Background: Relapses of multiple sclerosis decrease during pregnancy, when the hormone estriol is increased. Estriol treatment is anti-inflammatory and neuroprotective in preclinical studies. In a small single-arm study of people with multiple sclerosis estriol reduced gadolinium-enhancing lesions and was favourably immunomodulatory. We assessed whether estriol treatment reduces multiple sclerosis relapses in women. Methods: We did a randomised, double-blind, placebo-controlled phase 2 trial at 16 academic neurology centres in the USA, between June 28, 2007, and Jan 9, 2014. Women aged 18-50 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1) with a random permuted block design to either daily oral estriol (8 mg) or placebo, each in combination with injectable glatiramer acetate 20 mg daily. Patients and all study personnel, except for pharmacists and statisticians, were masked to treatment assignment. The primary endpoint was annualised relapse rate after 24 months, with a significance level of p=0.10. Relapses were confirmed by an increase in Expanded Disability Status Scale score assessed by an independent physician. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00451204. Findings: We enrolled 164 patients: 83 were allocated to the estriol group and 81 were allocated to the placebo group. The annualised confirmed relapse rate was 0.25 relapses per year (95% CI 0.17-0.37) in the estriol group versus 0.37 relapses per year (0.25-0.53) in the placebo group (adjusted rate ratio 0.63, 95% CI 0.37-1.05; p=0.077). The proportion of patients with serious adverse events did not differ substantially between the estriol group and the placebo group (eight [10%] of 82 patients vs ten [13%] of 76 patients). Irregular menses were more common in the estriol group than in the placebo group (19 [23%] vs three [4%], p=0.0005), but vaginal infections were less common (one [1%] vs eight [11%], p=0.0117). There were no differences in breast fibrocystic disease, uterine fibroids, or endometrial lining thickness as assessed by clinical examination, mammogram, uterine ultrasound, or endometrial lining biopsy. Interpretation: Estriol plus glatiramer acetate met our criteria for reducing relapse rates, and treatment was well tolerated over 24 months. These results warrant further investigation in a phase 3 trial. Funding: National Institutes of Health, National Multiple Sclerosis Society, Conrad N Hilton Foundation, Jack H Skirball Foundation, Sherak Family Foundation, and the California Community Foundation.
Bibliographical noteFunding Information:
RRV has received research grants from the National Institutes of Health and National Multiple Sclerosis Society, has received personal payment as a consultant from Synthetic Biologics, and is an inventor on a patent for estriol owned by UCLA. DLA has received payment from NeuroRx, has received research grant support from Biogen, and has received personal payment from Biogen, EMD Serono, Genentech, Genzyme, Hoffman-La Roche, Innate Immuntherapy, Medlmmune, Mitsubishi, Novartis, Receptos, Acorda, Sanofi-Aventis, Teva, and Xenoport. JTB has received payment for consultation from Novartis, and research grant support from Biogen Idec. JRC has received research grants from National Multiple Sclerosis Society, Novartis, Sun Pharma, and Diogenix, and has received personal payment from Novartis, Teva, and Biogen Idec. AHC has received personal payment for consulting, acting on a scientific advisory board, or speaking from Biogen Idec, Genzyme/Sanofi-Aventis, Hoffman-La Roche, Teva Neuroscience, Novartis, and Mallinckrodt, and has received research support from Hoffman-La Roche, EMD Serono, and Teva Neuroscience. SD-J has received personal payment for consulting, acting on a scientific advisory board, or speaking from Serono, Novartis, Bayer, Teva, Genetech, Genzyme, Mallinckrodt, and TG Pharmaceuticals, has received research support from Teva, Biogen Idec, and Serono, and has received research grants from Teva and Biogen Idec. EMF has received personal payment for speaking and consultation from Teva, Genzyme, Novartis, and Acorda. BG's family holds stock in Biogen and Pfizer. DJ has received personal payment for consulting and acting on a scientific advisory board or speaking from Questcor Pharmaceuticals, Teva Neuroscience, and Genzyme, and has received clinical trial support from Biogen Idec and Novartis. SL has received research support from Novartis, Biogen, Teva, Genzyme, Genentech, Berlex, Cognition Pharmaceuticals, UCB Pharmceuticals, Serono, Acorda, Sun Pharma, Opexa, and Actelion. MKR has received personal payment for consulting, acting on a scientific advisory board, or speaking from Biogen Idec, Revalesio, Novartis, and Roche, and has received research support from Diogenix. ATR has received payment for editorial activities from Medlink/Neurobase. JR has received research support from Teva and Biogen. DMW has received research support from Genentech, Genzyme, Alexion, and TerumoBCT. JB, RE, CCF, NI, LHK, FK, AJM-G, KN, GP, NLS, CHT, HW, and TCJW declare no competing interests.
This work is dedicated to Idolia “Dodie” Voskuhl (1923–2015), mother of Rhonda Voskuhl. We acknowledge the MRI technical assistance of Michael Montag. Synthetic Biologics provided estriol and placebo, free of charge. This study was funded by the National Institutes of Health, National Multiple Sclerosis Society, Conrad N Hilton Foundation, Jack H Skirball Foundation, Sherak Family Foundation, and the California Community Foundation.