Patients treated for two years with a combination of glatiramer acetate and estriol experienced a one-third reduction in relapse rate compared with patients who received glatiramer acetate and placebo.
Neurologists have long noted that symptoms of multiple sclerosis (MS) often improve in pregnancy. Research to flesh out the hypothesis that the hormonal surge of pregnancy may afford protection has led to trials of estrogens in non-pregnant females with MS, an avenue that would afford hope for many MS sufferers, of whom nearly two-thirds are women.
At the 2014 Joint ACTRIMS-ECTRIMS Meeting, held in Boston, MA, the University of California — Los Angeles’ Rhonda Voskuhl, MD, described results from a trial that evaluated a combination of estriol and glatiramer acetate (GA) for women with relapsing-remitting MS (RRMS).
The neuroprotective effects of estriol, Voskuhl explained, may be either direct or indirect. Citing preclinical data, she posited that estriol may afford some direct protective effects on the central nervous system’s astrocytes and or oligodendrocytes. Another possibility is that estriol, like other disease-modifying MS therapies, may influence the neuroinflammatory cascade that is thought to cause much of the damage seen in MS.
An earlier pilot trial of oral estriol 8 mg/day for six months (an amount that approximates mid-pregnancy levels) found a 70-80% reduction in gadolinium (GD) enhancing lesions on magnetic resonance imaging (MRI), as well as improvements in inflammatory markers and immune activity.
The pilot’s favorable results led to the present 24-month placebo-controlled, multi-site trial, whose primary outcome was relapse rate -- a clinical, rather than surrogate outcome. All patients (n=158) received GA; patients were randomized to receive GA and placebo (n=76) or GA and estriol (n=82).
Patients were females, age 18 to 50 with relapsing-remitting MS (RRMS), and Expanded Disability Status Scores (EDSS) of 4.5 or less. Women could not be pregnant, breastfeeding, have had a long period of estrogen deficiency, or be unwilling to discontinue other exogenous estrogen or progesterone treatments.
The primary outcome measure of relapse rate, the EDSS change was assessed by an examining neurologist blinded to the study arm of the patient. The study was powered at p=0.1 to detect a reduction in relapse rate of one-third over the 24-month study period. The observed result met the expected primary outcome measure: Relapses were reduced by 32% in the estriol group versus the placebo (p=0.11).
Further, women taking GA + estriol showed a more rapid reduction in relapse rate, with that group having reached essentially the full reduction in relapse rate by the study’s 12-month mark. Cognitive measures, including processing speed and tests of visual-spatial ability, also improved significantly from baseline and in comparison to the GA + placebo group. Trends were seen for improvement in EDSS and the 25-foot walk test, though these did not reach statistical significance.
In closing, Voskuhl pointed to the aspects of the study which met or exceeded standards set for Phase 2 studies, including it being fully federally funded, the use of a clinical rather than a surrogate endpoint, and the post-marketing level of safety already established for estriol. This study continues to add weight to the body of research teasing out sex differences in MS, and advances efforts to establish the efficacy of a treatment approach incorporating an estrogen ligand for the female MS population.