title: Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  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.affiliation: David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: rvoskuhl@ucla.edu.
authors.forename: Rhonda R
authors.initials: RR
authors.lastname: Voskuhl
authors.affiliation: David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: HeJing
authors.initials: H
authors.lastname: Wang
authors.affiliation: David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: T C Jackson
authors.initials: TC
authors.lastname: Wu
authors.affiliation: Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Sicotte
authors.affiliation: McGill University, Montreal, QC, Canada.
authors.forename: Kunio
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Kurth
authors.affiliation: David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Noriko
authors.initials: N
authors.lastname: Itoh
authors.affiliation: David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Bardens
authors.affiliation: University of Chicago Medical Center, Chicago, IL, USA.
authors.forename: Jacqueline T
authors.initials: JT
authors.lastname: Bernard
authors.affiliation: University of Colorado Denver, Aurora, CO, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Corboy
authors.affiliation: Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Anne H
authors.initials: AH
authors.lastname: Cross
authors.affiliation: Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
authors.forename: Suhayl
authors.initials: S
authors.lastname: Dhib-Jalbut
authors.affiliation: University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors.forename: Corey C
authors.initials: CC
authors.lastname: Ford
authors.affiliation: University of Texas Southwestern, Dallas, TX, USA.
authors.forename: Elliot M
authors.initials: EM
authors.lastname: Frohman
authors.affiliation: David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Giesser
authors.affiliation: University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Dina
authors.initials: D
authors.lastname: Jacobs
authors.affiliation: Geisel School of Medicine, Dartmouth College, Hanover, NH, USA.
authors.forename: Lloyd H
authors.initials: LH
authors.lastname: Kasper
authors.affiliation: University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Lynch
authors.affiliation: University of Minnesota, Minneapolis, MN, USA.
authors.forename: Gareth
authors.initials: G
authors.lastname: Parry
authors.affiliation: Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Racke
authors.affiliation: University of Chicago Medical Center, Chicago, IL, USA.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Reder
authors.affiliation: Salt Lake City VA Medical Center, Salt Lake City, UT, USA.
authors.forename: John
authors.initials: J
authors.lastname: Rose
authors.affiliation: Mayo Clinic Scottsdale, Scottsdale, AZ, USA.
authors.forename: Dean M
authors.initials: DM
authors.lastname: Wingerchuk
authors.affiliation: David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Allan J
authors.initials: AJ
authors.lastname: MacKenzie-Graham
authors.affiliation: McGill University, Montreal, QC, Canada.
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Arnold
authors.affiliation: David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Chi Hong
authors.initials: CH
authors.lastname: Tseng
authors.affiliation: David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Elashoff
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000328:Adult; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004964:Estriol / Q000008:administration & dosage*; D005260:Female; D000068717:Glatiramer Acetate / Q000008:administration & dosage*; D006801:Humans; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000175:diagnosis* / Q000188:drug therapy*
chemical_list: D000276:Adjuvants, Immunologic; D000068717:Glatiramer Acetate; D004964:Estriol