Mohamed Hamidou1, Antoine Néel2, Joel Poupon3, Zahir Amoura4, Mikael Ebbo5, Jean Sibilia6, Jean-Francois Viallard7, Benjamin Gaborit2, Christelle Volteau8, Jean Benoit Hardouin9, Eric Hachulla10, François Rieger11. 1. Department of Internal Medicine, CHU Nantes, Nantes Université, Nantes, France. mohamed.hamidou@chu-nantes.fr. 2. Department of Internal Medicine, CHU Nantes, Nantes Université, Nantes, France. 3. Department of Biological Toxicology, AP-HP, Lariboisière Hospital, University Paris VII, Paris, France. 4. Department of Internal Medicine 2, Centre National de Référence pour le Lupus, Institut E3M, Hôpital Pitié-Salpétrière, Paris, France. 5. Service de Médecine Interne, Aix Marseille Univ, APHM, CNRS, INSERM, CIML, Hôpital de la Timone, Marseille, France. 6. Department of Rheumatology, University of Strasbourg, Strasbourg, France. 7. Department of Internal Medicine, Haut-Lévêque University Hospital, Bordeaux, France. 8. Plateforme de Méthodologie et Biostatistiques, CHU Nantes, Université de Nantes, Nantes, France. 9. INSERM UMR 1246-SPHERE, Université de Nantes, Nantes, France. 10. Department of Internal Medicine, Centre de Référence des Maladies Autoimmunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), University of Lille, Lille, France. 11. MEDSENIC, SAS, a company with CNRS participation, Strasbourg, France.
Abstract
BACKGROUND: Lupus animal model has shown that arsenic trioxide (ATO), a treatment of acute promyelocytic leukaemia, could be effective in SLE. This is the first clinical study to determine the safety and efficacy of a short course of intravenous ATO in patients with active SLE. METHODS: This phase IIa, open-label, dose-escalating study enrolled 11 adult SLE patients with a non-organ threatening disease, clinically active despite conventional therapy. Patients received 10 IV infusions of ATO within 24 days. The first group received 0.10 mg/kg per injection, with dose-escalating to 0.15 mg/kg in a second group, and to 0.20 mg/kg in a third group. The primary endpoint was the occurrence of adverse events (AEs) and secondary endpoints were the number of SLE Responder Index 4 (SRI-4) responders at week 24 and reduction of corticosteroid dosage. In an exploratory analysis, we collected long-term data for safety and attainment of lupus low disease activity state (LLDAS). RESULTS: Four serious AEs occurred (grade 3 neutropenia, osteitis, neuropathy), 2 of which were attributable to ATO (neutropenia in the 2 patients treated with mycophenolate). Two patients suffered a severe flare during the last 4 weeks of the trial. At W24, five patients among 10 were SRI-4 responders. Overall, mean corticosteroid dosage decreased from 11.25 mg/day at baseline to 6 mg/day at W24 (P < 0.01). In the long term, 6 patients attained LLDAS at W52, which continued at last follow-up (median LLDAS duration 3 years, range 2-4). CONCLUSIONS: A short course of ATO has an acceptable safety profile in SLE patients and encouraging efficacy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01738360 registered 30 November 2012.
BACKGROUND: Lupus animal model has shown that arsenic trioxide (ATO), a treatment of acute promyelocytic leukaemia, could be effective in SLE. This is the first clinical study to determine the safety and efficacy of a short course of intravenous ATO in patients with active SLE. METHODS: This phase IIa, open-label, dose-escalating study enrolled 11 adult SLEpatients with a non-organ threatening disease, clinically active despite conventional therapy. Patients received 10 IV infusions of ATO within 24 days. The first group received 0.10 mg/kg per injection, with dose-escalating to 0.15 mg/kg in a second group, and to 0.20 mg/kg in a third group. The primary endpoint was the occurrence of adverse events (AEs) and secondary endpoints were the number of SLE Responder Index 4 (SRI-4) responders at week 24 and reduction of corticosteroid dosage. In an exploratory analysis, we collected long-term data for safety and attainment of lupus low disease activity state (LLDAS). RESULTS: Four serious AEs occurred (grade 3 neutropenia, osteitis, neuropathy), 2 of which were attributable to ATO (neutropenia in the 2 patients treated with mycophenolate). Two patients suffered a severe flare during the last 4 weeks of the trial. At W24, five patients among 10 were SRI-4 responders. Overall, mean corticosteroid dosage decreased from 11.25 mg/day at baseline to 6 mg/day at W24 (P < 0.01). In the long term, 6 patients attained LLDAS at W52, which continued at last follow-up (median LLDAS duration 3 years, range 2-4). CONCLUSIONS: A short course of ATO has an acceptable safety profile in SLEpatients and encouraging efficacy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01738360 registered 30 November 2012.
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