Centre de référence Lupus / SAPL Service Médecine Interne 2

Présentation au sujet: "Centre de référence Lupus / SAPL Service Médecine Interne 2"— Transcription de la présentation:

1 Etude PLUS Nathalie Costedoat-Chalumeau Zahir Amoura, Jean-Charles Piette et beaucoup d’entre vous…
Centre de référence Lupus / SAPL Service Médecine Interne 2 CHU Pitié-Salpêtrière Paris 6

2 Hydroxychloroquine-PLAQUENIL
Excellent rapport bénéfice/risque dans le lupus systémique. Un bénéfice supplémentaire : HCQ ½ vie longue dosage disponible Grande variabilité interindividuelle +++

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4 Study 1 of 3 for search of: lupus hydroxychloroquine
                   Home    Search    Study Topics    Glossary   Study 1 of 3 for search of:   lupus hydroxychloroquine Return to Search Results Next Study   Full Text View     Tabular View     Contacts and Locations     No Study Results Posted     Related Studies   The Reduction of Systemic Lupus Erythematosus Flares :Study PLUS This study is currently recruiting participants. Verified by Assistance Publique - Hôpitaux de Paris, May 2007 Sponsors and Collaborators: Assistance Publique - Hôpitaux de Paris Sanofi-Synthelabo Information provided by: Assistance Publique - Hôpitaux de Paris ClinicalTrials.gov Identifier: NCT   Purpose The main objective of study PLUS is to determine the potential benefits of individualized HCQ dosing schedules aimed at maintaining the whole-blood HCQ concentration above 1000 ng/ml Condition Intervention Phase Systemic Lupus Erythematosus Drug: versus hydroxychloroquine Phase IV MedlinePlus related topics:   Lupus     Drug Information available for:   Hydroxychloroquine     Hydroxychloroquine sulfate    U.S. FDA Resources Study Type:   Interventional Study Design:   Prevention, Randomized, Double Blind (Caregiver, Investigator), Dose Comparison, Parallel Assignment, Efficacy Study Official Title:   Study of the Reduction of Systemic Lupus Erythematosus Flares Through Adaptation of the Dosage of Hydroxychloroquine to Its Whole-Blood Concentration. National Multicenter Randomized Prospective Study Further study details as provided by Assistance Publique - Hôpitaux de Paris: Primary Outcome Measures: The number of patient in each group who developed a flare (according to the SELENA-SLEDAI composite criteria) during the study period. [ Time Frame: 7 months of follow up ] Secondary Outcome Measures: The number of patients in each group who developed a flare during the study period. [ Time Frame: 7 months of follow up ] The total number of flares in each group [ Time Frame: 7 months of follow up ] the total dose of steroids in each group [ Time Frame: 7 months of follow up ] the area under the curve of SELENA SLEDAI in each group [ Time Frame: 7 months of follow up ] the mean change of the quality of life questionnaire SF-36 [ Time Frame: 7 months of follow up ] the mean change on the score of analogical visual scale in each group [ Time Frame: 7 months of follow up ] Treatment tolerance evaluation will include clinical, electrocardiographic and ophthalmologic screening. [ Time Frame: 7 months of follow up ] Estimated Enrollment:   800 Study Start Date:   June 2007 Estimated Study Completion Date:   February 2011 Arms Assigned Interventions A: Placebo Comparator placebo Drug: versus hydroxychloroquine B: Experimental versus hydroxychloroquine Detailed Description: Hydroxychloroquine (HCQ) is a treatment which allows preventing Systemic Lupus Erythematosus (SLE) exacerbations. HCQ can be measured in whole-blood by HPLC (High Performance Liquid Chromatography). Interindividual variability in blood HCQ concentrations is important and a correlation between HCQ level and clinical efficacy of HCQ has been demonstrated in SLE in a monocentric study of 143 unselected SLE patients. The main objective of study PLUS is to determine the potential benefits of individualized HCQ dosing schedules aimed at maintaining the whole-blood HCQ concentration above 1000 ng/ml The secondary objectives are: To define biological and clinical hallmarks present at M1 (month 1) which are predictor of SLE exacerbations in the next 6 month, To establish the parameters of HCQ pharmacokinetic model, by a study of population, using a "Bayésienne" approach. To study the influence of allelic variants of drug carriers and other genes in the interindividual variability of blood HCQ concentrations. To study the influence of the compliance in the blood HCQ concentration variability To study the relation between blood HCQ concentrations, SLE activity and quality of life To study the relation between blood HCQ concentrations, SLE activity and lipid profile of the patients To study the relation between ECG abnormalities and blood HCQ concentrations To constitute a bank of serum, a DNAbank, and a RNAbank to permit subsequent studies   Eligibility Ages Eligible for Study:   18 Years and older Genders Eligible for Study:   Both Accepts Healthy Volunteers:   No Criteria Inclusion Criteria: Age of 18 and above Diagnosis of Systemic Lupus Erythematosus (SLE) according to the American College of Rheumatology (ACR) Classification Criteria. Treatment with HCQ for at least 6 months, without modification of HCQ dosage for 2 months Stable dosage of HCQ from one day to another (200 g x 2/day or 400 mg once a day or 200 mg once a day) No increase in the steroids dosage during the 3 previous weeks Steroids dosage lower or equal to 0. 5 mg/kg/day of prednisone equivalent No modifications of a possible immunosuppressor during the 2 previous months SELENA-SLEDAI < or = 12 Signature of the consent of participation Exclusion Criteria: Known retinopathy, present or passed Severe cataract obstructing the ophthalmologic monitoring MONOPHTALM patients Past history of intolerance with HCQ (in particular gastro-intestinal, or retinal) during the possible former use of a higher dosage Use of nivaquine during the 3 previous months Treatment with biotherapy (for example Rituximab) during the 12 previous months Calculated clearance of creatinin lower than 60 ml/min Chronic alcoholism Liver failure Desire of pregnancy in the next 7 months Known non compliance, and risks of random follow-up Absence of social security cover People profiting from a particular protection: Pregnant women Age under 18 Patient under supervision and TRUSTEESHIP People who are hospitalized without their consent and not protected by the law People who are private of freedom. Criteria of inclusion at the visit of randomization (D0): All the patients responding to the next criterions can be randomized: Blood HCQ concentration ranging between 100 and 750 ng/ml at the time of the visit of preselection, No increase in the steroids dosage since last visit No modifications of a possible immunosuppressor since last visit SELENA-SLEDAI < or = 12 Activity of the lupus remaining stable (no increase of more than 2 points of the SELENA-SLEDAI), Ophthalmologic examination in the 6 previous months with no contra-indication for the use of HCQ, Absences of conductive disorders on the ECG Use of an effective contraception, Negative Beta-HCG.   Contacts and Locations Please refer to this study by its ClinicalTrials.gov identifier: NCT Contacts Contact: Nathalie COSTEDOAT-CHALUMEAU, MD     +33 (0)         Locations France Chu Pitie Salpetriere     Recruiting       PARIS, France, 75013       Contact: Nathalie COSTEDOAT-CHALUMEAU, MD,PhD     +33(0)         Hopital la Pitié Salpétrière Assistance Publique           Paris, France, 75013       Contact: Jean Charles PIETTE, MdPh                   Contact: Zahir AMOURA, MdPh                   Sub-Investigator: Philippe LECHAT, Md-Ph                   Sub-Investigator: Jean Sébastien HULOT, Md             Sponsors and Collaborators Assistance Publique - Hôpitaux de Paris Sanofi-Synthelabo Investigators Principal Investigator:     Nathalie COSTEDOAT-CHALUMEAU, MD,     Assistance Publique - Hôpitaux de Paris       More Information Study ID Numbers:   P051070 First Received:   December 18, 2006 Last Updated:   September 7, 2007 ClinicalTrials.gov Identifier:   NCT Health Authority:   France: Ministry of Health Keywords provided by Assistance Publique - Hôpitaux de Paris: Systemic Lupus Erythematosus   Hydroxychloroquine   Study placed in the following topic categories: Autoimmune Diseases Lupus Erythematosus, Systemic Hydroxychloroquine Connective Tissue Diseases Additional relevant MeSH terms: Anti-Infective Agents Antimalarials Antiparasitic Agents Antiprotozoal Agents Molecular Mechanisms of Pharmacological Action Immune System Diseases Therapeutic Uses Enzyme Inhibitors Antirheumatic Agents Pharmacologic Actions ClinicalTrials.gov processed this record on November 16, 2008 U.S. National Library of Medicine ,  Contact Help Desk U.S. National Institutes of Health,  U.S. Department of Health & Human Services, USA.gov,  Copyright,  Privacy,  Accessibility,  Freedom of Information Act                Links to all studies - primarily for crawlers

5 Schéma de l’étude

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8 « Résultats »

9 Courbe des inclusions 9

10 40 centres ouverts, 3 inactifs
Lille (n = 2) Amiens (n = 15) Beaujon (n=2) Rouen : (n = 3) Jean Verdier (n=20) Bichat (Med.Int. n= 20 Rhumato. n = 5; Néphro. n = 2) Robert Ballanger (n = 2) Foch (n = 20) St Louis (Imm clin n= 40 Méd. Int n= 10; Dermato n= 4) Lariboisière (n = 16) Brest (n = 3) Strasbourg (Rhum. n=5; Med.Int n=2) Pitié Salpêtrière (Med. Int 2 n = 217; Med Int. 1 n = 2; Rhumato. n= 4) Tenon (Dermato. n= 16; Néphro. n= 1) Cochin (n = 16) Bicêtre (Med Int. n = 12; Rhumato. n = 1) Henri Mondor (n = 15) Limoges (n = 12) Clermont-Ferrand ( n = 17) Lyon : Lyon Sud (n = 5); Hôtel Dieu (n = 5); E.Herriot (n = 24) Bordeaux (n = 11) Grenoble (n = 7) Toulouse : Rangueil (n = 11) La Grave (n = 10) Marseille : Conception (n = 8) ; Timone (n = 4) 40 centres ouverts, 3 inactifs

11 Patients non randomisés
Patients inclus n = 573 [HCQ < 100 ng/ml] n=10 100<[HCQ]<750 n=209 [HCQ > 750 ng/ml] n=354 Patients randomisés (n=176) Patients non randomisés (n=33) refus (n=11) Contre indication (n=9) Poussée (n=4) Non compliance (n=4) Grossesse (n=2) Autres (n=3) Étude finie (n=157) Étude en cours (n=10) Arrêt prématuré (n=9)

12 Résultats 3 communications Reims/3 posters EULAR.
Taux de poussée 28,5 % (versus 30 % attendus) Analyses intermédiaires… Arrêt proche.

13 Etudes ancillaires Définir les marqueurs cliniques et biologiques, prédictifs de poussée lupique dans les 6 mois (score ?). Étudier la compliance. Interactions médicamenteuses (dont mopral… antiacides…inh enz…). Étudier l’influence de variants alléliques des transporteurs de médicaments (P-GP), des cytochromes expliquant les variations de [HCQ] Etude du bilan lipidique et glucidique Etudes descriptives : de la cohorte; des lupus gériatriques…

14 Etudes ancillaires Etablir les paramètres du modèle pharmacocinétique de l’HCQ, Etudier l’expression du transcriptome (RNAthèque, rando et M7 avec étude des TLR) => PHRC qui va être REdéposé sérothèque : SRAGE (Lille), Vitamine D, Ac anti-NMDA… Sérothèque, RNAthèque et DNAthèque à disposition Etude de morbi-mortalité pour la suite

15 Merci…