Rhonda R Voskuhl1, HeJing Wang2, T C Jackson Wu2, Nancy L Sicotte3, Kunio Nakamura4, Florian Kurth2, Noriko Itoh2, Jenny Bardens2, Jacqueline T Bernard5, John R Corboy6, Anne H Cross7, Suhayl Dhib-Jalbut8, Corey C Ford9, Elliot M Frohman10, Barbara Giesser2, Dina Jacobs11, Lloyd H Kasper12, Sharon Lynch13, Gareth Parry14, Michael K Racke15, Anthony T Reder5, John Rose16, Dean M Wingerchuk17, Allan J MacKenzie-Graham2, Douglas L Arnold4, Chi Hong Tseng2, Robert Elashoff2. 1. David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: rvoskuhl@ucla.edu. 2. David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, USA. 3. Cedars-Sinai Medical Center, Los Angeles, CA, USA. 4. McGill University, Montreal, QC, Canada. 5. University of Chicago Medical Center, Chicago, IL, USA. 6. University of Colorado Denver, Aurora, CO, USA. 7. Washington University School of Medicine, St Louis, MO, USA. 8. Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA. 9. University of New Mexico Health Sciences Center, Albuquerque, NM, USA. 10. University of Texas Southwestern, Dallas, TX, USA. 11. University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. 12. Geisel School of Medicine, Dartmouth College, Hanover, NH, USA. 13. University of Kansas Medical Center, Kansas City, KS, USA. 14. University of Minnesota, Minneapolis, MN, USA. 15. Wexner Medical Center, The Ohio State University, Columbus, OH, USA. 16. Salt Lake City VA Medical Center, Salt Lake City, UT, USA. 17. Mayo Clinic Scottsdale, Scottsdale, AZ, USA.
Abstract
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.
RCT Entities:
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 sclerosisestriol 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.
Authors: Jan Broder Engler; Nina Kursawe; María Emilia Solano; Kostas Patas; Sabine Wehrmann; Nina Heckmann; Fred Lühder; Holger M Reichardt; Petra Clara Arck; Stefan M Gold; Manuel A Friese Journal: Proc Natl Acad Sci U S A Date: 2017-01-03 Impact factor: 11.205