E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Systemic lupus erythematosus |
Patients atteints de Lupus sous traitement corticoïdes |
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E.1.1.1 | Medical condition in easily understood language |
LUPUS patients |
Patients atteints de LUPUS |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10042945 |
E.1.2 | Term | Systemic lupus erythematosus |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the DECOR study is to determine whether there is a relationship between the cumulative individual prednisolone exposure from Day 0 to Month 3 and SLE's activity assessed by SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index) score after three months of treatment in SLE patients requiring oral high-dose corticosteroid treatment (>= 0,5 mg/Kg/day) in association with MMF.
Such a relationship would make it possible to optimize therapy and minimize adverse events, allowing to determine individualized dosing regimen of prednisone and a target AUC of prednisolone in children and adults with severe SLE requiring a combination of prednisone and MMF.
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L'objectif principal de l'étude DECOR est de déterminer s'il existe une relation entre l'exposition individuelle cumulée à la prednisolone de J0 à M3 et l'activité du LES évaluée par le score SELENA-SLEDAI après trois mois de traitement chez les patients atteints de LES nécessitant un traitement oral à haute dose de corticostéroïde (>= 0,5 mg/kg/jour) en association avec du MMF. Une telle relation permettrait d'optimiser la thérapie, permettant de déterminer un schéma individualisé de doses de la prednisone et un AUC cible chez les enfants et les adultes atteints d'un LES sévère nécessitant une combinaison de prednisone et MMF.
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E.2.2 | Secondary objectives of the trial |
1) To study the pharmacokinetics of prednisolone in a population of patients with SLE receiving prednisone and MMF 2) To search for the relationship between the individual cumulative prednisolone area under the curve from D0 to M1 and the global lupus's activity assessed with SELENA-SLEDAI score at M3. 3) To study the relationship between the individual cumulative exposure to prednisolone from D0 to M3 and tolerability to prednisone 4) To study the relationship between clinical and biological parameters, age drugs interactions, and prednisolone PK. 5) To study the relationship between polymorphisms of MDR-1 gene and prednisolone PK. 6) To study the relationship between polymorphisms of NR3C1 gene and SLE's activity. 7) To analyze the mRNA expression genes between M1 and M3 of the prednisolone treatment in order to identify the activated transduction pathways and correlate them with the AUC of prednisone 8) To constitute a DNA bank for further pharmacogenomic analysis |
Etudier : 1) la pharmacocinétique de la prednisolone chez des patients atteints de LES recevant une combinaison de prednisone orale et de MMF 2) la relation entre l'AUC individuelle de la prednisolone de J0 à M1 et l'activité du lupus évaluée avec le score SELENA-SLEDAI à M3 3) la relation entre l'exposition cumulée individuelle à la prednisolone de J0 à M3 et la tolérance à la prednisone 4) la relation entre les paramètres cliniques et biologiques, l'âge, les interactions médicamenteuses et la pharmacocinétique de la prednisolone 5) la relation entre les polymorphismes du gène MDR-1 et de la pharmacocinétique de la prednisolone 6) la relation entre les polymorphismes du gène NR3C1 et l'activité du LES 7) l'expression génique par ARNm entre M1 et M3 du traitement par prednisone afin d'identifier les voies de transduction activées et de les corréler avec l'AUC de la prednisolone
8) Constituer une banque d'ADN pour des analyses pharmacogénomiques ultérieures |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Patient aged >= 6 years 2) Patient who met the American College of Rheumatology criteria (ACR) or the Systemic Lupus International Collaborating Clinics Classification (SLICC) for systemic lupus erythematosus (Addenda 3) 3) Patient needs initiation of oral prednisone regimen at least at 0,5 mg/Kg/d in combination with mycophenolate mofetyl at usual dose (2 to 3 g/d in adults; 1200 mg/m2 in children with dose <= 2 g/d), including i) patient who will receive bolus of methylprednisolone within the first week of inclusion for treating the lupus flare, ii) patient who was previously treated by a low-dose prednisone (<= 7,5 mg/day for patient >= 60 kg and 0,1 mg/kg/day for patients < 60 kg). 4) Patients does not receive other immunosuppressive or biological drugs at inclusion 5) Signed Informed consent form by the patient (if aged >= 18 years), or by parents / legal guardian and patient's agreement (if aged < 18 years) 6) Patient affiliated to the health insurance system |
1) Age du patient >= 6 ans 2) Patient présentant un lupus systémique erythémateux répondant aux critères de classifications ACR (American College of Rheumatology) ou SLICC (Systemic Lupus International Collaborating Clinics Classification) 3) Patient ayant besoin de débuter un traitement oral par prednisone d'au moins 0.5 mg/kg/j en combinaison avec du MMF (mycophenolate mofetyl) à dose habituelle (2 à 3 g/j chez l'adulte ; 1200 mg/m² chez l'enfant avec une dose <= 2 g/j), y compris : i) Patient qui recevra un bolus de methylprednisolone dans la 1ère semaine suivant l'inclusion pour traiter la poussée du lupus ii) Patient ayant précédemment été traité par faible dose de prednisone (<= 7.5 mg/j pour les patients >= 60 kg et 0.1 mg/kg/j pour les patients < 60 kg) 4) Patient ne recevant aucun autre traitement immunosuppresseur ou biothérapie à l'inclusion 5) Consentement signé par le patient (si âge >= 18 ans), ou par les titulaires de l'autorité parentale et accord de l'enfant (si âge < 18 ans) 6) Patient affilié à un régime de sécurité sociale |
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E.4 | Principal exclusion criteria |
1) Patient presents contraindications to corticosteroids and/or MMF 2) Patients cannot be treated by oral way 3) Patient whose physician has planned to stop prednisone in less than 3 months 4) Patient (or parents for minor) are unable to give a written informed consent for physical or psychical reasons 5) Patient disagrees with the study |
1) Patient présentant des contre-indications aux corticoïdes et/ou MMF 2) Patient ne pouvant pas être traité par voie orale 3) Patient pour lequel son médecin a prévu un arrêt de la prednisone dans moins de 3 mois 4) Patient (ou titulaires de l'autorité parentale si mineur) incapable de donner son consentement écrit pour des raisons physiques ou psychiques. 5) Patient ayant refusé l'étude |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary assessment criterion is SLE activity (mild to severe flare) at month 3 : disease activity will be measured using the SELENA-SLEDAI score (Annex 2) (41, 42, 43). This score is among the most commonly used valid and reliable clinical indices for the assessment of global SLE activity (paragraph 18.2). The SELENA-SLEDAI flare composite score included three elements : - the SLEDAI score (range 0 to 105, with 0 indicating inactive disease) ; - an assessment of new or worsening disease activity, medication changes, and hospitalizations not captured with the use of the SLEDAI ; - and the score on the physician's global-assessment visual-analogue scale (range 0 to 3, with 0 indicating inactive disease and 3 severe disease)
Secondary assessment criteria 1) PK parameters of prednisolone : - primary parameters : volume of distribution, elimination clearance and absorption constant - secondary parameters : trough concentration, maximum concentration, AUC and elimination half-life. 2) SELENA-SLEDAI score at Month 3 3) Occurrence of adverse events related to prednisone according to the investigator's judgment during the 3-month period follow-up. All the adverse events will be collected and reported in the CRF. 4) Variability factors of Prednisolone PK : clinical and biological parameters, age, drugs interactions 5) Analysis of the MDR-1 gene polymorphisms * 6) Analysis of the NR3C1 gene polymorphisms * * Given the number of patients, we will examine polymorphisms with a MAF (Minor Allele Frequency) > 20%, in order to have enough statistic power, and that have potential impact on GC pharmacokinetics or pharmacodynamics. 7) Gene expression profiling analysis 8) Further Pharmacogenomic analysis
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Critère d'évaluation principal: Patients atteints de LES actif à M3. L'activité de la maladie sera mesurée à l'aide du SELENA (Safety of Estrogens in Lupus Erythematosus National Assessment)-SLEDAI (Systemic Lupus Erythematosus Disease Activity Index), qui est l'un des index clinique le plus utilisé valide et fiable pour l'évaluation de l'activité globale du LES.
Critères d'évaluation secondaire : 1) Paramètres pharmacocinétiques de la prednisolone: - paramètres primaires : volume de distribution, clairance, constante d'absorption - paramètres secondaires : concentration minimale, concentration maximale, AUC et demi-vie d'élimination. 2) Score SELENA-SLEDAI à M3 3) Apparition d'événements indésirables liés à la prednisone selon l'appréciation de l'investigateur pendant le suivi de 3 mois. Tous les événements indésirables seront recueillis et signalés dans le CRF. 4) Facteurs de variabilité de la pharmacocinétique de la Prednisolone : paramètres cliniques et biologiques, âge, interactions médicamenteuses 5) Analyse des polymorphismes du gène MDR-1 6) Analyse des polymorphismes du gène NR3C1 7) Analyse du profil d'expression génique 8) Analyse pharmacogénomique |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Assessment criterion : Patients with active SLE at Month 3. Disease activity will be measured using the SELENA (Safety of Estrogens in Lupus Erythematosus National Assessment)-SLEDAI (Systemic Lupus Erythematosus Disease Activity Index), which is one of the most commonly used valid and reliable clinical index for the assessment of global SLE activity. |
Critère d'évaluation : Patients atteints de LES actif à M3. L'activité de la maladie sera mesurée à l'aide du SELENA (Safety of Estrogens in Lupus Erythematosus National Assessment)-SLEDAI (Systemic Lupus Erythematosus Disease Activity Index), qui est l'un des index clinique le plus utilisé valide et fiable pour l'évaluation de l'activité globale du LES. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 26 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |