REVISED December 8, 2015
- Results of a multi-center phase 2 clinical trial of the pregnancy hormone estriol involving 164 women with relapsing-remitting MS have been published.
- This study was inspired by the observation that MS relapses are less frequent during later pregnancy, a time when estriol is at high levels.
- The trial, led by Rhonda Voskuhl, MD (University of California, Los Angeles), compared disease activity in those given oral estriol (Trimesta,TM Synthetic Biologics), in combination with glatiramer acetate (Copaxone,® Teva Neuroscience) with those taking glatiramer acetate and placebo.
- The combination of estriol and glatiramer acetate appeared to be safe over the two-year study period, but further studies will be necessary to confirm long-term safety of estriol for use in relapsing MS.
- The trial demonstrated a 32% reduction in the relapse rate at two years in the group receiving the combination of glatiramer acetate and estriol compared to the glatiramer only group. However, additional trials with larger numbers of patients are needed to confirm this result.
- Trends in some of the secondary outcomes measures including cognition and fatigue look promising, but need to be followed up in future studies.
- The trial, published in Lancet Neurology online on November 24, 2015, was funded by the National MS Society, the National Institute of Neurological Disorders and Stroke, and private donors.
: MS affects women two to three times as often as men and pregnancy has been shown to provide some protection from MS relapses in women. These findings along with a series of others prompted the National MS Society to launch a special five-year, $10 million research initiative in the late 1990’s to explore the importance of the meaning behind these observations. Among the results from the 50 projects supported through this initiative was the possibility that the female hormone estriol may help protect women from MS relapses. Understanding gender differences and the protection provided by pregnancy is still an active area of research investment and interest in the MS community.
Estriol levels naturally rise during later pregnancy, a time when many women’s MS disease activity declines. This led some to suspect that estriol may be responsible for this easing of symptoms during pregnancy. Rhonda Voskuhl, MD (University of California, Los Angeles) and others explored this lead in mice with an MS-like disease. Later, with National MS Society support, Dr. Voskuhl conducted a small, early-phase trial of estriol in 12 women with relapsing-remitting MS. Results suggested that estriol might decrease disease activity.
Phase 2 trials such as the one reported in this published paper are designed to provide information about a therapy’s safety and potential effectiveness, but longer, larger Phase 3 studies are needed to confirm potential benefits and risks and to gain approval from drug regulators such as the U.S. Food and Drug Administration.
: Estriol is one of several estrogen sex hormones in the body. Some forms of estrogen are available for prescription as methods of birth control and for the treatment of symptoms associated with menopause. Estriol has been used in Europe and Asia as a treatment for symptoms of menopause. The oral form of estriol used in this trial is not available in the United States.
: Investigators recruited 164 women with relapsing-remitting MS between the ages of 18-50 at 16 sites across the U.S. All participants had recently begun standard glatiramer acetate therapy (injected daily under the skin) and were randomly assigned to also take estriol in pill form, or inactive placebo, for two years. The dosage of estriol used in this trial was four times that customarily used for treating menopausal symptoms.
The primary outcome measure for this trial was the effect of the treatment combination on confirmed relapse rates at the end of the second year. Secondary outcomes included several clinical and MRI (magnetic resonance imaging), measures of disability progression, cognitive function and fatigue. There were also laboratory and gynecological tests built into the study to monitor for potential safety issues that have been associated with the use of estriol and other estrogen hormones, including breast and endometrial (uterine) cancers.
Detailed results of this phase 2 trial were published
in Lancet Neurology online on November 24, 2015 and additional details
were communicated by the study’s authors. The trial was funded by the National MS Society, the National Institute of Neurological Disorders and Stroke, and additional private donors. Synthetic Biologics, a Maryland pharmaceutical company, provided the estriol for the trial at no charge. Preliminary results were originally presented at the 2014 Annual Meeting of the American Academy of Neurology.
: The combination of glatiramer acetate and estriol appeared safe over the two-year trial period, and there were few severe adverse events experienced by those in either treatment group. Women taking estriol had significantly more irregularities in their menstrual cycles.
At the end of two years, there was a reduction in the annual relapse rate between the estriol group (0.25) and the placebo group (0.37) that achieved only a modest (p=0.077) level of “statistical significance,” a calculation used to determine whether differences relate to chance alone or to the impact of the therapy being tested. This means the study needs to be repeated with a larger number of participants before a definitive conclusion about the effectiveness of estriol can be made. There were no statistically significant differences in secondary outcomes related to the number or size of brain lesions measured by MRI, measures of disability, or quality of life.
There was a benefit suggested for the estriol group in cognitive testing compared to those on placebo after the first year, but this benefit was not seen during the second year of the study. In addition, there was a significant reduction in a measure of fatigue at two years that was not apparent after the first year.
: “While the outcomes of this trial are intriguing, important questions remain regarding the potential benefits and long-term safety of high dose estriol for MS,” said Bruce Bebo, PhD, Executive Vice President, Research at the Society. “These results contribute to our understanding that the pregnancy effects in MS are more complex than previously appreciated. We applaud Dr. Voskuhl’s diligence and persistence in completing this trial. The Society continues to support research in this important area of gender differences and pregnancy in MS, since it may provide clues to improving treatment for women and men with all forms of the disease.”
Copaxone is a registered trademark of Teva Pharmaceutical Industries Ltd.
Trimesta is a trademark of Synthetic Biologics