration of AZD5634 in Part B
At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Volume of Distribution for AZD5634 at Steady State (IV Administration), Estimated by Dividing the MRT by the Systemic CL (Part B IV Dosing Only) (Vss)
Délai: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
To assess the pharmacokinetic parameter Vss of AZD5634 following single-dose IV administration of AZD5634 in Part B
At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Volume of Distribution for AZD5634 at Terminal Phase (IV Administration), Estimated by Dividing the Systemic CL by λz (Part B IV Dosing Only) (Vz)
Délai: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
To assess the pharmacokinetic parameter Vz of AZD5634 following single-dose IV administration of AZD5634 in Part B
At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Apparent Volume of Distribution for AZD5634 at Terminal Phase (Inhaled Administration), Estimated by Dividing the CL/F by λz (Part A and Part B Inhaled Dosing Only) (Vz/F)
Délai: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
To assess the pharmacokinetic parameter Vz/F of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics.
At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)

Collaborateurs et enquêteurs

C'est ici que vous trouverez les personnes et les organisations impliquées dans cette étude.

Parrainer

Les enquêteurs

  • Chercheur principal: Ronald Goldwater, MDCM, M.Sc, CPI, PAREXEL Early Phase Clinical Unit Baltimore

Publications et liens utiles

La personne responsable de la saisie des informations sur l'étude fournit volontairement ces publications. Il peut s'agir de tout ce qui concerne l'étude.

Dates d'enregistrement des études

Ces dates suivent la progression des dossiers d'étude et des soumissions de résultats sommaires à ClinicalTrials.gov. Les dossiers d'étude et les résultats rapportés sont examinés par la Bibliothèque nationale de médecine (NLM) pour s'assurer qu'ils répondent à des normes de contrôle de qualité spécifiques avant d'être publiés sur le site Web public.

Dates principales de l'étude

Début de l'étude (Réel)

11 février 2016

Achèvement primaire (Réel)

24 octobre 2016

Achèvement de l'étude (Réel)

24 octobre 2016

Dates d'inscription aux études

Première soumission

3 février 2016

Première soumission répondant aux critères de contrôle qualité

5 février 2016

Première publication (Estimation)

10 février 2016

Mises à jour des dossiers d'étude

Dernière mise à jour publiée (Réel)

5 novembre 2018

Dernière mise à jour soumise répondant aux critères de contrôle qualité

16 mars 2018

Dernière vérification

1 mars 2018

Plus d'information

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