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Efficacy and safety of oral contraceptives as add-on therapy in patients with relapsing-remitting multiple sclerosis receiving subcutaneous interferon beta-1a: a multicenter, randomized investigator-run clinical trialC. Pozzilli, L. De Giglio, V. Barletta, F. Marinelli, F. De Angelis, V. Gallo, V.A. Pagano, M.A. Bassano, M.C. Piattella, V. Tomassini, P. Pantano (Rome, IT)
Background: Several experimental studies have demonstrated the immunomodulatory properties of oestrogen, however whether oral contraceptive (OC) might affect disease activity in multiple sclerosis (MS) is debated. OC use has been related to an older age at onset of MS suggesting a protective effect, however, there is also evidence that OC may enhance the progression of the disease.
Objectives: To evaluate the efficacy, safety and tolerability of OC at different dosage of estradiol as an add-on therapy in patients who were eligible for treatment with s.c. interferon beta-1a (IFN).
Methods: In a multicenter study, 150 women with RRMS were randomised in a 1:1:1 ratio to one of three treatment groups: IFN beta 1a 44 µg sc (tiw) only (Group I), or IFN beta 1a 44 µg sc (tiw) plus ethilenestradiolo 40 mcg and desogestril 125 mcg (Group II), or IFN beta 1a 44 µg sc (tiw) plus ethilenestradiolo 20 mcg and desogestril 150mcg (Group III), as add-on therapy for 96 weeks. The primary endpoint was the mean number of combined unique active lesions (CUA) on brain MRI scan at week 96, analysed using adjusted-poisson regression model in the ITT-protocol set.
Presence of enhanced brain MRI scan; total number and volume of new or enlarged Gd-enhancing lesions; total number and volume of lesions on T1- and T2-weighted MRI; annualised relapse rate (ARR) and proportion of patients free from confirmed EDSS progression, were secondary efficacy endpoints measured at weeks 48 and 96. Safety endpoints were evaluated from all completed trial visits, including the occurrence of adverse events (AEs) and adherence to treatment.
Results: Baseline characteristics were well balanced across groups. As compared to IFN beta only, the primary endpoint was reduced by 26.5% (p<0.05) in Group II, and 14.1% (p=0.239) in Group III at week 96.
Enhanced brain MRI scans at week 96 were less frequent in Group II than in Group I (p<0.05). No significant differences were detected among groups in the other secondary efficacy endpoints. AEs causing IFN beta treatment discontinuation were equally distributed across groups. Thirteen (26%) women in Group II and 12 (24%) in Group III discontinued OC during study period.
Conclusion: In comparison to IFN beta alone or IFN beta plus OC with low oestrogen dose, OC with an high oestrogen dose shows a beneficial effect on reducing MRI disease activity. The results support experimental work findings and suggest directions for future research in this field.
Carlo Pozzilli has served on scientific advisory boards for Novartis, Merck Serono, Biogen Idec, sanofi-aventis and Bayer Schering and has received funding for travel and speaker honoraria from sanofi-aventis, Biogen Idec AG, Bayer Schering, Teva Neurosciences, Merck Serono and Novartis, and receives research support from Merck Serono, Biogen Idec, Bayer Schering and sanofi-aventis.
All other authors have nothing to disclose.