Notably, the percentage of participants reporting no vaginal pain or mild vaginal pain with sexual activity on week 12 was greater in the ospemifene group (38.0% or 25.1%, respectively) than in the placebo group (28.1% or 19.2%, respectively). Also, the severity of vaginal pain on week 12 in the ITT population improved by two to three levels in 52.8% of participants in the ospemifene group compared with 38.8% of participants in the placebo group (a three-level improvement being a change from “severe” to “none”; a two-level improvement being either a change from “severe” to “mild” or from “moderate to “none”).
In the PP population analysis (n = 506), ospemifene 60 mg/day demonstrated statistically significant efficacy compared with placebo in the mean change from baseline for each of the four coprimary endpoints. After 12 weeks of treatment, the percentage of parabasal cells and superficial cells significantly changed in the ospemifene group (decreased by 42.1% and increased by 13.2%, respectively) compared with the placebo group (decreased by 0.2% and increased by 1.9%, respectively; P < 0.0001; Figs. 3 and 4). Also, the reduction in vaginal pH in the ospemifene group (−1.1) was significantly greater than that observed in the placebo group (−0.08; P < 0.0001; Fig. 5), as was the reduction in MBS severity score (ospemifene −1.6 vs placebo −1.2; P = 0.0004; Fig. 6). Furthermore, within the PP population, the percentage of participants reporting no vaginal pain and mild vaginal pain with sexual activity on week 12 was greater in the ospemifene group (38.8% and 27.1%, respectively) than in the placebo group (29.5% and 21.5%, respectively). On week 12, 55.7% of participants in the ospemifene group changed their rating of vaginal pain severity from “severe” to “none” (a three-level improvement) or from “severe” to “mild” or from “moderate” to “none” (a two-level change) compared with 41.8% of participants in the placebo group.
Secondary efficacy analysis
A secondary analysis of the coprimary endpoints in the ITT population on week 4 demonstrated differences between ospemifene 60 mg/day and placebo in the mean change from baseline in MI and vaginal pH. Ospemifene 60 mg/day demonstrated efficacy compared with placebo in the percentage reduction in parabasal cells (−38.0% vs 0.3%, respectively) and in the percentage increase in superficial cells (13.0% vs 1.8%, respectively). Similarly, the reduction in vaginal pH on week 4 was different between the ospemifene group and the placebo group (−0.82 vs −0.15). A trend toward better improvement in vaginal pain associated with sexual activity in the ospemifene group compared with the placebo group was noted at 4 weeks as well, although the difference between the study groups was not statistically significant (P = 0.1698).
Each of the five parameters assessed by visual examination of the vagina showed the ospemifene group at 12 weeks to have a greater number of participants with an improvement of two to three levels from baseline (a three-level improvement being a change from “severe” to “none”; a two-level improvement being a change from “severe” to “mild” or from “moderate” to “none”) compared with the placebo group (petechiae, 10.4% vs 6.3%; pallor, 21.3% vs 10.0%; friability, 13.2% vs 7.7%; vaginal redness, 12.1% vs 8.2%; vaginal mucosal dryness, 36.6% vs 13.7%).
Use of lubricant
During the first week of treatment, similar proportions of participants used lubricants (41.7% and 43.1% in the ospemifene and placebo groups, respectively). On week 12, the percentage of women using lubricants somewhat decreased for both groups, but more so in the ospemifene group (35.1%) compared with the placebo group (39.3%). In contrast, the frequency of sexual activity remained consistent across the study groups from week 1 to week 12.
Safety and tolerability
More participants in the ospemifene group (91.7%) than in the placebo group (88.1%; Fig. 2) completed the study. The percentage of participants who discontinued the study because of an AE was higher for the ospemifene group (4.6%) than for the placebo group (3.3%); 3.3% and 1.3% of participants discontinued because of a treatment-related AE, respectively (Table 3).
Of 605 participants, 186 (61.4%) in the ospemifene group and 154 (51.0%) in the placebo group experienced at least one TEAE; most were considered mild to moderate. Most TEAEs were classified as not related to the study drug or unlikely to be related to the study drug. Those considered related to the study drug were reported in 79 (26.1%) participants in the ospemifene group and in 44 (14.6%) participants in the placebo group. The most frequently reported treatment-related AEs were hot flushes, reported by 6.6% of participants in the ospemifene group and 3.6% of participants in the placebo group. However, hot flushes led to treatment discontinuation for only one participant in the ospemifene group and for one participant in the placebo group. The other TEAEs that occurred in at least 3% of participants in the ospemifene group were urinary tract infection, vaginal candidiasis, vaginal discharge, vulvar and vaginal mycotic infections, nasopharyngitis, and headache (Table 4).
The incidence of serious AEs was the same for the ospemifene and placebo groups (four participants [1.3%] for both), with no serious AEs considered related to the study drug. Vaginal bleeding was not reported in any of the participants in the ospemifene group and in two (0.7%) participants in the placebo group. In the placebo group, one (0.3%) participant experienced a cerebrovascular event (ischemic stroke).
Endometrial thickness was assessed by centrally read TVU at screening and 12 weeks. Within each treatment group, one participant was suspected to have a polyp based on centrally read TVU set at a low threshold; therefore, local “live” reads were used for confirmation. The presence of a polyp was confirmed by a local read for the placebo participant but was found to be benign upon excision. A local read of the treatment participant, however, returned a normal result; thus, the polyp was not confirmed. Ospemifene caused a slight increase in endometrial thickness (Table 5). Endometrial histology assessments showed two (1.4%) cases of active proliferation in the ospemifene group, which resolved after the study; no cases were observed in the placebo group. At 12 weeks, no cases of endometrial hyperplasia, polyps, or cancer were observed in the endometrial biopsy samples of either study group.
Results from this phase 3 randomized, placebo-controlled study provide further evidence of the efficacy and tolerability of ospemifene 60 mg/day for treating symptoms of VVA associated with menopause.10,21 Twelve weeks of oral treatment with ospemifene 60 mg/day induced statistically significant beneficial changes in the four coprimary efficacy endpoints: parabasal cells decreased by 40.2% and superficial cells increased by 12.3% (compared with a 0% reduction and a 1.7% increase in the placebo group; P < 0.0001), vaginal pH decreased by −0.94 (compared with −0.07 in the placebo group; P < 0.0001), and the self-reported MBS severity score of dyspareunia decreased by −1.5 (compared with −1.2 in the placebo group; P = 0.0001).
Notably, in the secondary endpoint analysis, improvements in vaginal pH, parabasal cells, and superficial cells were observed at the earliest point assessed, 4 weeks after initiation of treatment. The improvements in the vaginal epithelium and vaginal pH related to VVA were reflected in the superior efficacy of ospemifene compared with placebo in reducing vaginal pain associated with sexual intercourse. In addition, there was a reduction in nonhormonal lubricant use in the ospemifene group compared with the placebo group, despite no decrease in the frequency of sexual activity in either of the two groups. Many women in the postmenopausal population use over-the-counter lubricants but continue to have painful intercourse. The beneficial impact of ospemifene on sexual health observed in this study where women concomitantly used over-the-counter lubricants is likely to extend to women in the general population. Further research and analyses are needed to evaluate whether sexual function and quality-of-life measures in this population improve as well.
Consistent with previously reported trials, ospemifene was shown to be safe and well tolerated. Hot flushes occurred more frequently in the ospemifene group, as was the case in another clinical trial.10 However, discontinuation rates for hot flushes were low and similar in both groups, as only one participant in the ospemifene group and one participant in the placebo group discontinued because of hot flushes.
Endometrial safety has been an important consideration during the clinical development of new SERMs, especially when they are being considered for use in the management of a chronic condition such as VVA.15 In this study, no clinically meaningful estrogenic effects on the endometrium were seen. Endometrial thickness, as assessed by TVU, increased slightly. Based on endometrial biopsies, no cases of endometrial hyperplasia or carcinoma were reported. This study adds to evidence from animal data and clinical trials indicating that ospemifene does not have clinically relevant effects on the uterus or endometrium.21-25
In addition to this study, two other phase 3 studies have evaluated the tissue selectivity of ospemifene. One study—a 12-week initial efficacy and safety study with an additional 40 weeks of long-term safety (total 52 wk)10,19—demonstrated no clinically meaningful endometrial changes with long-term treatment with oral ospemifene 60 mg/day in 180 postmenopausal women with VVA.19 A second study of 52 weeks similarly demonstrated minimal estrogenic effects on the endometrium.20
The present study demonstrated the efficacy and safety of ospemifene in the largest population of postmenopausal women with dyspareunia reported to date. Ospemifene provides a needed oral therapeutic option for the large population of postmenopausal women who experience moderate to severe vaginal dyspareunia caused by the chronic hypoestrogenic state of menopause that does not resolve spontaneously and often worsens with age. Because women are living longer5 and many continue to be sexually active past menopause,26 a well-tolerated and effective treatment could potentially benefit a great number of postmenopausal women and their partners.
Although the population may not be completely representative of that seen in clinical practice since it focused on only one of the several common symptoms experienced by a majority of women with postmenopausal VVA, the design of the study, as well as the large sample size, did make it appropriate for assessing the safety and efficacy of ospemifene.
Ospemifene 60 mg/day, compared with placebo, effectively reduces the physiological signs of VVA and dyspareunia in postmenopausal women while not inducing significant estrogenic effects on endometrial tissue or clinically important AEs. In this phase 3 study, ospemifene 60 mg/day demonstrated significant improvements relative to placebo for all coprimary endpoints in both the ITT population and the PP population and was generally well tolerated. Furthermore, ospemifene 60 mg/day demonstrated significant efficacy in the presence of lubricant use, with numerically less lubricant use observed in the treated cohort compared with participants given placebo. There are no currently available SERMs with a tissue-selective profile conducive for the treatment of postmenopausal VVA (ie, estrogenic action on the vaginal epithelium concurrent with minimal effects on the endometrium and neutral effects on the breast). Based on the results of this trial and previously reported trials, ospemifene has the potential to be the first oral alternative to vaginal estrogens for the treatment of dyspareunia associated with VVA.
Ospemifene study group (clinical centers—principal investigators): Adams Patterson Gynecology & Obstetrics, Memphis, TN — Judith Williams; Advanced Clinical Research, West Jordan, UT—Judith Kirstein; Quality of Life Medical and Research Center, Tucson, AZ—Walter Patton; Center for Women’s Health, Plainsboro, NJ—Scott Eder; Essential Women’s Associates, Henderson, NV—Edmond Pack; Centennial Hills OB-Gyn Associates, North Las Vegas, NV—Nader Abdelsayed; Affiliated Clinical Research, Inc, Las Vegas, NV—R. Garn Mabey Jr; Altus Research, Lake Worth, FL—Samuel Lederman; American Health Network of Indiana, LLC, Franklin, Greenfield, and Avon, IN—Jill Beavins and Joseph R. Schnecker; Atlantic Institute of Clinical Research, Daytona Beach, FL—Thomas Stavoy; BlueGrass Clinical Research, Inc., Louisville, KY—Arthur Donovan; Advanced Research Associates, Corpus Christi, TX—Charles Eubank; Center for Fertility and Women’s Health, PC, New Britain, CT—Anthony Luciano; Clinical Research of South Florida, Coral Gables, FL-Jeffrey Rosen; Clinical Trials of Virginia, Inc., Richmond, VA—Bruce Johnson; ClinSite, LLC, Ann Arbor, MI—Gayle Moyer and Donna Hrozenzik; Columbus Center for Women’s Health Research, Inc., Columbus, OH—David J. Portman; Comprehensive Clinical Trials, LLC, West Palm Beach, FL—Ronald Ackerman; Eastern Carolina Women’s Center, New Bern, NC—Jeffrey Michelson; Fellows Research Alliance, Inc, Savannah, GA and Hilton Head Isle, SC—Debra Walland; Holston Medical Group, P.C. (Seasons), Bristol, TN—Dennis Samuel; Holzer Clinic, Inc, Gallipolis, OH—James Strafford; Horizons Clinical Research Center, LLC, Denver, CO—Theodore Cooper; Jackson Clinic, PA, Jackson, TN—Stephen Hammond; Lyndhurst Clinical Research/Lyndhurst Gynecologic Associates, Winston-Salem, NC—Robert Parker Jr; Medical Center for Clinical Research, San Diego, CA—William Koltun; Medisphere Medical Research Center, LLC, Evansville, IN—Steven Elliott; Meridien Research, Inc, St. Petersburg, FL—Gigi Lefebvre; Mount Vernon Clinical Research, LLC, Sandy Springs, GA—Stephen Blank; OB/GYN Specialist of the Palm Beaches, P.A., West Palm Beach, FL—John Burigo; Philadelphia Clinical Research, LLC, Philadelphia, PA—Larry Seidman; Phoenix OB-GYN Associates, Moorestown, NJ—Bruce Levine; Puget Sound Osteoporosis Center, Seattle, WA—Susan Nattrass; Radiant Research, Atlanta, GA, Chicago, IL, Cincinnati, OH, and San Antonio, TX—Sidney Funk, Phyllis Marx, Michael Noss, and William Jennings; Springfield Clinic, LLP, Springfield, IL—Randolph Roller; Suncoast Clinical Research, Inc, New Port Richey, FL—Robert Smith; Tidewater Clinical Research, Inc, Virginia Beach, VA—Franklin Morgan Jr.; Valley Women’s Clinic, PLLC, Renton, WA—James Rice; Virginia Women’s Center, Richmond, VA—Peter Zedler; Visions Clinical Research, Boynton Beach, FL—Keith Aqua; Wake Research Associates, LLC, Raleigh, NC—Pouru Bhiwandi; Westlake Medical Research, Inc, Westlake Village, CA—Edward Portnoy; Woman’s Clinic, LLP, Boise, ID—Kerry B. Lowder; Women’s Clinic of Lincoln, PC, Lincoln, NE—Stephen Swanson; Hudson Valley Urology, PC, Poughkeepsie, NY—Evan Goldfischer; Clinical Trials of America, Inc, Eugene, OR—Richard Beyerlein; ObGYN Associates, Richmond, VA—Boyden B. Clary III; Hawthorne Medical Research, Winston-Salem, NC—Richard Hedrick Jr; Jacksonville Center for Clinical Research, LTD, Jacksonville, FL—Neil Sager; COR Clinical Research LLC, Oklahoma City, OK—Clinton Corder; IGO Medical Group, San Diego, CA—Philip Young; Lyndhurst Clinical Research, Kerersville, NC—Melvin Seid; Clinical Physiology Associates, Inc, Ft. Myers, FL—Mary Yankaskas; Downtown Women’s Health Care, Denver, CO—Arthur Waldbaum; Nature Coast Clinical Research, LLC, Crystal River, FL—Scott Redrick; North Spokane Women’s Clinic, Spokane, WA—Ronald Hardy.
We thank the study staff at each site and all the women who participated in this study.
Technical and editorial assistance was provided by Diane Kwiatkoski, PhD, and Rebecca A. Bachmann, PhD (not related to author Gloria A. Bachmann, MD) of Quintiles.
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Key Words: Dyspareunia; Ospemifene; Vulvar and vaginal atrophy; Postmenopausal© 2013 by The North American Menopause Society.